02078nas a2200397 4500008004100000022001400041245014100055210006900196260001300265300001200278490000700290520092000297653001601217653000901233653002101242653002101263653002801284653002901312653001101341653001101352653004401363653004001407653000901447653002401456653002001480100001701500700001601517700001801533700001501551700001401566700001301580700001501593700001901608700001701627856003601644 1991 eng d a0039-249900aUse of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. CHS Collaborative Research Group.0 aUse of sonography to evaluate carotid atherosclerosis in the eld c1991 Sep a1155-630 v223 a
Carotid sonography is being performed on more than 5,000 participants in the Cardiovascular Health Study, a prospective, multicenter study of cardiovascular disease in men and women aged 65 years and older. The sonographic methods used to examine and measure the extracranial carotid arteries are described. Initial validation studies were performed on 61 subjects with a mean age of 68.6 years. Analysis of within- and between-sonographer differences and between-reader differences were performed for selected variables. In general, the mean absolute differences for within- and between-sonographer comparisons were small, with even less variability between readers. Variability was less for the common carotid artery than for the internal carotid artery. These data suggest that carotid sonography is a reliable and reproducible method for use in the study of carotid atherosclerosis in population studies.
10aAge Factors10aAged10aArteriosclerosis10aCarotid Arteries10aCarotid Artery Diseases10aCarotid Artery, Internal10aFemale10aHumans10aImage Interpretation, Computer-Assisted10aImage Processing, Computer-Assisted10aMale10aProspective Studies10aUltrasonography1 aO'Leary, D H1 aPolak, J, F1 aWolfson, S, K1 aBond, M, G1 aBommer, W1 aSheth, S1 aPsaty, B M1 aSharrett, A, R1 aManolio, T A uhttps://chs-nhlbi.org/node/108202695nas a2200349 4500008004100000022001400041245018200055210006900237260001300306300001100319490000700330520167100337653000902008653002202017653003002039653002102069653002002090653002102110653001102131653001102142653000902153653002402162653001702186653001802203100001502221700001102236700001702247700001602264700001702280700001302297856003502310 1992 eng d a0895-435600aAssessing the use of medications in the elderly: methods and initial experience in the Cardiovascular Health Study. The Cardiovascular Health Study Collaborative Research Group.0 aAssessing the use of medications in the elderly methods and init c1992 Jun a683-920 v453 aThe Cardiovascular Health Study (CHS), a cohort study of risk factors for coronary heart disease and stroke, recruited 5201 community-dwelling adults aged 65 years or older. To assess the prevalence of medication use at baseline, we used the method of medication inventory and transcribed information about drug names and doses from prescription bottles. Using a specially-written computer program, persons without a knowledge of drug nomenclature coded 10,511 (89%) of the 11,846 medicines entered. We compared the results of the medication inventory and answers to questions on specific medications for reliability and validity. The use of beta-blockers and beta-agonists assessed by the method of medication inventory, but not by the method of directed recall, was associated with a significant effect on mean heart rate. Among 5197 participants with medication data, 76.1% were taking at least one medicine, and the mean number of drugs per person was 2.28. Among those with a reported history of high blood pressure, participants with cardiovascular disease (CVD) were more likely to be treated, and they were more likely to be taking beta-blockers and calcium-channel blockers than those without CVD. Daily aspirin use was also more common among those with CVD (30.5% of women and 43.2% of men) than among those without CVD (14.0% of women and 14.0% of men). The prevalence of post-menopausal estrogen use differed significantly among the four clinical centers (range = 5.5%-22.5% of women). We conclude that this method of assessing medications was easy to use and provided estimates of exposure to drugs that may affect risk of cardiovascular disease.
10aAged10aAged, 80 and over10aCerebrovascular Disorders10aCoronary Disease10aData Collection10aDrug Utilization10aFemale10aHumans10aMale10aProspective Studies10aRisk Factors10aUnited States1 aPsaty, B M1 aLee, M1 aSavage, P, J1 aRutan, G, H1 aGerman, P, S1 aLyles, M uhttps://chs-nhlbi.org/node/84803587nas a2200421 4500008004100000022001400041245015700055210006900212260001300281300001200294490000700306520239900313653000902712653002102721653001702742653002802759653003002787653002102817653001102838653001102849653000902860653002002869653001502889653002402904653001702928653002002945100001702965700001602982700001802998700001803016700001503034700001803049700001403067700001603081700001603097700001703113856003503130 1992 eng d a0039-249900aDistribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group.0 aDistribution and correlates of sonographically detected carotid c1992 Dec a1752-600 v233 aBACKGROUND AND PURPOSE: This article describes the prevalence of extracranial carotid atherosclerosis assessed by ultrasonography, its association with risk factors, and its relation to symptomatic coronary disease and stroke in men and women aged > or = 65 years.
METHODS: Maximum percent stenosis, maximum common carotid artery wall thickness, and maximum internal carotid artery wall thickness were assessed using duplex ultrasound in 5,201 men and women aged > or = 65 years in the Cardiovascular Health Study, a study of the risk factors and natural history of cardiovascular disease in the elderly. Existing coronary disease and stroke were assessed by physical examination and participant history.
RESULTS: Detectable carotid stenosis was present in 75% of men and 62% of women, although the prevalence of > or = 50% stenosis was low, 7% in men and 5% in women. Maximum stenosis and maximum wall thickness measurements increased with age and were uniformly greater at all ages in men than in women (p < 0.00001). Established risk factors for atherosclerosis (hypertension, smoking, diabetes) and indications of vascular disease (left ventricular hypertrophy, major electrocardiographic abnormality, bruits, and history of heart disease or stroke) related to all three carotid artery measures in the elderly. Of the three ultrasound measures, the best correlate for a history of coronary disease was maximum internal carotid artery wall thickness. For stroke the best correlate was common carotid artery wall thickness. Multiple logistic regression models of prevalent coronary heart disease and stroke that included the ultrasound findings indicated, after adjustment for age and sex, that maximum internal wall thickness and maximum common carotid wall thickness were significant correlates of both. Maximum stenosis did not add significantly to the correlation.
CONCLUSIONS: In the elderly the incidence of carotid atherosclerosis was high, although the frequency of severe disease was low. The prevalence and severity of carotid atherosclerosis continued to increase with age even in the late decades of life, and more disease was found in men than in women at all ages. Known risk factors for atherosclerosis continued to relate to carotid abnormalities in the later decades of life, both in symptomatic and asymptomatic subjects.
10aAged10aArteriosclerosis10aCardiomegaly10aCarotid Artery Diseases10aCerebrovascular Disorders10aCoronary Disease10aFemale10aHumans10aMale10aMedical Records10aPrevalence10aRegression Analysis10aRisk Factors10aUltrasonography1 aO'Leary, D H1 aPolak, J, F1 aKronmal, R, A1 aKittner, S, J1 aBond, M, G1 aWolfson, S, K1 aBommer, W1 aPrice, T, R1 aGardin, J M1 aSavage, P, J uhttps://chs-nhlbi.org/node/74902024nas a2200385 4500008004100000022001400041245014300055210006900198260001300267300001100280490000600291520096300297653003901260653001601299653000901315653002801324653001901352653001501371653001601386653001101402653001501413653001101428653000901439653001601448653001701464100001501481700001701496700001501513700001301528700001401541700001601555700001501571700001701586856003501603 1992 eng d a1047-279700aThe distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study.0 adistribution of coagulation factors VII and VIII and fibrinogen c1992 Jul a509-190 v23 aThe Cardiovascular Health Study (CHS) was designed to examine cardiovascular disease and its risk factors in older adults. We report here the distributions of the coagulation factors fibrinogen, factor VII, and factor VIII in a population-based cohort of men and women 65 years or older. In other studies of middle-aged individuals, these factors were shown to be associated with cardiovascular risk. In the CHS cohort, all three factors were elevated, compared to levels reported in middle-aged individuals, and fibrinogen and factor VIII values were higher in each successive age group; factor VII values, in contrast, declined slightly with age in the CHS cohort. Compared to white subjects, blacks had higher values for fibrinogen and factor VIII and lower values for factor VII. While women had markedly higher values for factor VII and factor VIII than men at all ages in the CHS, mean fibrinogen values were not different between men and women.
10aAfrican Continental Ancestry Group10aAge Factors10aAged10aCardiovascular Diseases10aCohort Studies10aFactor VII10aFactor VIII10aFemale10aFibrinogen10aHumans10aMale10aMiddle Aged10aRisk Factors1 aTracy, R P1 aBovill, E, G1 aFried, L P1 aHeiss, G1 aLee, M, H1 aPolak, J, F1 aPsaty, B M1 aSavage, P, J uhttps://chs-nhlbi.org/node/74703412nas a2200469 4500008004100000022001400041245014500055210006900200260001600269300001200285490000800297520208700305653000902392653002202401653001702423653002802440653002802468653003002496653002102526653002802547653002102575653002402596653001102620653001102631653001702642653000902659653002602668653002402694653001702718653001202735100001502747700001702762700001602779700001702795700002102812700001702833700001502850700001502865700001502880700001202895856003502907 1992 eng d a0098-748400aIsolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial findings from the Cardiovascular Health Study.0 aIsolated systolic hypertension and subclinical cardiovascular di c1992 Sep 09 a1287-910 v2683 aOBJECTIVE: To assess the association between isolated systolic hypertension (ISH) and subclinical disease in adults aged 65 years and above.
DESIGN: Medicare eligibility lists were used to obtain a representative sample of 5201 community-dwelling elderly persons for the Cardiovascular Health Study, a National Heart, Lung, and Blood Institute--sponsored cohort study of risk factors for coronary heart disease and stroke. In this cross-sectional analysis of baseline data, we excluded 3012 participants who were receiving antihypertensive medications, had clinical cardiovascular disease, or had a diastolic blood pressure of at least 90 mm Hg.
MAIN OUTCOME MEASURES: For electrocardiogram: myocardial infarction, left ventricular hypertrophy, and left ventricular mass as measures of myocardial damage and strain; for echocardiography: left ventricular mass, fractional shortening, and Doppler flow velocities as measures of cardiac systolic and diastolic function; and for carotid sonography: carotid arterial intima-media thickness as a measure of atherosclerosis.
RESULTS: Among the 2189 men and women in this analysis, 195 (9%) had ISH (systolic blood pressure, greater than or equal to 160 mm Hg) and 596 (23%) had borderline ISH (systolic blood pressure, 140 to 159 mm Hg). Systolic blood pressure was associated with myocardial infarction by electrocardiogram (P = .02). Borderline and definite ISH were strongly associated with left ventricular mass (P less than .001). While there was little association with cardiac systolic function, borderline and definite ISH were associated with cardiac diastolic function (P less than .001). Isolated systolic hypertension was also strongly associated with increased intima-media thickness of the carotid artery (P less than .001).
CONCLUSIONS: While cohort analyses of future repeated measures will provide a better assessment of risk, both borderline and definite ISH were strongly related to a variety of measures of subclinical disease in elderly men and women.
10aAged10aAged, 80 and over10aCardiomegaly10aCardiovascular Diseases10aCarotid Artery Diseases10aCerebrovascular Disorders10aCoronary Disease10aCross-Sectional Studies10aEchocardiography10aElectrocardiography10aFemale10aHumans10aHypertension10aMale10aMyocardial Infarction10aProspective Studies10aRisk Factors10aSystole1 aPsaty, B M1 aFurberg, C D1 aKuller, L H1 aBorhani, N O1 aRautaharju, P, M1 aO'Leary, D H1 aBild, D, E1 aRobbins, J1 aFried, L P1 aReid, C uhttps://chs-nhlbi.org/node/74802586nas a2200409 4500008004100000022001400041245017300055210006900228260001600297300001200313490000700325520141600332653001601748653000901764653002201773653002501795653002801820653002401848653001101872653001901883653001101902653002001913653000901933653001501942653001701957653001601974653001801990100001702008700001702025700001502042700001502057700001702072700001402089700001702103700002102120856003502141 1992 eng d a0002-914900aMajor electrocardiographic abnormalities in persons aged 65 years and older (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group.0 aMajor electrocardiographic abnormalities in persons aged 65 year c1992 May 15 a1329-350 v693 aElectrocardiographic abnormalities are often found in older patients, but their prevalence in free-living elderly populations is not well-defined. In addition, the clinical significance of many of these abnormalities is uncertain. The prevalence of major electrocardiographic abnormalities was determined in 5,150 adults aged greater than or equal to 65 years from the Cardiovascular Health Study--a study of risk factors for stroke and coronary heart disease in the elderly. Ventricular conduction defects, major Q/QS waves, left ventricular hypertrophy, isolated major ST-T-wave abnormalities, atrial fibrillation and first-degree atrioventricular block were collectively categorized as major electrocardiographic abnormalities. Prevalence of any major electrocardiographic abnormality was 29% in the entire cohort, 19% among 2,413 participants who reported no history of coronary artery disease or systemic hypertension, and 37% among 2,737 participants with a history of coronary artery disease or hypertension. Prevalence of major electrocardiographic abnormalities was higher in men than in women regardless of history, and tended to increase with age. Major Q/QS waves were found in 5.2%, and more than half were in those who did not report a previous myocardial infarction. Major electrocardiographic abnormalities are common in elderly men and women irrespective of the history of heart disease.
10aAge Factors10aAged10aAged, 80 and over10aArrhythmias, Cardiac10aChi-Square Distribution10aElectrocardiography10aFemale10aHeart Diseases10aHumans10aLogistic Models10aMale10aPrevalence10aRisk Factors10aSex Factors10aUnited States1 aFurberg, C D1 aManolio, T A1 aPsaty, B M1 aBild, D, E1 aBorhani, N O1 aNewman, A1 aTabatznik, B1 aRautaharju, P, M uhttps://chs-nhlbi.org/node/83503864nas a2200373 4500008004100000022001400041245012500055210006900180260001300249300001200262490000700274520283300281653003103114653002103145653000903166653002203175653002803197653001103225653001103236653000903247653001503256653002103271653002603292100001503318700001903333700001503352700001503367700001503382700001303397700001403410700001603424700001403440856003603454 1993 eng d a0002-861400aAge-related trends in cardiovascular morbidity and physical functioning in the elderly: the Cardiovascular Health Study.0 aAgerelated trends in cardiovascular morbidity and physical funct c1993 Oct a1047-560 v413 aOBJECTIVE: To describe relationships between age and sub-clinical cardiovascular disease, manifest chronic disease, and physical functioning and limitations among persons aged 65 years and older, with emphasis on the "oldest old," those 85 years and older.
DESIGN: Observational population-based study.
SETTING: Four U.S. communities: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania.
PARTICIPANTS: 5,201 men and women aged 65 years and older.
MEASUREMENTS: Demographic data; histories of cardiovascular disease (CVD), chronic lung disease, arthritis, diabetes, and hypertension; measures of subclinical disease including arm and ankle blood pressures, internal carotid wall thickness and stenosis, ejection fraction, left ventricular mass, fractional shortening, and diastolic function, electrocardiographic left ventricular hypertrophy and cardiac injury score, forced expiratory flow and volume; functional status including self-reported physical functioning, hearing and sight limitations and health status, and performance-based measures of function. These variables were examined among men and women in three age groups: 65-74 years, 75-84 years, and 85 + years. Subgroups of participants with and without manifest CVD were also examined.
MAIN RESULTS: In women, the prevalence of CVD and other chronic conditions increased with age, and the highest rates occurred among those 85 years and older. In men, prevalence rates increased between the two younger groups, but the oldest group had lower than expected rates for coronary heart disease, cerebrovascular disease, hypertension, and chronic lung disease. In contrast, there were strong age-related linear trends in most of the subclinical measures of blood pressure, atherosclerosis and pulmonary function and in virtually all measures of functional status in both gender groups across the age range. There was a particularly marked decline in functional status between the two older age groups. While subclinical disease was greater and functional status was poorer among those with manifest CVD, with few exceptions, age-related trends were not significantly different between the two groups.
CONCLUSIONS: Lower than expected prevalence rates of CVD among those aged 85 years and older, particularly among men, in this study of community-dwelling elderly may represent selection bias or a real plateauing in disease prevalence with age. However, subclinical disease appears to increase and functional status to decline across the age range in both men and women regardless of the presence of CVD. The apparent increase in subclinical disease with age indicates potential for CVD prevention after age 65.
10aActivities of Daily Living10aAge Distribution10aAged10aAged, 80 and over10aCardiovascular Diseases10aFemale10aHumans10aMale10aPrevalence10aSex Distribution10aSocioeconomic Factors1 aBild, D, E1 aFitzpatrick, A1 aFried, L P1 aWong, N, D1 aHaan, M, N1 aLyles, M1 aBovill, E1 aPolak, J, F1 aSchulz, R uhttps://chs-nhlbi.org/node/144203948nas a2200385 4500008004100000022001400041245015000055210006900205260001300274300001100287490000700298520283000305653000903135653001003144653000803154653002103162653003303183653002803216653001103244653001103255653000903266653002603275653003303301653002803334653003003362653001703392100001703409700002003426700001703446700001303463700001503476700001703491700001803508856003603526 1993 eng d a0009-732200aAnkle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group.0 aAnklearm index as a marker of atherosclerosis in the Cardiovascu c1993 Sep a837-450 v883 aBACKGROUND: Peripheral arterial disease measured noninvasively by the ankle-arm index (AAI) is common in older adults, largely asymptomatic, and associated with clinically manifest cardiovascular disease (CVD). The criteria for an abnormal AAI have varied in previous studies. To determine whether there is an inverse dose-response relation between the AAI and clinical CVD, subclinical disease, and risk factors, we examined the relation of the AAI to cardiovascular risk factors, other noninvasive measures of subclinical atherosclerosis using carotid ultrasound, echocardiography and electrocardiography, and clinical CVD.
METHODS AND RESULTS: The AAI was measured in 5084 participants > or = 65 years old at the baseline examination of the Cardiovascular Health Study. All subjects had detailed assessment of prevalent CVD, measures of cardiovascular risk factors, and noninvasive measures of disease. Participants were stratified by baseline clinical CVD status and AAI (< 0.8, > or = 0.8 to < 0.9, > or = 0.9 to < 1.0, > or = 1.0 to < 1.5). Analyses tested for a dose-response relation of the AAI with clinical CVD, risk factors, and subclinical disease. The cumulative frequency of a low AAI was 7.4% of participants < 0.8, 12.4% < 0.9, and 23.6% < 1.0. participants with an AAI < 0.8 were more than twice as likely as those with an AAI of 1.0 to 1.5 to have a history of myocardial infarction, angina, congestive heart failure, stroke, or transient ischemic attack (all P < .01). In participants free of clinical CVD at baseline, the AAI was inversely related to history of hypertension, history of diabetes, and smoking, as well as systolic blood pressure, serum creatinine, fasting glucose, fasting insulin, measures of pulmonary function, and fibrinogen level (all P < .01). Risk factor associations with the AAI were similar in men and women free of CVD except for serum total and low-density lipoprotein cholesterol, which were inversely associated with AAI level only in women. Risk factors associated with an AAI of < 1.0 in multivariate analysis included smoking (odds ratio [OR], 2.55), history of diabetes (OR, 3.84), increasing age (OR, 1.54), and nonwhite race (OR, 2.36). In the 3372 participants free of clinical CVD, other noninvasive measures of subclinical CVD, including carotid stenosis by duplex scanning, segmental wall motion abnormalities by echocardiogram, and major ECG abnormalities were inversely related to the AAI (all P < .01).
CONCLUSIONS: There was an inverse dose-response relation of the AAI with CVD risk factors and subclinical and clinical CVD among older adults. The lower the AAI, the greater the increase in CVD risk; however, even those with modest, asymptomatic reductions in the AAI (0.8 to 1.0) appear to be at increased risk of CVD.
10aAged10aAnkle10aArm10aArteriosclerosis10aBlood Pressure Determination10aCardiovascular Diseases10aFemale10aHumans10aMale10aMultivariate Analysis10aPeripheral Vascular Diseases10aPopulation Surveillance10aPredictive Value of Tests10aRisk Factors1 aNewman, A, B1 aSiscovick, D, S1 aManolio, T A1 aPolak, J1 aFried, L P1 aBorhani, N O1 aWolfson, S, K uhttps://chs-nhlbi.org/node/144101917nas a2200325 4500008004100000022001400041245007800055210006900133260001300202300001000215490000600225520105000231653000901281653002201290653003001312653001901342653002101361653001101382653001101393653003101404653002501435653000901460653001501469100001601484700001301500700001501513700001301528700001401541856003601555 1993 eng d a1047-279700aAssessment of cerebrovascular disease in the Cardiovascular Health Study.0 aAssessment of cerebrovascular disease in the Cardiovascular Heal c1993 Sep a504-70 v33 aThe Cardiovascular Health Study (CHS) is a longitudinal population-based study of coronary heart disease and stroke in men and women 65 years and older. The initial CHS cohort consisted of 5201 men and women recruited from a random sample of the Health Care Financing Administration (HCFA) Medicare eligibility lists in four communities in the United States. Extensive historical, physical, and laboratory evaluations were performed at the baseline examination in 1989 to 1990 to identify risk factors and subclinical disease. Periodic contacts are carried out to ascertain and verify incident cardiac and stroke events and their sequelae. Since only a short time has passed since entry of all the patients into the study, data are not available on time trends in the mortality rate of stroke, but we expect to contribute in this area in the years ahead. This article then is a description of the CHS, of methods of assessing stroke in the CHS cohort, and of prevalence of stroke and transient ischemic attacks at the initial examination.
10aAged10aAged, 80 and over10aCerebrovascular Disorders10aCohort Studies10aCoronary Disease10aFemale10aHumans10aIschemic Attack, Transient10aLongitudinal Studies10aMale10aPrevalence1 aPrice, T, R1 aPsaty, B1 aO'Leary, D1 aBurke, G1 aGardin, J uhttps://chs-nhlbi.org/node/143102954nas a2200397 4500008004100000022001400041245015100055210006900206260001300275300001200288490000700300520182900307653000902136653001002145653002802155653002102183653002102204653002402225653003302249653001102282653001002293653002102303653001102324653002302335653001702358653001202375653002002387100001702407700001702424700001702441700001502458700001702473700001502490700001502505856003602520 1993 eng d a0009-732200aAssociations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. The CHS Collaborative Research Group.0 aAssociations of postmenopausal estrogen use with cardiovascular c1993 Nov a2163-710 v883 aBACKGROUND: Postmenopausal estrogen replacement therapy has been associated with favorable levels of cardiovascular disease risk factors, but these associations and the relations between estrogen use and subclinical disease have not been examined in large samples of older women.
METHODS AND RESULTS: Present and past estrogen use was ascertained in 2955 women > or = 65 years old in the Cardiovascular Health Study, a study of risk factors for coronary heart disease and stroke in the elderly. Present estrogen use was reported by 12% of these women and past use by an additional 26.5%. Estrogen use (past or present) was strongly associated with lower low-density lipoprotein cholesterol, fibrinogen, glucose, insulin, obesity, and age and higher high-density lipoprotein cholesterol and socioeconomic status (all P < .0001). Estrogen users also had lower levels of subclinical disease as measured by carotid intimal-medial thickness, carotid stenosis grade, ECG left ventricular mass, and Doppler mitral peak flow velocities (each P < .02). Relations were similar in younger and older women (65 to 74 versus > or = 75 years) and smokers and nonsmokers and were unchanged after women with poor medication compliance were excluded. After adjustment for other factors, estrogen use was associated with decreased carotid wall thickness, although this association was of borderline significance after further adjustment for lipids.
CONCLUSIONS: Postmenopausal estrogen use in this sample of older women was associated with favorable cardiovascular disease risk factor profiles and with lower measures of subclinical disease. These findings suggest that postmenopausal estrogen use may be associated with lower risk of cardiovascular disease in women well into the eighth decade of life.
10aAged10aAging10aCardiovascular Diseases10aCarotid Arteries10aCarotid Stenosis10aElectrocardiography10aEstrogen Replacement Therapy10aFemale10aHeart10aHeart Ventricles10aHumans10aPatient Compliance10aRisk Factors10aSmoking10aUltrasonography1 aManolio, T A1 aFurberg, C D1 aShemanski, L1 aPsaty, B M1 aO'Leary, D H1 aTracy, R P1 aBush, T, L uhttps://chs-nhlbi.org/node/143502897nas a2200457 4500008004100000022001400041245009500055210006900150260001600219300001000235490000800245520167300253653001601926653000901942653002201951653000901973653001501982653002801997653002402025653001102049653001902060653001102079653002502090653000902115653001302124653001902137653001902156653001702175653002802192653001502220653003102235100002102266700001502287700002102302700001502323700001702338700001502355700001602370700001702386856003602403 1993 eng d a0002-926200aPrevalence of cardiovascular diseases among older adults. The Cardiovascular Health Study.0 aPrevalence of cardiovascular diseases among older adults The Car c1993 Feb 01 a311-70 v1373 aThe Cardiovascular Health Study is a population-based longitudinal study of 5,201 adults aged 65 years and older. Prevalences of myocardial infarction, angina pectoris, congestive heart failure, peripheral artery disease, stroke, and transient ischemic attack were ascertained between June 1989 and May 1990 in participants recruited from Forsyth County, North Carolina; Washington County, Maryland; Sacramento County, California; and Pittsburgh, Pennsylvania. A medical history was taken to obtain self-reports of prevalent disease. For all participants, use of nitrates was ascertained to document angina, electrocardiograms were used to document prevalent myocardial infarction, and ankle-arm blood pressure studies were used to document peripheral artery disease. Self-reports of disease that were not confirmed by examination findings were further investigated by examination of medical records. Reported disease that was confirmed by examination findings or by medical records was classified as "definite." Disease that was documented by examination, but not reported by the participant, was classified as "unreported." The prevalence rates of definite myocardial infarction and angina were 11% and 15%, respectively, among men aged 65-69 years, 18% and 17% among men aged 80-84 years, 4% and 8% among women aged 65-69 years, and 3% and 13% among women aged 80-84 years. Twenty-three percent of men and 38% of women with electrocardiographic evidence of myocardial infarction did not report it. These results suggest that prevalent disease estimates based only on self-report may underestimate the prevalence of cardiovascular diseases in older Americans.
10aAge Factors10aAged10aAged, 80 and over10aBias10aCalifornia10aCardiovascular Diseases10aElectrocardiography10aFemale10aHealth Surveys10aHumans10aLongitudinal Studies10aMale10aMaryland10aMass Screening10aNorth Carolina10aPennsylvania10aPopulation Surveillance10aPrevalence10aReproducibility of Results1 aMittelmark, M, B1 aPsaty, B M1 aRautaharju, P, M1 aFried, L P1 aBorhani, N O1 aTracy, R P1 aGardin, J M1 aO'Leary, D H uhttps://chs-nhlbi.org/node/144602397nas a2200385 4500008004100000022001400041245015100055210006900206260001300275300001100288490000800299520128200307653000901589653002101598653002801619653002901647653002101676653003001697653001101727653001101738653003101749653000901780653002001789100001601809700001701825700001801842700001801860700001501878700001501893700001601908700001801924700001601942700001701958856003601975 1993 eng d a0033-841900aSonographic evaluation of carotid artery atherosclerosis in the elderly: relationship of disease severity to stroke and transient ischemic attack.0 aSonographic evaluation of carotid artery atherosclerosis in the c1993 Aug a363-700 v1883 aDoppler and real-time ultrasound (US) were performed to evaluate the extent of atherosclerotic changes in the carotid artery and to assess their relationship to prevalent cerebrovascular disease. Real-time US scans and Doppler measurements of the carotid arteries were analyzed in 5,201 subjects aged 65 years or older. Severity of atherosclerotic lesions was associated with increased frequencies of hyperechoic, irregular, and heterogeneous textured lesions (P < .0001). The severity of internal carotid artery stenosis was associated with thickening of the intima-media layer of the common carotid artery wall (r = .37, P < .0001). A history of stroke and transient ischemic attack (TIA) was more likely when hyperechoic, heterogeneous, and irregular lesions were seen in the carotid artery. Internal carotid artery stenosis correlated better with prevalent stroke and TIA than did sonographic descriptions of plaque texture. However, the prevalence of hyperechoic, heterogeneous, and irregular lesions increased as the degree of internal carotid stenosis increased. On real-time images alone, the average of the internal carotid artery maximal wall thickness is the sonographic measure of atherosclerosis that enables the best prediction of prevalent stroke and TIA.
10aAged10aArteriosclerosis10aCarotid Artery Diseases10aCarotid Artery, Internal10aCarotid Stenosis10aCerebrovascular Disorders10aFemale10aHumans10aIschemic Attack, Transient10aMale10aUltrasonography1 aPolak, J, F1 aO'Leary, D H1 aKronmal, R, A1 aWolfson, S, K1 aBond, M, G1 aTracy, R P1 aGardin, J M1 aKittner, S, J1 aPrice, T, R1 aSavage, P, J uhttps://chs-nhlbi.org/node/144003802nas a2200469 4500008004100000022001400041245011400055210006900169260001600238300001200254490000800266520247300274653003202747653000902779653002502788653004502813653002802858653002902886653001902915653001402934653002102948653001102969653002202980653001103002653001703013653001803030653002003048653000903068653001303077653003503090653001503125653001803140653002303158100001503181700001703196700001503213700001603228700001703244700001603261700001903277856003603296 1993 eng d a0098-748400aTemporal patterns of antihypertensive medication use among elderly patients. The Cardiovascular Health Study.0 aTemporal patterns of antihypertensive medication use among elder c1993 Oct 20 a1837-410 v2703 aOBJECTIVES: To estimate the incidence of newly treated hypertension and to describe the patterns of antihypertensive medication use among those aged 65 years and older.
DESIGN: Medicare eligibility lists from four US communities (Forsyth County, North Carolina; Washington County, Maryland; Sacramento County, California; and Pittsburgh, Pa) were used to obtain a representative sample of 5201 community-dwelling elderly for the Cardiovascular Health Study, a prospective cohort study of risk factors for coronary heart disease and stroke. Participants were examined at baseline and again 1 year later. The two examinations included standardized questionnaires, blood pressure measurements, and the assessment of medication use by medication inventory. In this cohort analysis, we excluded 231 subjects (4.4%) who did not return for follow-up, 69 (1.3%) who had missing data for medications, and another 495 (9.5%) who were taking "antihypertensive" medications for an indication other than high blood pressure.
INTERVENTIONS: None.
RESULTS: Among the 4406 participants, 1613 used antihypertensive medications at both visits. Between the two visits, 144 started and 115 stopped antihypertensive therapy. Among nonusers at baseline, the annual incidence of newly treated hypertension was 5.2% in women and 5.6% in men. Due to the number of participants who stopped therapy, the overall prevalence of antihypertensive treatment increased only slightly, from 40.7% to 41.1% in women and from 37.1% to 38.2% in men, during 1 year of follow-up. After adjustment for age, systolic blood pressure, number of antihypertensive drugs, diabetes, and cardiovascular disease, the newly treated hypertensives were about half as likely as the previously treated hypertensives to receive diuretics (odds ratio [OR], 0.59; P = .008) or beta-blockers (OR, 0.52; P = .01); and they were about twice as likely to receive calcium channel blockers (OR, 1.88; P < .004) or angiotensin converting enzyme inhibitors (OR, 2.40; P < .001). A similar pattern of within-person changes over time was apparent among the continuous users.
CONCLUSIONS: Between June 1990 and June 1991, physicians were increasingly prescribing angiotensin converting enzyme inhibitors and calcium channel blockers in place of diuretics and beta-blockers for the treatment of hypertension in elderly patients, especially for those just starting therapy.
10aAdrenergic beta-Antagonists10aAged10aAnalysis of Variance10aAngiotensin-Converting Enzyme Inhibitors10aAntihypertensive Agents10aCalcium Channel Blockers10aCohort Studies10aDiuretics10aDrug Utilization10aFemale10aFollow-Up Studies10aHumans10aHypertension10aLinear Models10aLogistic Models10aMale10aMedicare10aPractice Patterns, Physicians'10aRecurrence10aUnited States10aVasodilator Agents1 aPsaty, B M1 aSavage, P, J1 aTell, G, S1 aPolak, J, F1 aHirsch, C, H1 aGardin, J M1 aMcDonald, R, H uhttps://chs-nhlbi.org/node/142902942nas a2200373 4500008004100000022001400041245016600055210006900221260001300290300001000303490000700313520187400320653000902194653002202203653001002225653001902235653001902254653002102273653001102294653001902305653001102324653003402335653000902369653002402378653001802402100001502420700001602435700001802451700001502469700001602484700001502500700001702515856003602532 1994 eng d a0194-911X00aCorrelates of blood pressure in community-dwelling older adults. The Cardiovascular Health Study. Cardiovascular Health Study (CHS) Collaborative Research Group.0 aCorrelates of blood pressure in communitydwelling older adults T c1994 Jan a59-670 v233 aAlthough elevated blood pressure is an important predictor of cardiovascular disease and stroke in the elderly, little information exists on the distribution and risk factor correlates of blood pressure in this group. As part of the Cardiovascular Health Study, a population-based cohort study of 5201 men and women aged 65 to 101 years, we investigated correlates of systolic and diastolic blood pressure. Multiple regression analyses were conducted for all participants and a subgroup of 2482 without coronary heart disease and not on antihypertensive therapy (the "healthier" subgroup). In the total group, independent predictors of diastolic blood pressure included heart rate, aortic root dimension, creatinine, hematocrit, alcohol use, and black race (positive associations) and internal carotid artery wall thickness, mitral early/late peak flow velocity, white blood cell count, cigarette smoking, and age (negative associations). Positive predictors of systolic blood pressure included mitral late peak flow velocity, left ventricular mass, common carotid artery wall thickness, serum albumin, factor VII, diabetes, alcohol use, and age; negative predictors were coronary heart disease, uric acid, height, and smoking. In the healthier subgroup, positive predictors of diastolic blood pressure included heart rate, hematocrit, serum albumin, creatinine, and body weight, whereas mitral early/late peak flow velocity, serum potassium, smoking, and age inversely related to diastolic pressure. For the same group, common carotid artery wall thickness, left ventricular mass, serum albumin, factor VII, high-density lipoprotein cholesterol, and age were directly related to systolic blood pressure, whereas serum potassium was inversely related. Both systolic and diastolic pressures varied considerably by geographic site.(ABSTRACT TRUNCATED AT 250 WORDS)
10aAged10aAged, 80 and over10aAging10aBlood Pressure10aCohort Studies10aCoronary Disease10aFemale10aHealth Surveys10aHumans10aHypertrophy, Left Ventricular10aMale10aRegression Analysis10aUnited States1 aTell, G, S1 aRutan, G, H1 aKronmal, R, A1 aBild, D, E1 aPolak, J, F1 aWong, N, D1 aBorhani, N O uhttps://chs-nhlbi.org/node/143700860nas a2200289 4500008004100000022001400041245014300055210006900198260001600267300001300283490000700296653000900303653002200312653001100334653001100345653002000356653002100376653002500397653000900422653001600431100002100447700001700468700001500485700001700500700001700517856003600534 1994 eng d a0002-914900aCorrelates of QT prolongation in older adults (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group.0 aCorrelates of QT prolongation in older adults the Cardiovascular c1994 May 15 a999-10020 v7310aAged10aAged, 80 and over10aFemale10aHumans10aLogistic Models10aLong QT Syndrome10aLongitudinal Studies10aMale10aSex Factors1 aRautaharju, P, M1 aManolio, T A1 aPsaty, B M1 aBorhani, N O1 aFurberg, C D uhttps://chs-nhlbi.org/node/143302266nas a2200385 4500008004100000022001400041245008900055210006900144260001300213300001100226490000600237520123600243653000901479653002201488653002001510653002801530653003001558653001501588653000901603653001701612653002801629653001101657653001101668653000901679653002001688653002401708653001701732653001601749100001701765700001501782700001701797700001301814700001701827856003601844 1994 eng d a1047-279700aEating patterns of community-dwelling older adults: the Cardiovascular Health Study.0 aEating patterns of communitydwelling older adults the Cardiovasc c1994 Sep a404-150 v43 aWe analyzed eating patterns of 4643 adults (1988 men and 2655 women) aged 65 years and older at the time of their enrollment in the Cardiovascular Health Study. Diet was assessed with a qualitative, picture-sort food frequency questionnaire along with supplemental questions on other eating pattern variables. Consumption of high fat foods and low fiber foods was more frequent in older participants, men, minorities, and persons with body mass index > or = 30 kg/m2 and less common among persons who reported following self-prescribed or medically prescribed special diets. Few associations of consumption of specific food groups with disease status were identified. Participants with coronary heart disease, diabetes, hypertension, and cardiovascular disease were significantly more likely to report following a special diet and using low-calorie or low-sodium food products, however. Although the percentage of participants with prevalent disease who reported following special diets was relatively low from a clinical perspective, it was sufficiently high to suggest that controlling for dietary modifications may be important when attempting to identify associations of diet with prevalent disease in older populations.
10aAged10aAged, 80 and over10aBody Mass Index10aCardiovascular Diseases10aCerebrovascular Disorders10aDemography10aDiet10aDiet Surveys10aDiet, Sodium-Restricted10aFemale10aHumans10aMale10aMinority Groups10aProspective Studies10aRisk Factors10aSex Factors1 aKumanyika, S1 aTell, G, S1 aShemanski, L1 aPolak, J1 aSavage, P, J uhttps://chs-nhlbi.org/node/142502941nas a2200421 4500008004100000022001400041245011400055210006900169260001300238300001100251490000700262520179700269653001602066653000902082653002202091653002502113653001202138653001002150653002402160653003002184653001102214653001102225653003102236653000902267653002402276653001702300653001602317100001702333700001802350700001602368700001502384700001702399700001602416700001502432700002002447700001602467856003602483 1994 eng d a0039-249900aMagnetic resonance abnormalities and cardiovascular disease in older adults. The Cardiovascular Health Study.0 aMagnetic resonance abnormalities and cardiovascular disease in o c1994 Feb a318-270 v253 aBACKGROUND AND PURPOSE: Cerebral magnetic resonance imaging often detects abnormalities whose significance is unknown. The prevalence and correlates of findings such as ventricular enlargement, sulcal widening, and increased white matter signal intensity were examined in 303 men and women aged 65 to 95 years participating in a multicenter study of cardiovascular disease.
METHODS: Cerebral magnetic resonance imaging was performed and interpreted according to a standard protocol, and findings were correlated with measures of cardiovascular disease and its risk factors.
RESULTS: Measures of cerebral atrophy increased with age and were greater in men than in women (each P < .01). Ventricular enlargement and sulcal widening were associated with prior stroke, hypertension, diabetes, and white race (each P < .03). Extent of white matter hyperintensity was associated with age, prior stroke, hypertension, and use of diuretics (each P < .004). On multivariate analysis, age, male gender, white race, and prior stroke retained strong associations with increased ventricular and sulcal scores. After adjustment for age, prior stroke, and other risk factors, white matter hyperintensity was associated with atherosclerosis as measured by increased internal carotid artery thickness on ultrasound.
CONCLUSIONS: Cerebral atrophy and white matter hyperintensity are common in the elderly and are associated with age, prior stroke, and known cardiovascular risk factors. Though these findings have been suggested to represent normal aging, their wide variability and associations with cardiovascular disease argue against their inevitability with advancing age and support the need to identify modifiable risk factors for these abnormalities.
10aAge Factors10aAged10aAged, 80 and over10aAnalysis of Variance10aAtrophy10aBrain10aCerebral Ventricles10aCerebrovascular Disorders10aFemale10aHumans10aMagnetic Resonance Imaging10aMale10aRegression Analysis10aRisk Factors10aSex Factors1 aManolio, T A1 aKronmal, R, A1 aBurke, G, L1 aPoirier, V1 aO'Leary, D H1 aGardin, J M1 aFried, L P1 aSteinberg, E, P1 aBryan, R, N uhttps://chs-nhlbi.org/node/143803595nas a2200493 4500008004100000022001400041245012300055210006900178260001300247300001200260490000700272520218400279653000902463653001002472653002402482653002402506653003002530653001902560653002102579653002802600653002802628653002402656653001102680653001102691653004402702653001402746653002502760653003102785653000902816653001902825653002302844653001902867653002402886653001702910653001802927100001602945700001702961700001802978700001602996700001803012700001703030700001803047856003603065 1994 eng d a0195-610800aA method for using MR to evaluate the effects of cardiovascular disease on the brain: the cardiovascular health study.0 amethod for using MR to evaluate the effects of cardiovascular di c1994 Oct a1625-330 v153 aPURPOSE: To do a pilot study for the Cardiovascular Health Study (a population-based, longitudinal study of coronary heart disease and stroke in adults 65 years of age and older designed to identify risk factors related to cerebrovascular disease, particularly stroke): (a) to determine the feasibility of adding brain MR to the full-scale study; (b) to evaluate the reliability of standardized MR image interpretation in a multicenter study; and (c) to compare the prevalence of stroke determined by MR with that by clinical history.
METHODS: Protocol-defined MR studies were performed in 100 subjects with clinical histories of stroke and 203 subjects without reported histories of stroke. MR scans were independently evaluated by two trained neuroradiologists for the presence of small (< or = 3 mm) and large (> 3 mm) "infarctlike" lesions. The sizes of the cerebral sulci and lateral ventricles and the extent of white matter disease were graded on a scale of 0 to 9.
RESULTS: Eighty percent of the Cardiovascular Health Study participants who were invited to undergo MR studies agreed to do so; 95% of those agreeing to the procedure successfully completed the exams. Intrareader and interreader reliability of infarctlike lesion identification was high for large lesions (kappa, 0.71 and 0.78, respectively) but not for small lesions (kappa, 0.71 and 0.32, respectively). Relaxed intrareader and interreader kappa scores for sulcal and ventricular sizes and extent of white matter disease were greater than 0.8 MR evidence of infarctlike lesions was present in 77% of the participants with histories of stroke but was also present in 23% of the participants without clinical histories of stroke. Seventy-nine percent of the infarctlike lesions were larger than 3 mm.
CONCLUSIONS: This preliminary study indicates that a large, prospective, epidemiologic study of elderly subjects using MR scans of the brain for identification of cerebrovascular disease is feasible and that the interpretative results are reproducible, and suggests that MR evidence of stroke is more prevalent than reported clinical history of stroke.
10aAged10aBrain10aCerebral Infarction10aCerebral Ventricles10aCerebrovascular Disorders10aCohort Studies10aCoronary Disease10aCross-Sectional Studies10aDiagnosis, Differential10aFeasibility Studies10aFemale10aHumans10aImage Interpretation, Computer-Assisted10aIncidence10aLongitudinal Studies10aMagnetic Resonance Imaging10aMale10aMass Screening10aObserver Variation10aPilot Projects10aProspective Studies10aRisk Factors10aUnited States1 aBryan, R, N1 aManolio, T A1 aSchertz, L, D1 aJungreis, C1 aPoirier, V, C1 aElster, A, D1 aKronmal, R, A uhttps://chs-nhlbi.org/node/142001804nas a2200385 4500008004100000022001400041245010100055210006900156260001300225300001100238490000600249520076700255653000901022653002801031653002001059653001101079653001601090653002501106653001801131653001101149653000901160653002601169653002401195653002001219653001601239653001801255100001401273700001801287700001501305700001601320700001701336700001401353700001601367856003501383 1994 eng d a0898-264300aPredictors of perceived health status in elderly men and women. The Cardiovascular Health Study.0 aPredictors of perceived health status in elderly men and women T c1994 Nov a419-470 v63 aBaseline data on the perceived health status of participants (N = 5,201) in the Cardiovascular Health Study of the Elderly (CHS) are reported. The authors examined the predictive utility of health-related factors representing eight different domains, assessed gender differences in the prediction of perceived health, and tested a hypothesis regarding the role of known clinical conditions versus subclinical disease in predicting perceived health. Multivariate analyses showed that the majority of the explained variance in self-assessed health is accounted for by variables that fall into four general categories. Although gender differences were small, the analysis showed that the relative importance of several predictor variables did vary by gender.
10aAged10aCardiovascular Diseases10aData Collection10aFemale10aForecasting10aGeriatric Assessment10aHealth Status10aHumans10aMale10aMultivariate Analysis10aRegression Analysis10aSelf-Assessment10aSex Factors10aUnited States1 aSchulz, R1 aMittelmark, M1 aKronmal, R1 aPolak, J, F1 aHirsch, C, H1 aGerman, P1 aBookwala, J uhttps://chs-nhlbi.org/node/58702395nas a2200397 4500008004100000022001400041245009300055210006900148260001600217300001100233490000700244520129700251653000901548653002201557653002701579653001901606653002401625653001801649653002801667653002801695653002101723653002401744653001101768653001101779653000901790653001501799653002401814653002101838100001701859700001501876700001701891700001601908700001601924700002101940856003601961 1994 eng d a0002-914900aPrevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study).0 aPrevalence of atrial fibrillation in elderly subjects the Cardio c1994 Aug 01 a236-410 v743 aAtrial fibrillation (AF) is a common arrhythmia in elderly persons and a common cause of embolic stroke. Most studies of the prevalence and correlates of AF have used selected, hospital-based populations. The Cardiovascular Health Study is a population-based, longitudinal study of risk factors for coronary artery disease and stroke in 5,201 men and women aged > or = 65 years. AF was diagnosed in 4.8% of women and in 6.2% of men at the baseline examination, and prevalence was strongly associated with advanced age in women. Prevalence of AF was 9.1% in men and women with clinical cardiovascular disease, 4.6% in patients with evidence of subclinical but no clinical cardiovascular disease, and only 1.6% in subjects with neither clinical nor subclinical cardiovascular disease. A history of congestive heart failure, valvular heart disease and stroke, echocardiographic evidence of enlarged left atrial dimension, abnormal mitral or aortic valve function, treated systemic hypertension, and advanced age were independently associated with the prevalence of AF. The low prevalence of AF in the absence of clinical and subclinical cardiovascular disease calls into question the existence and clinical usefulness of the concept of so-called "lone atrial fibrillation" in the elderly.
10aAged10aAged, 80 and over10aAnti-Arrhythmia Agents10aAnticoagulants10aAtrial Fibrillation10aBlood Glucose10aCardiovascular Diseases10aChi-Square Distribution10aCoronary Disease10aElectrocardiography10aFemale10aHumans10aMale10aPrevalence10aRegression Analysis10aSampling Studies1 aFurberg, C D1 aPsaty, B M1 aManolio, T A1 aGardin, J M1 aSmith, V, E1 aRautaharju, P, M uhttps://chs-nhlbi.org/node/142702432nas a2200373 4500008004100000022001400041245014300055210006900198260001600267300001200283490000800295520139700303653000901700653002201709653002101731653002801752653001101780653001101791653002001802653002501822653000901847653001501856653001701871653001801888100001401906700001501920700001501935700001401950700001501964700001501979700001301994700001502007856003602022 1994 eng d a0002-926200aPrevalence of subclinical atherosclerosis and cardiovascular disease and association with risk factors in the Cardiovascular Health Study.0 aPrevalence of subclinical atherosclerosis and cardiovascular dis c1994 Jun 15 a1164-790 v1393 aThe prevalence of subclinical atherosclerosis and cardiovascular disease was evaluated among the 5,201 adults aged > or = 65 years in four communities participating in the Cardiovascular Health Study from June 1989 through May 1990. A combined index based on electrocardiogram and echocardiogram abnormalities, carotid artery wall thickness and stenosis based on carotid ultrasound, decreased ankle-brachial blood pressure, and positive response to a Rose Questionnaire for angina or intermittent claudication defined subclinical disease. The prevalence of subclinical disease was 36% in women and 38.7% in men and increased with age. Among women, low-density lipoprotein cholesterol, systolic blood pressure, blood glucose, and cigarette smoking were positively associated, and high-density lipoprotein cholesterol negatively associated, with subclinical disease. In men, systolic blood pressure, blood glucose, and cigarette smoking were independent risk factors in multiple logistic regression analyses. The risk factors for subclinical disease are, therefore, similar to those for clinical disease at younger ages, especially among women. It is possible that older individuals with subclinical disease are at very high risk of developing clinical disease and that more aggressive interventions to prevent clinical disease should be oriented to individuals with subclinical disease.
10aAged10aAged, 80 and over10aArteriosclerosis10aCardiovascular Diseases10aFemale10aHumans10aLogistic Models10aLongitudinal Studies10aMale10aPrevalence10aRisk Factors10aUnited States1 aKuller, L1 aBorhani, N1 aFurberg, C1 aGardin, J1 aManolio, T1 aO'Leary, D1 aPsaty, B1 aRobbins, J uhttps://chs-nhlbi.org/node/143402834nas a2200325 4500008004100000022001400041245019000055210006900245260001300314300001100327490000700338520187600345653000902221653002202230653002102252653002102273653001902294653001102313653001102324653000902335653001202344653002002356100001502376700001602391700001502407700001802422700001702440700001502457856003602472 1994 eng d a0009-732200aRelation of smoking with carotid artery wall thickness and stenosis in older adults. The Cardiovascular Health Study. The Cardiovascular Health Study (CHS) Collaborative Research Group.0 aRelation of smoking with carotid artery wall thickness and steno c1994 Dec a2905-80 v903 aBACKGROUND: Cigarette smoking has been associated with increased risk of atherosclerotic diseases in hospital-based studies and in studies of middle-aged populations but not in population-based studies of older adults with and without clinical cardiovascular disease.
METHODS AND RESULTS: We investigated the relation of smoking to carotid artery atherosclerotic disease, expressed as intimal-medial wall thickness and arterial lumen narrowing (stenosis) measured by ultrasound. Subjects were 5116 older adults participating in the baseline examination of the Cardiovascular Health Study, a community-based study of cardiovascular diseases in older age. With increased smoking there was significantly greater internal and common carotid wall thickening and internal carotid stenosis: current smokers > former smokers > never-smokers; for instance, the unadjusted percent stenosis was 24%, 20%, and 16%, respectively (P < .0001). A significant dose-response relation was seen with pack-years of smoking. These findings persisted after adjusting for other cardiovascular risk factors and were also confirmed when analyses were restricted to those without prevalent cardiovascular disease. The difference in internal carotid wall thickness between current smokers and nonsmokers was greater than the difference associated with 10 years of age among never-smoking participants (0.39 mm versus 0.31 mm). Among all participants, the prevalence of clinically significant (> or = 50%) internal carotid stenosis increased from 4.4% in never-smokers to 7.3% in former smokers to 9.5% in current smokers (P < .0001).
CONCLUSIONS: These findings extend previous reports of a positive relation between smoking and carotid artery disease to a population-based sample of older adults using several different indicators of atherosclerotic disease.
10aAged10aAged, 80 and over10aCarotid Arteries10aCarotid Stenosis10aCohort Studies10aFemale10aHumans10aMale10aSmoking10aUltrasonography1 aTell, G, S1 aPolak, J, F1 aWard, B, J1 aKittner, S, J1 aSavage, P, J1 aRobbins, J uhttps://chs-nhlbi.org/node/142602199nas a2200397 4500008004100000022001400041245015300055210006900208260001300277300001200290490000700302520104400309653003901353653000901392653002801401653002101429653004001450653001101490653002501501653001101526653000901537653002601546653001501572653002401587653001701611653001601628100001701644700001601661700001501677700001701692700001201709700001201721700001501733700001701748856003601765 1995 eng d a0895-435600aBlack-white differences in subclinical cardiovascular disease among older adults: the Cardiovascular Health Study. CHS Collaborative Research Group.0 aBlackwhite differences in subclinical cardiovascular disease amo c1995 Sep a1141-520 v483 aCardiovascular and all-cause mortality are higher in black than white Americans, but racial differences in clinical and subclinical cardiovascular disease (CVD) have not been examined in older adults. Clinical and subclinical CVD and its risk factors were compared in 4926 white and 244 black men and women aged 65 years and older. Black participants had lower socioeconomic status and generally higher prevalences of CVD and its risk factors, except for adverse lipid profiles. Common carotid wall thickness was greater in black than white women, and ankle-arm blood pressure ratios were lower in black women and men (p < 0.01). After adjustment for CVD risk factors, common carotid walls were significantly thicker and ankle-arm ratios were lower in blacks than whites of both sexes, while internal carotid walls were significantly thinner in black women. Racial differences in clinical and subclinical CVD in older adults are similar to those reported in younger populations and do not appear to be explained by CVD risk factors.
10aAfrican Continental Ancestry Group10aAged10aCardiovascular Diseases10aCarotid Arteries10aEuropean Continental Ancestry Group10aFemale10aGeriatric Assessment10aHumans10aMale10aMultivariate Analysis10aPrevalence10aRegression Analysis10aRisk Factors10aSex Factors1 aManolio, T A1 aBurke, G, L1 aPsaty, B M1 aNewman, A, B1 aHaan, M1 aPowe, N1 aTracy, R P1 aO'Leary, D H uhttps://chs-nhlbi.org/node/141403165nas a2200409 4500008004100000022001400041245018100055210006900236260001300305300001200318490000700330520198400337653000902321653002202330653001902352653002802371653002102399653001902420653001502439653001602454653001502470653001102485653002602496653002402522653002402546653001702570100001502587700001702602700001302619700001502632700001502647700001302662700001102675700001602686700001702702856003602719 1995 eng d a1079-564200aFibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study.0 aFibrinogen and factor VIII but not factor VII are associated wit c1995 Sep a1269-790 v153 aNo studies have examined the associations of coagulation factor levels with measures of subclinical cardiovascular disease (CVD) in the elderly. The Cardiovascular Health Study (CHS) is a prospective, population-based cohort study of CVD in persons older than 65 years. At the baseline examination, we measured fibrinogen, factor VII, and factor VIII levels in 5024 of the 5201 participants of the CHS and examined the associations of these coagulation factors with measures of subclinical CVD in a cross-sectional analysis. Subclinical CVD measures were based on electrocardiography, carotid ultrasonography, echocardiography, and ankle-arm blood pressure measurements (AAI). For analyses, we used the full cohort as well as two mutually exclusive subgroups: those with prevalent clinical CVD at baseline and those without. Fibrinogen and to a lesser extent factor VIII showed positive associations with a variety of subclinical CVD measures. In age-adjusted analyses, fibrinogen and factor VIII were significantly associated with 8 of 10 measures. In multivariate analyses, fibrinogen was significantly associated with carotid artery stenosis, internal (but not common) carotid artery wall thickness, and AAI. Factor VIII was associated with abnormal wall motion and AAI in the full cohort only. Factor VII was not consistently associated with subclinical disease measures. In bivariate analyses that included data from all three groups, there were 5 positive subclinical disease associations and 5 negative associations for factor VII. In multivariate analyses, there were no significant associations between factor VII and subclinical CVD in the full cohort or in either subgroup. We conclude that in these cross-sectional analyses, fibrinogen and to a lesser extent factor VIII are associated with subclinical CVD in the elderly, even in those without symptoms or a history of clinical CVD. Factor VII, however, was not associated with subclinical CVD in the elderly.
10aAged10aAged, 80 and over10aBlood Pressure10aCardiovascular Diseases10aCarotid Stenosis10aCohort Studies10aFactor VII10aFactor VIII10aFibrinogen10aHumans10aMultivariate Analysis10aProspective Studies10aRegression Analysis10aRisk Factors1 aTracy, R P1 aBovill, E, G1 aYanez, D1 aPsaty, B M1 aFried, L P1 aHeiss, G1 aLee, M1 aPolak, J, F1 aSavage, P, J uhttps://chs-nhlbi.org/node/141602401nas a2200409 4500008004100000022001400041245010300055210006900158260001300227300001000240490000700250520132900257653001601586653000901602653002501611653001501636653002801651653001901679653001101698653001801709653001101727653000901738653001301747653001601760653001901776653001701795653002101812653001701833653002401850100001501874700001201889700001401901700001501915700001201930700001301942856003601955 1995 eng d a0002-861400aHematological and biochemical laboratory values in older Cardiovascular Health Study participants.0 aHematological and biochemical laboratory values in older Cardiov c1995 Aug a855-90 v433 aOBJECTIVE: To define reference hematologic and biochemical lab values in older individuals.
DESIGN: Randomly selected, age- and gender-stratified participants.
SETTING: Visits by participants to four research clinics.
PATIENTS: A total of 5201 participants in the Cardiovascular Health Study, an observational study of older Medicare-eligible individuals living at home.
MEASUREMENT: Information about health status, previous illness, and medication use was obtained from participants and/or their MDs. This information was used to define a healthy subset of the population. Blood samples were obtained for Cholesterol, HDL and LDL cholesterol, fasting and 2-hour postload glucose and insulin, fibrinogen, factors VII and VIII, potassium, creatinine, albumin, uric acid, white blood count, hematocrit, hemoglobin, and platelet count.
RESULTS: Significant differences were found for age group and/or gender for all mean values. Many tests were significantly different from the generally accepted reference ranges used in clinical laboratories.
CONCLUSIONS: In some situations accepted laboratory norms for the general population can not be extrapolated to older adults. There are implications for both research and clinical practice.
10aAge Factors10aAged10aAnalysis of Variance10aCalifornia10aCardiovascular Diseases10aCohort Studies10aFemale10aHealth Status10aHumans10aMale10aMaryland10aMiddle Aged10aNorth Carolina10aPennsylvania10aReference Values10aRisk Factors10aSex Characteristics1 aRobbins, J1 aWahl, P1 aSavage, P1 aEnright, P1 aPowe, N1 aLyles, M uhttps://chs-nhlbi.org/node/141302886nas a2200445 4500008004100000022001400041245009400055210006900149260001300218300001000231490000600241520166800247653000901915653003001924653001901954653002101973653002401994653002602018653002902044653001102073653001102084653000902095653002802104653001502132653002402147653003102171653001702202653002002219653001802239100001502257700001602272700001202288700001602300700001802316700001802334700001602352700002102368700001502389856003602404 1995 eng d a1047-279700aMethods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study.0 aMethods of assessing prevalent cardiovascular disease in the Car c1995 Jul a270-70 v53 aThe objective of this article is to describe the methods of assessing cardiovascular conditions among older adults recruited to the Cardiovascular Health Study (CHS), a cohort study of risk factors for coronary disease and stroke. Medicare eligibility lists from four US communities were used to obtain a representative sample of 5201 community-dwelling elderly, who answered standardized questionnaires and underwent an extensive clinic examination at baseline. For each cardiovascular condition, self-reports were confirmed by components of the baseline examination or, if necessary, by a validation protocol that included either the review of medical records or surveys of treating physicians. Potential underreporting of a condition was detected either by the review of medical records at baseline for other self-reported conditions or, during prospective follow-up, by the investigation of potential incident events. For myocardial infarction, 75.5% of the self-reports in men and 60.6% in women were confirmed. Self-reported congestive heart failure was confirmed in 73.3% of men and 76.6% of women; stroke, in 59.6% of men and 53.8% of women; and transient ischemic attack, in 41.5% of men and 37.0% of women. Underreporting was also common. During prospective follow-up of an average of about 3 years per person, approximately 50% of men and 38% of women were hospitalized or investigated for at least one potential incident event; for each cardiovascular condition, about 1 to 4% of those investigated during prospective follow-up were found to have had the cardiovascular condition prior to entry into the cohort.(ABSTRACT TRUNCATED AT 250 WORDS)
10aAged10aCerebrovascular Disorders10aCohort Studies10aCoronary Disease10aElectrocardiography10aEpidemiologic Methods10aFalse Negative Reactions10aFemale10aHumans10aMale10aPopulation Surveillance10aPrevalence10aProspective Studies10aReproducibility of Results10aRisk Factors10aSelf Disclosure10aUnited States1 aPsaty, B M1 aKuller, L H1 aBild, D1 aBurke, G, L1 aKittner, S, J1 aMittelmark, M1 aPrice, T, R1 aRautaharju, P, M1 aRobbins, J uhttps://chs-nhlbi.org/node/144902686nas a2200409 4500008004100000022001400041245008200055210006900137260001600206300001000222490000700232520161900239653000901858653002801867653001901895653002101914653001101935653001101946653001401957653002501971653000901996653002602005653001502031653002102046653001702067100001602084700001702100700001502117700001702132700001402149700001502163700001702178700001702195700001502212700001302227856003602240 1995 eng d a0009-732200aSubclinical disease as an independent risk factor for cardiovascular disease.0 aSubclinical disease as an independent risk factor for cardiovasc c1995 Aug 15 a720-60 v923 aBACKGROUND: The primary aim of the present study was to determine the relation between measures of subclinical cardiovascular disease and the incidence of clinical cardiovascular disease among 5201 adults 65 years of age or older who were participating in the Cardiovascular Health Study.
METHODS AND RESULTS: A new method of classifying subclinical disease at baseline examination in the Cardiovascular Health Study included measures of ankle-brachial blood pressure, carotid artery stenosis and wall thickness, ECG and echocardiographic abnormalities, and positive response to the Rose Angina and Claudication Questionnaire. Participants were followed for an average of 2.39 years (maximum, 3 years). For participants without evidence of clinical cardiovascular disease at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a significant increased risk of incident total coronary heart disease including CHD deaths and nonfatal MI and angina pectoris for both men and women. For individuals with subclinical disease, the increased risk of total coronary heart disease was 2.0 for men and 2.5 for women, and the increased risk of total mortality was 2.9 for men and 1.7 for women. The increased risk changed little after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes.
CONCLUSIONS: The measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.
10aAged10aCardiovascular Diseases10aCohort Studies10aCoronary Disease10aFemale10aHumans10aIncidence10aLongitudinal Studies10aMale10aMyocardial Infarction10aOdds Ratio10aReference Values10aRisk Factors1 aKuller, L H1 aShemanski, L1 aPsaty, B M1 aBorhani, N O1 aGardin, J1 aHaan, M, N1 aO'Leary, D H1 aSavage, P, J1 aTell, G, S1 aTracy, R uhttps://chs-nhlbi.org/node/141502025nas a2200385 4500008004100000022001400041245009400055210006900149260001300218300001100231490000600242520098000248653000901228653003001237653002101267653002601288653001101314653002001325653001101345653001401356653002501370653000901395653002801404653002001432653001801452100001501470700002201485700001501507700001501522700001601537700001801553700001701571700001501588856003601603 1995 eng d a1047-279700aSurveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study.0 aSurveillance and ascertainment of cardiovascular events The Card c1995 Jul a278-850 v53 aWhile previous prospective multicenter studies have conducted cardiovascular disease surveillance, few have detailed the techniques relating to the ascertainment of and data collection for events. The Cardiovascular Health Study (CHS) is a population-based study of coronary heart disease and stroke in older adults. This article summarizes the CHS events protocol and describes the methods of surveillance and ascertainment of hospitalized and nonhospitalized events, the use of medical records and other support documents, organizational issues at the field center level, and the classification of events through an adjudication process. We present data on incidence and mortality, the classification of adjudicated events, and the agreement between classification by the Events Subcommittee and the medical records diagnostic codes. The CHS techniques are a successful model for complete ascertainment, investigation, and documentation of events in an older cohort.
10aAged10aCerebrovascular Disorders10aCoronary Disease10aEpidemiologic Methods10aFemale10aHospitalization10aHumans10aIncidence10aLongitudinal Studies10aMale10aPopulation Surveillance10aQuality Control10aUnited States1 aIves, D, G1 aFitzpatrick, A, L1 aBild, D, E1 aPsaty, B M1 aKuller, L H1 aCrowley, P, M1 aCruise, R, G1 aTheroux, S uhttps://chs-nhlbi.org/node/145003221nas a2200385 4500008004100000022001400041245015700055210006900212260001600281300001100297490000800308520208200316653000902398653002802407653002902435653003702464653002802501653001102529653001102540653001702551653000902568653003502577653001802612100001502630700001902645700001602664700001502680700001702695700001802712700001702730700001602747700002002763700001602783856003602799 1995 eng d a0098-748400aTemporal patterns of antihypertensive medication use among older adults, 1989 through 1992. An effect of the major clinical trials on clinical practice?0 aTemporal patterns of antihypertensive medication use among older c1995 May 10 a1436-80 v2733 aOBJECTIVE: To describe the changing patterns of antihypertensive medication use in the years immediately before and after the publication of the results of three major clinical trials of the treatment of hypertension in older adults.
DESIGN: In this cohort study, adults 65 years or older were examined annually on four occasions between June 1989 and May 1992, and the use of antihypertensive medications was assessed by inventory at each visit. The four visits defined the boundaries of three study periods. For each study period, participants receiving antihypertensive therapy were either continuous users (n = 1667, 1643, and 1605, respectively) or starters (n = 157, 142, 120) of hypertensive therapy. The large clinical trials that convincingly proved the efficacy and safety of low-dose diuretic therapy in older adults were published during the latter parts of period 2 and the early parts of period 3.
RESULTS: Among starters, the proportion initiating therapy on diuretics increased from 35.9% in period 2 to 47.5% in period 3, significantly so among women (P = .04). The proportions initiating other drugs displayed no significant trends. Among continuous users, the use of diuretics, beta-blockers, and vasodilators generally decreased over the 3-year period, while the use of calcium channel blockers and angiotensin-converting enzyme inhibitors increased significantly in each of the three periods (P < .05). The decline of 2.7% in the prevalence of diuretic use in period 1 abated during period 2 (1.8% decline), and it slowed significantly (P = .03) to almost a complete halt during period 3 (0.2% decline). The rate of increase in the use of calcium channel blockers slowed significantly (P = .01) between period 1 (+6.7%) and period 3 (+2.8%).
CONCLUSIONS: Although other factors such as cost may have been important, the temporal trends in antihypertensive drug therapy coincided in time with and may have reflected in part the influence of the major clinical trials on the patterns of clinical practice.
10aAged10aAntihypertensive Agents10aClinical Trials as Topic10aData Interpretation, Statistical10aDrug Utilization Review10aFemale10aHumans10aHypertension10aMale10aPractice Patterns, Physicians'10aUnited States1 aPsaty, B M1 aKoepsell, T, D1 aYanez, N, D1 aSmith, N L1 aManolio, T A1 aHeckbert, S R1 aBorhani, N O1 aGardin, J M1 aGottdiener, J S1 aRutan, G, H uhttps://chs-nhlbi.org/node/141802703nas a2200457 4500008004100000022001400041245019200055210006900247260001600316300001100332490000800343520141800351653002101769653000901790653002201799653002501821653002801846653001901874653001501893653001601908653001101924653001501935653001101950653001801961653002001979653000901999653001502008653001702023653002102040653001802061100001502079700001302094700001502107700001502122700001302137700001102150700001602161700001702177700001502194856003602209 1996 eng d a0002-926200aAssociation of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators.0 aAssociation of fibrinogen and coagulation factors VII and VIII w c1996 Apr 01 a665-760 v1433 aThe cross-sectional correlates of three hemostatic factors--fibrinogen, factor VII, and factor VIII--were examined in the Cardiovascular Health Study, a population-based cohort study of 5,201 subjects over age 65 years. Subjects were recruited in 1989-1990 in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. In multivariate linear regression models, cardiac risk factors significantly associated with fibrinogen were current smoking, race, lipids, and white blood count. In women, alcohol use, obesity, physical activity, and insulin level were also significant, while in men hypertension was correlated. The significant correlates of factor VII were lipids and white blood count in men and estrogen use, alcohol use, race, lipids, insulin level, white blood count, and obesity in women. The independent correlates of factor VIII were insulin, glucose, and race in both sexes; low density lipoprotein cholesterol, white blood count, and diuretic use in men; and alcohol use in women. In multivariate models, factors known to be modifiable risk factors for cardiovascular disease accounted for more of the population variance of these hemostatic factors in women than in men, especially for factor VII. The hemostatic factors may mediate some effects of risk factors on disease, and this should be considered in longitudinal studies.
10aAge Distribution10aAged10aAged, 80 and over10aAnalysis of Variance10aCardiovascular Diseases10aCohort Studies10aFactor VII10aFactor VIII10aFemale10aFibrinogen10aHumans10aLinear Models10aLogistic Models10aMale10aPrevalence10aRisk Factors10aSex Distribution10aUnited States1 aCushman, M1 aYanez, D1 aPsaty, B M1 aFried, L P1 aHeiss, G1 aLee, M1 aPolak, J, F1 aSavage, P, J1 aTracy, R P uhttps://chs-nhlbi.org/node/145702240nas a2200337 4500008004100000022001400041245014400055210006900199260001600268300001100284490000700295520126800302653000901570653002101579653001901600653001101619653002101630653001101651653003401662653000901696653002401705653001701729653002001746100001801766700001601784700001701800700001601817700001601833700001701849856003601866 1996 eng d a0002-914900aCarotid artery measures are strongly associated with left ventricular mass in older adults (a report from the Cardiovascular Health Study).0 aCarotid artery measures are strongly associated with left ventri c1996 Mar 15 a628-330 v773 aAssociations of carotid artery diameter and intimal-medial thickness by ultrasound with echocardiographic left ventricular (LV) structure were examined in 3,409 participants in the Cardiovascular Health Study, a population-based study of risk factors for coronary heart disease and stroke in men and women aged > or = 65 years. At baseline, sector-guided M-mode echocardiography and B-mode ultrasound were used to evaluate the left ventricle and carotid arteries, respectively. Common carotid artery diameter and intimal-medial thickness were significantly related to LV mass in correlational analysis (r=0.40 and 0.20, respectively, p<0.01), and each was independently associated with LV mass after adjustment for age, gender, weight, systolic and diastolic blood pressure, antihypertensive medication use, prior coronary heart disease, electrocardiographic abnormalities, high-density lipoprotein, and factor VII. We speculate that changes in the arterial wall affect impedance to LV ejection leading to increases in LV mass. Further follow-up of this cohort is in progress and will help to determine whether such carotid artery measures could, by exacerbating LV hypertrophy, constitute another important risk factor for adverse cardiovascular outcomes.
10aAged10aCarotid Arteries10aCohort Studies10aFemale10aHeart Ventricles10aHumans10aHypertrophy, Left Ventricular10aMale10aRegression Analysis10aRisk Factors10aUltrasonography1 aKronmal, R, A1 aSmith, V, E1 aO'Leary, D H1 aPolak, J, F1 aGardin, J M1 aManolio, T A uhttps://chs-nhlbi.org/node/145402751nas a2200373 4500008004100000022001400041245016800055210006900223260001300292300001100305490000700316520167800323653000902001653001902010653002702029653002802056653002102084653001102105653002102116653001102137653001702148653000902165653001802174653001702192100001602209700001802225700001502243700001702258700001702275700001602292700001602308700001702324856003602341 1996 eng d a0039-249900aCompensatory increase in common carotid artery diameter. Relation to blood pressure and artery intima-media thickness in older adults. Cardiovascular Health Study.0 aCompensatory increase in common carotid artery diameter Relation c1996 Nov a2012-50 v273 aBACKGROUND AND PURPOSE: Common carotid artery (CCA) diameter is thought to increase as a consequence of hypertension and may increase as the thickness of the arterial wall increases. The purpose of this study was to determine CCA dimensions and correlate them with clinical features.
METHODS: We performed a cross-sectional, community-based study of adults 65 years of age and older, measuring inner and outer diameter of the CCA in vivo with carotid sonography. Findings were correlated against risk factors for atherosclerosis, CCA intima-media thickness (IMT), and echocardiographically determined left ventricular (LV) mass.
RESULTS: Independent variables showing strong positive associations with outer and inner CCA diameter included age, male sex, height, weight, and systolic blood pressure. As an independent variable, LV mass (r = .40 and r = .37, respectively; P < .00001) had a strong positive relation to inner and outer CCA diameters. The relationship between diameter and IMT was different. In a model that controlled for age, sex, and estimated LV mass, an increase of 1 mm in CCA IMT corresponded to a 1.9 mm increase in the outer diameter of the artery (P < .00001) but was not significantly related to the inner diameter (slope = +0.07 mm; P = .26).
CONCLUSIONS: Increase in the outer diameter of the CCA is associated with subject size, sex, age, echocardiographically estimated LV mass, and CCA IMT. Increases in internal diameter of the CCA have similar relationships but are not related to IMT. This supports the hypothesis that the human CCA dilates as the thickness of the artery wall increases.
10aAged10aBlood Pressure10aCarotid Artery, Common10aCross-Sectional Studies10aEchocardiography10aFemale10aHeart Ventricles10aHumans10aHypertension10aMale10aTunica Intima10aTunica Media1 aPolak, J, F1 aKronmal, R, A1 aTell, G, S1 aO'Leary, D H1 aSavage, P, J1 aGardin, J M1 aRutan, G, H1 aBorhani, N O uhttps://chs-nhlbi.org/node/146602360nas a2200337 4500008004100000022001400041245009700055210006900152260001300221300001100234490000700245520147900252653000901731653001501740653002801755653001901783653001101802653001501813653001101828653000901839653001701848653001301865100001501878700001501893700001201908700001701920700001801937700001601955700001501971856003601986 1996 eng d a1079-564200aCorrelates of thrombin markers in an elderly cohort free of clinical cardiovascular disease.0 aCorrelates of thrombin markers in an elderly cohort free of clin c1996 Sep a1163-90 v163 aStudies suggest that thrombosis is important in the progression of atherosclerotic lesions. The biochemical markers prothrombin fragment 1-2 and fibrinopeptide A reflect in vivo thrombin generation and activity, respectively. As such, they are markers that might be associated with cardiovascular risk. From the Cardiovascular Health Study, a cohort study of 5201 persons over 65 years of age, 399 persons free of clinical cardiovascular disease (CVD) at the baseline examination were selected for study of specialized markers of hemostasis. We report the cross-sectional relationships of the thrombin markers to CVD risk factors and measures of subclinical CVD. The range of fragment 1-2 2 was 0.12 to 0.85 nmol/L. The range of fibrinopeptide A was 0.9 to 44.1 micrograms/L. High levels of fragment 1-2 and fibrinopeptide A were associated with age, with levels higher in women than men. Fragment 1-2 was associated with smoking; high levels of triglyceride, creatinine, and C-reactive protein; and low levels of glucose. Fibrinopeptide A was associated with high C-reactive protein and apolipoprotein(a) and lower ankle-brachial index. There were no significant associations of the thrombin markers with race, fibrinogen, alcohol consumption, diabetes, or most measures of subclinical CVD. Study findings support a hypothesis that there are physiological interrelationships between cardiac risk factors, hemostasis, inflammation, and progression of atherosclerosis.
10aAged10aBiomarkers10aCardiovascular Diseases10aCohort Studies10aFemale10aHemostasis10aHumans10aMale10aRisk Factors10aThrombin1 aCushman, M1 aPsaty, B M1 aMacy, E1 aBovill, E, G1 aCornell, E, S1 aKuller, L H1 aTracy, R P uhttps://chs-nhlbi.org/node/146403350nas a2200481 4500008004100000022001400041245018700055210006900242260001300311300001100324490000600335520193200341653000902273653002102282653002102303653002102324653001902345653002502364653002802389653002302417653003002440653003302470653001402503653001102517653002902528653001102557653001502568653001502583653002502598653002002623653001802643653001902661100001602680700001802696700001502714700001702729700001802746700001502764700001502779700001802794700002002812856003602832 1996 eng d a1047-279700aCurrent estrogen-progestin and estrogen replacement therapy in elderly women: association with carotid atherosclerosis. CHS Collaborative Research Group. Cardiovascular Health Study.0 aCurrent estrogenprogestin and estrogen replacement therapy in el c1996 Jul a314-230 v63 aThe cardioprotective effects of combined estrogen/progestin replacement therapy have been questioned. Therefore, we have compared carotid arterial wall thickening and the prevalence of carotid stenosis in elderly women (> or = 65 years old) currently using replacement estrogen/progestins (E + P) with arterial pathology and its prevalence in women using unopposed estrogens (E). This cross-sectional study used baseline data from all 2962 women participating in the Cardiovascular Health Study, a population-based study of coronary heart disease and stroke in elderly adults. Users of hormone replacement therapy (HRT) were categorized as never (n = 1726), past (n = 787), current E (n = 280), or current E + P (n = 73). Maximal intimal-medial thicknesses of the internal and common carotid arteries and stenosis of the internal carotid arteries were measured by ultrasonography. Current E + P users resembled current E users in most respects, although some lifestyle factors were more favorable among E + P users. Current E + P use and current E use (as compared with no use) were associated with smaller internal carotid wall thicknesses (-0.22 mm; P = 0.003; and -0.09 mm; P = 0.05, respectively) and smaller common carotid wall thicknesses (-0.05 mm; P = 0.03; and -0.02 mm; P = 0.1, respectively) and lower odds ratios (OR) for carotid stenosis (> or = 1% vs. 0%); OR = 0.61; 95% confidence interval [CI]: 0.36 to 1.01; and OR = 0.91, 95% CI: 0.67 to 1.24, respectively), after adjustment for current lifestyle and risk factors. When both groups of current HRT users were compared, there were no significant differences in carotid wall thicknesses or prevalence of carotid stenosis. For this sample of elderly women, both current E + P therapy and current E therapy were associated with decreased measures of carotid atherosclerosis. These measures did not differ significantly between the two groups of HRT users.
10aAged10aArteriosclerosis10aCarotid Arteries10aCarotid Stenosis10aCohort Studies10aConfidence Intervals10aCross-Sectional Studies10aDatabases, Factual10aDrug Therapy, Combination10aEstrogen Replacement Therapy10aEstrogens10aFemale10aHealth Status Indicators10aHumans10aOdds Ratio10aProgestins10aReproductive History10aUltrasonography10aUnited States10aWomen's Health1 aJonas, H, A1 aKronmal, R, A1 aPsaty, B M1 aManolio, T A1 aMeilahn, E, N1 aTell, G, S1 aTracy, R P1 aRobbins, J, A1 aAnton-Culver, H uhttps://chs-nhlbi.org/node/146502450nas a2200313 4500008004100000022001400041245008700055210006900142260001300211300001100224490000600235520155800241653002901799653002601828653002801854653001101882653001701893653003701910100001501947700002001962700001601982700001901998700002002017700001102037700001802048700001702066700001702083856003602100 1996 eng d a0895-706100aHypertension and outcomes research. From clinical trials to clinical epidemiology.0 aHypertension and outcomes research From clinical trials to clini c1996 Feb a178-830 v93 aOutcomes research seeks to identify effective evidence-based methods of providing the best medical care. While randomized clinical trials (RCT) usually provide the clearest answers, they are often not done or not practicable. More than a decade after the introduction of calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors, clinical trial data about their effect on major disease endpoints in patients with hypertension are still not available. The primary alternatives are the use of randomized trials that include surrogate endpoints, such as level of blood pressure or extent of carotid atherosclerosis, and the use of observational studies that include major disease endpoints. Both approaches, their strengths and limitations, are discussed in detail. The possibility of residual confounding limits the strength of inferences that can be drawn from observational studies. Similarly, the possibility of important drug effects, other than those involving the surrogate endpoint, limits the inferences that can be drawn from randomized trials that rely solely on surrogate outcomes as guides to therapy. In the absence of evidence from large clinical trials that include major disease endpoints, treatment decisions and guidelines need to synthesize the best available information from a variety of sources. Consistency of findings across various study designs, outcomes, and populations is critical to the practice of evidence-based medicine and the effort to maximize the health benefits of antihypertensive therapies.
10aClinical Trials as Topic10aEpidemiologic Methods10aEvidence-Based Medicine10aHumans10aHypertension10aOutcome Assessment (Health Care)1 aPsaty, B M1 aSiscovick, D, S1 aWeiss, N, S1 aKoepsell, T, D1 aRosendaal, F, R1 aLin, D1 aHeckbert, S R1 aWagner, E, H1 aFurberg, C D uhttps://chs-nhlbi.org/node/146803089nas a2200409 4500008004100000022001400041245009500055210006900150260001300219300001200232490000700244520195700251653001602208653000902224653004302233653003002276653001902306653001102325653001802336653001102354653001402365653002502379653000902404653002602413653001402439653003202453653002402485653001702509653001602526653001702542100001702559700001802576700001602594700001702610700001602627856003602643 1996 eng d a0039-249900aShort-term predictors of incident stroke in older adults. The Cardiovascular Health Study.0 aShortterm predictors of incident stroke in older adults The Card c1996 Sep a1479-860 v273 aBACKGROUND AND PURPOSE: Risk factors for incident stroke have been examined in middle-aged persons, but less is known about stroke precursors in the elderly, who suffer the highest rates of stroke. Short-term risk factors for incident stroke were examined in a longitudinal, population-based study including extensive measures of subclinical disease.
METHODS: Prospective study of 5201 women and men aged 65 years and older was undertaken in the multicenter Cardiovascular Health Study.
RESULTS: During an average 3.31-year follow-up, 188 incident strokes occurred. Stroke incidence increased significantly with age and was similar in women and men. Factors associated with increased stroke risk in multivariate analysis included age, aspirin use, diabetes, impaired glucose tolerance, higher systolic blood pressure, increased time needed to walk 15 ft. frequent falls, elevated creatinine level, abnormal left ventricular (LV) wall motion and increased LV mass on echocardiography, ultrasound-defined carotid stenosis, and atrial fibrillation. Increased LV mass and carotid stenosis were associated with twofold and threefold increases in incidences of stroke, respectively (P < .001). Aspirin users had a 52% higher risk of stroke (relative risk, 1.52; 95% confidence interval, 1.1 to 2.0; P < .007) after adjustment for other factors. This association was present only among aspirin users without prior coronary disease, atrial fibrillation, claudication, or transient ischemic attack, who had an 84% higher risk (relative risk, 1.84; 95% confidence interval, 1.2 to 2.8).
CONCLUSIONS: Short-term risk of stroke has a complex relationship with aspirin use and is strongly related to subclinical disease in this sample of older adults. These relationships should be considered in assessing stroke risk in the elderly, in whom recognized and subclinical cardiovascular disease is highly prevalent.
10aAge Factors10aAged10aCardiovascular Physiological Phenomena10aCerebrovascular Disorders10aCohort Studies10aFemale10aHealth Status10aHumans10aIncidence10aLongitudinal Studies10aMale10aMultivariate Analysis10aPrognosis10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSex Factors10aTime Factors1 aManolio, T A1 aKronmal, R, A1 aBurke, G, L1 aO'Leary, D H1 aPrice, T, R uhttps://chs-nhlbi.org/node/146303950nas a2200565 4500008004100000022001400041245013900055210006900194260001300263300001100276490000700287520238100294653001002675653000902685653002102694653001902715653002702734653002902761653002102790653002102811653001902832653002102851653002202872653002602894653002402920653001102944653001102955653000902966653002702975653002503002653002403027653002403051653001703075653002403092653001203116653001803128653001703146653002003163100001703183700001603200700001803216700001703234700001703251700001803268700001303286700001603299700001603315700001703331856003603348 1996 eng d a0039-249900aThickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group.0 aThickening of the carotid wall A marker for atherosclerosis in t c1996 Feb a224-310 v273 aBACKGROUND AND PURPOSE: We investigated the relationships between prevalent coronary heart disease (CHD), clinically manifest atherosclerotic disease (ASD), and major established risk factors for atherosclerosis and intima-media thickness (IMT) in the common carotid arteries (CCA) and internal carotid arteries (ICA) separately and in combination in older adults. We wished to determine whether a noninvasive measurement can serve as an indicator of clinically manifest atherosclerotic disease and to determine which of the two variables, CCA IMT or ICA IMT, is a better correlate.
METHODS: IMT of the CCA and ICA was measured with duplex ultrasound in 5117 of 5201 individuals enrolled in the Cardiovascular Health Study, a study of the risk factors and the natural history of cardiovascular disease in adults aged 65 years or more. Histories of CHD, peripheral arterial disease, and cerebrovascular disease were obtained during baseline examination. Risk factors included cholesterol levels, cigarette smoking, elevated blood pressure, diabetes, age, and sex. Relationships between risk factors and IMT were studied by multiple regression analysis and canonical variate analysis. Prediction of prevalent CHD and ASD by IMT measurements in CCAs and ICAs were made by logistic regression, adjusting for age and sex.
RESULTS: IMT measurements of the CCAs and ICAs were greater in persons with CHD and ASD than those without, even after controlling for sex (P < .001). IMT measurements in the ICA were greater than those in the CCA. Risk factors for ASD accounted for 17% and 18% of the variability in IMT in the CCA and ICA, respectively. These same risk factors accounted for 25% of the variability of a composite measurement consisting of the sum of the ICA IMT and CCA IMT. The ability to predict CHD and ASD was greater for ICA IMT (odds ratio [confidence interval]: 1.36 [1.31 to 1.41] and 1.35 [1.25 to 1.44], respectively) than for CCA IMT (1.09 [1.05 to 1.13] and 1.17 [1.09 to 1.25]).
CONCLUSIONS: Whereas CCA IMT is associated with major risk factors for atherosclerosis and existing CHD and ASD in older adults, this association is not as strong as that for ICA IMT. The combination of these measures relates more strongly to existing CHD and ASD and cerebrovascular disease risk factors than either taken alone.
10aAdult10aAged10aArteriosclerosis10aBlood Pressure10aCarotid Artery, Common10aCarotid Artery, Internal10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aCoronary Disease10aDiabetes Mellitus10aDiabetic Angiopathies10aElectrocardiography10aFemale10aHumans10aMale10aMedical History Taking10aPhysical Examination10aProspective Studies10aRegression Analysis10aRisk Factors10aSex Characteristics10aSmoking10aTunica Intima10aTunica Media10aUltrasonography1 aO'Leary, D H1 aPolak, J, F1 aKronmal, R, A1 aSavage, P, J1 aBorhani, N O1 aKittner, S, J1 aTracy, R1 aGardin, J M1 aPrice, T, R1 aFurberg, C D uhttps://chs-nhlbi.org/node/145303061nas a2200433 4500008004100000022001400041245014300055210006900198260001300267300001200280490000700292520182800299653003202127653000902159653002202168653002802190653001002218653002902228653001402257653001902271653002802290653001402318653001102332653002502343653001102368653003102379653000902410653001702419100001802436700002002454700001502474700001702489700001502506700001702521700002102538700001502559700001702574856003602591 1997 eng d a0002-861400aThe association of antihypertensive agents with MRI white matter findings and with Modified Mini-Mental State Examination in older adults.0 aassociation of antihypertensive agents with MRI white matter fin c1997 Dec a1423-330 v453 aOBJECTIVES: To examine the association of antihypertensive regimen with magnetic resonance imaging (MRI) white matter hyperintensity and with cognitive impairment in older adults.
DESIGN: Cross-sectional study.
SETTING: The Cardiovascular Health study, an observational prospective cohort study of risk factors for coronary heart disease and stroke in men and women 65 years of age and older.
PARTICIPANTS: 1268 men and women with pharmacologically treated hypertension.
MEASUREMENTS: Information on medication use, medical history, and health habits was collected at clinic examinations. Participants completed the Modified Mini-Mental State Examination (3MS) and underwent MRI examination. Without clinical information, study neuroradiologists assigned an overall grade of white matter signal intensity on MRI on a scale from 0 (no findings) to 9 (extensive findings).
RESULTS: Adjusted mean white matter grade was higher for users of calcium channel blockers (2.59, P = .007) and users of loop diuretics (2.60, P = .015) than for users of beta blockers (2.12). The association was present for both dihydropyridine and non-dihydropyridine calcium channel blockers. Adjusted mean 3MS scores were lower for users of calcium channel blockers (89.6, P < .002), especially dihydropyridines, and users of loop diuretics (89.7, P < .006) than for users of beta blockers (92.3). No statistically significant association could be shown for users of other drug regimens, including thiazides and ACE inhibitors.
CONCLUSION: In this study, users of antihypertensive regimens which included calcium channel blockers or loop diuretics had more severe white matter hyperintensity on MRI and worse performance on 3MS than users of beta blockers.
10aAdrenergic beta-Antagonists10aAged10aAged, 80 and over10aAntihypertensive Agents10aBrain10aCalcium Channel Blockers10aCognition10aCohort Studies10aCross-Sectional Studies10aDiuretics10aFemale10aGeriatric Assessment10aHumans10aMagnetic Resonance Imaging10aMale10aRisk Factors1 aHeckbert, S R1 aLongstreth, W T1 aPsaty, B M1 aMurros, K, E1 aSmith, N L1 aNewman, A, B1 aWilliamson, J, D1 aBernick, C1 aFurberg, C D uhttps://chs-nhlbi.org/node/149102719nas a2200301 4500008004100000022001400041245009800055210006900153260001300222300001200235490000700247520191200254653000902166653002802175653001902203653001502222653001102237653001102248653000902259100001502268700001502283700001802298700001902316700001602335700001602351700001402367856003602381 1997 eng d a0895-706100aThe association of antihypertensive medication with serum creatinine changes in older adults.0 aassociation of antihypertensive medication with serum creatinine c1997 Dec a1368-770 v103 aMany of the potential effects of antihypertensive therapy, including renal function, have been inadequately investigated in clinical trials in older adults. In an observational study, we examined the association between treatment with various classes of antihypertensive agents and 3-year changes in serum creatinine in 1296 older adults with treated hypertension and without prior renal disease (mean age 72.2 years; 60% female; 30% diabetic; 42% with cardiovascular disease (CVD)) from the Cardiovascular Health Study. Baseline antihypertensive medications included thiazides (HCT), beta-adrenergic blockers, angiotensin converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), vasodilators (VAS), HCT + BB, HCT + ACE-I, HCT + CCB, HCT + VAS, loop diuretics (LOOP), and other combinations. Unadjusted results indicated that minimal changes in mean serum creatinine occurred over time for all therapies and only a few changes were statistically significant (HCT: +0.02 mg/dL, ACE-I: +0.04, CCB: +0.04; all P < .05; LOOP: +0.06 mg/dL; P < .001). In multivariate analyses with HCT users as the reference group and adjusting for baseline serum creatinine, age, sex, smoking, diabetes mellitus, CVD, height, weight, common carotid intima-media thickness, and use of allopurinol, phenytoin, cimetidine, and nonsteroidal antiinflammatory drugs, all of the relative changes were small and statistically nonsignificant except for HCT + VAS users (+0.07 mg/dL; P < .05). When users of the same therapy at baseline and follow-up were restricted, only LOOP users had significant albeit small changes in serum creatinine (+0.05 mg/dL; P < .05). Although results from clinical trials are needed to confirm these findings, these observational data suggest no major differences between specific antihypertensive therapies in 3-year serum creatinine changes in older adults without prior renal disease.
10aAged10aAntihypertensive Agents10aCohort Studies10aCreatinine10aFemale10aHumans10aMale1 aSmith, N L1 aPsaty, B M1 aHeckbert, S R1 aLemaitre, R, N1 aKates, D, M1 aRutan, G, H1 aBleyer, A uhttps://chs-nhlbi.org/node/149302375nas a2200337 4500008004100000022001400041245012700055210006900182260001300251300000900264490000800273520142100281653000901702653002201711653001001733653001901743653002801762653001901790653001101809653001101820653002501831653003101856653000901887100001401896700002001910700001701930700001901947700001701966700001801983856003602001 1997 eng d a0033-841900aClinically serious abnormalities found incidentally at MR imaging of the brain: data from the Cardiovascular Health Study.0 aClinically serious abnormalities found incidentally at MR imagin c1997 Jan a41-60 v2023 aPURPOSE: To determine the prevalence of clinically serious findings unrelated to stroke on cranial magnetic resonance (MR) images in a population of community-dwelling elderly people.
MATERIALS AND METHODS: Neuroradiologists reviewed MR images of 3,672 people aged 65 years and older who were enrolled in a longitudinal, population-based study of cardiovascular and cerebrovascular disease. The neuroradiologists alerted MR imaging field centers about potentially serious abnormalities. Clinical information was obtained from clinical examinations performed before MR imaging, hospital discharge summaries, and the field centers at which MR imaging was performed.
RESULTS: On 3,672 image sets, 64 (1.74%) clinically serious abnormalities were found. Among the presumptive diagnoses were 19 meningiomas (0.52%), six pituitary adenomas (0.16%), five cavernous malformations (0.14%), eight vascular stenoses (0.22%), four aneurysms (0.11%), two intraventricular masses (0.05%), two subdural fluid collections (0.05%), and two other tumors (0.05%). Only nine participants with these abnormalities required surgery. All but one of the meningiomas were in women, and the prevalence of the tumor decreased with increasing age.
CONCLUSION: Physicians should be alert to the possible presence of clinically serious conditions in otherwise asymptomatic elderly individuals.
10aAged10aAged, 80 and over10aBrain10aBrain Diseases10aCardiovascular Diseases10aCohort Studies10aFemale10aHumans10aLongitudinal Studies10aMagnetic Resonance Imaging10aMale1 aYue, N, C1 aLongstreth, W T1 aElster, A, D1 aJungreis, C, A1 aO'Leary, D H1 aPoirier, V, C uhttps://chs-nhlbi.org/node/147003067nas a2200457 4500008004100000022001400041245007500055210006900130260001600199300001200215490000700227520187100234653001002105653000902115653002402124653001802148653001902166653003002185653001902215653002102234653002402255653001102279653002202290653002102312653001102333653001402344653000902358653002402367653001702391653001802408100001502426700001702441700001602458700001802474700001502492700001502507700001302522700001702535700002102552856003602573 1997 eng d a0009-732200aIncidence of and risk factors for atrial fibrillation in older adults.0 aIncidence of and risk factors for atrial fibrillation in older a c1997 Oct 07 a2455-610 v963 aBACKGROUND: This study aimed to describe the incidence of atrial fibrillation (AF) among older adults during 3 years of follow-up.
METHODS AND RESULTS: In this cohort study, 5201 adults > or = 65 years old were examined annually on four occasions between June 1989 and May 1993. At baseline, participants answered questionnaires and underwent a detailed examination that included carotid ultrasound, pulmonary function tests, ECG, and echocardiography. Subjects with a pacemaker or AF at baseline (n=357) were excluded. New cases of AF were identified from three sources: (1) annual self-reports, (2) annual ECGs, and (3) hospital discharge diagnoses. Cox proportional-hazards models were used to assess baseline risk factors as predictors of incident AF. Among 4844 participants, 304 developed a first episode of AF during an average follow-up of 3.28 years, for an incidence of 19.2 per 1000 person-years. The onset was strongly associated with age, male sex, and the presence of clinical cardiovascular disease. For men 65 to 74 and 75 to 84 years old, the incidences were 17.6 and 42.7, respectively, and for women, 10.1 and 21.6 events per 1000 person-years. In stepwise models, the use of diuretics, a history of valvular heart disease, coronary disease, advancing age, higher levels of systolic blood pressure, height, glucose, and left atrial size were all associated with an increased risk of AF. The use of beta-blockers and high levels of alcohol use, cholesterol, and forced expiratory volume in 1 second were associated with a reduced risk of AF.
CONCLUSIONS: The incidence of AF in older adults may be higher than estimated by previous population studies. Left atrial size appears to be an important risk factor, and the control of blood pressure and glucose may be important in preventing the development of AF.
10aAdult10aAged10aAtrial Fibrillation10aBlood Glucose10aBlood Pressure10aCerebrovascular Disorders10aCohort Studies10aCoronary Disease10aElectrocardiography10aFemale10aFollow-Up Studies10aHospital Records10aHumans10aIncidence10aMale10aProspective Studies10aRisk Factors10aUnited States1 aPsaty, B M1 aManolio, T A1 aKuller, L H1 aKronmal, R, A1 aCushman, M1 aFried, L P1 aWhite, R1 aFurberg, C D1 aRautaharju, P, M uhttps://chs-nhlbi.org/node/148802876nas a2200361 4500008004100000022001400041245015100055210006900206260001300275300001000288490000800298520184500306653000902151653001002160653002802170653002402198653001902222653001102241653001102252653002502263653003102288653000902319653001502328100001602343700001602359700001702375700001702392700001902409700001802428700001502446700001702461856003602478 1997 eng d a0033-841900aInfarctlike lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly--data from the Cardiovascular Health Study.0 aInfarctlike lesions in the brain prevalence and anatomic charact c1997 Jan a47-540 v2023 aPURPOSE: To determine the prevalence and anatomic characteristics of infarctlike lesions seen on cranial magnetic resonance (MR) images.
MATERIALS AND METHODS: The study cohort consisted of 5,888 community-living individuals aged 65 years and older enrolled in a longitudinal, population-based study of cardiovascular disease. MR images were obtained from 3,658 participants and evaluated by trained readers. Lesion size, anatomic location, and signal intensity were recorded. Infarctlike lesion was defined as a nonmass, hyperintense region on spin-density- and T2-weighted images and, in cerebral white matter and brain stem, a hypointense region on T1-weighted images.
RESULTS: Infarctlike lesions were depicted on MR images of 1,323 (36%) participants. Eighty-five percent (1,128 participants) had lesions 3 mm or larger in maximum dimension, although 70.9% (1,320 of 1,861) of these lesions were 10 mm or less. Lesion prevalence increased with age, especially with lesions 3 mm or larger, which increased from 22.1% (86 of 389) in the 65-69-year age group to 42.9% (88 of 205) in the over-85-year age group (P < .0001). Lesion prevalence was slightly greater in men (497 of 1,527 [32.5%]) than in women (631 of 2,131 [29.6%]), but did not differ between blacks and non-blacks. The deep nuclei were the most commonly affected anatomic sites, with 78.2% (1,451 of 1,856) of lesions. Lesions that involved the cerebrum and posterior fossa accounted for 11.7% (218 of 1,856) and 10.1% (187 of 1,856) of lesions, respectively.
CONCLUSION: If the lesions reported in this study indicate cerebrovascular disease, subclinical disease may be more prevalent than clinical disease, and the prevalence of disease may rise with age. Also, infarctlike lesions have a distinctive anatomic profile.
10aAged10aBrain10aCardiovascular Diseases10aCerebral Infarction10aCohort Studies10aFemale10aHumans10aLongitudinal Studies10aMagnetic Resonance Imaging10aMale10aPrevalence1 aBryan, R, N1 aWells, S, W1 aMiller, T, J1 aElster, A, D1 aJungreis, C, A1 aPoirier, V, C1 aLind, B, K1 aManolio, T A uhttps://chs-nhlbi.org/node/147103130nas a2200337 4500008004100000022001400041245017000055210006900225260001300294300001200307490000700319520215600326653000902482653002002491653002302511653002802534653001102562653001102573653000902584653002602593653001702619653001202636100001502648700001502663700001202678700001702690700001502707700001802722700001602740856003602756 1997 eng d a1079-564200aLifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects.0 aLifetime smoking exposure affects the association of Creactive p c1997 Oct a2167-760 v173 aBlood levels of C-reactive protein (CRP), a marker of inflammation, are related to cardiovascular disease risk. To determine cross-sectional correlates in the elderly, we measured CRP in 400 men and women older than 65 years and free of clinical cardiovascular disease at baseline as part of the Cardiovascular Health Study. Only 2% of the values were greater than 10 mg/L, the cut-point usually used to identify inflammation. CRP levels appeared tightly regulated, since there were strong bivariate correlations between CRP and the following: inflammation-sensitive proteins such as fibrinogen (r = .52); measures of fibrinolysis such as plasmin-antiplasmin complex (r = .23); pack-years of smoking (r = .30); and body mass index (r = .24; all P values < or = .001). The association with pack-years was independent of the length of time since cessation of smoking. CRP levels were also associated with coagulation factors VIIc, IXc, and Xc; HDL cholesterol (negative) and triglyceride; diabetes status; diuretic use; ECG abnormalities; and level of exercise. Because of effect modification, two multiple linear regression prediction models were developed for CRP, one each for never smokers and ever smokers. An a priori physiologic model was used to guide these analyses, which disallowed the use of other inflammation-sensitive variables such as fibrinogen. In never smokers, the independent predictors were body mass index (+), diabetes status (+), plasmin-antiplasmin complex (+), and the presence of ECG abnormalities (+); this model predicted 15% of the CRP population variance. In ever smokers, the predictors were body mass index (+), plasmin-antiplasmin complex (+), pack-years of smoking (+), HDL cholesterol (-), and ankle-arm blood pressure index (-); this model predicted 42% of the population variance. We conclude that levels of CRP in the healthy elderly are tightly regulated and reflect lifetime exposure to smoking as well as level of obesity, ongoing level of fibrinolysis, diabetes status, and level of subclinical atherothrombotic disease. Moreover, exposure to smoking affects the relation of CRP to these other factors.
10aAged10aBody Mass Index10aC-Reactive Protein10aCardiovascular Diseases10aFemale10aHumans10aMale10aMultivariate Analysis10aRisk Factors10aSmoking1 aTracy, R P1 aPsaty, B M1 aMacy, E1 aBovill, E, G1 aCushman, M1 aCornell, E, S1 aKuller, L H uhttps://chs-nhlbi.org/node/149002957nas a2200349 4500008004100000022001400041245017400055210006900229260001300298300001100311490000700322520194700329653000902276653001002285653002302295653002802318653002502346653001102371653001102382653000902393653002402402653001602426100001502442700001902457700001502476700001502491700001602506700001502522700001802537700001602555856003602571 1997 eng d a1079-564200aRelationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project.0 aRelationship of Creactive protein to risk of cardiovascular dise c1997 Jun a1121-70 v173 aMarkers of inflammation, such as C-reactive protein (CRP), are related to risk of cardiovascular disease (CVD) events in those with angina, but little is known about individuals without prevalent clinical CVD. We performed a prospective, nested case-control study in the Cardiovascular Health Study (CHS; 5201 healthy elderly men and women). Case subjects (n = 146 men and women with incident CVD events including angina, myocardial infarction, and death) and control subjects (n = 146) were matched on the basis of sex and the presence or absence of significant subclinical CVD at baseline (average follow-up, 2.4 years). In women but not men, the mean CRP level was higher for case subjects than for control subjects (P < or = .05). In general, CRP was higher in those with subclinical disease. Most of the association of CRP with female case subjects versus control subjects was in the subgroup with subclinical disease; 3.33 versus 1.90 mg/L, P < .05, adjusted for age and time of follow-up. Case-control differences were greatest when the time between baseline and the CVD event was shortest. The strongest associations were with myocardial infarction, and there was an overall odds ratio for incident myocardial infarction for men and women with subclinical disease (upper quartile versus lower three quartiles) of 2.67 (confidence interval [CI] = 1.04 to 6.81), with the relationship being stronger in women (4.50 [CI = 0.97 to 20.8]) than in men (1.75 [CI = 0.51 to 5.98]). We performed a similar study in the Rural Health Promotion Project, in which mean values of CRP were higher for female case subjects than for female control subjects, but no differences were apparent for men. Comparing the upper quintile with the lower four, the odds ratio for CVD case subjects was 2.7 (CI = 1.10 to 6.60). In conclusion, CRP was associated with incident events in the elderly, especially in those with subclinical disease at baseline.
10aAged10aAging10aC-Reactive Protein10aCardiovascular Diseases10aCase-Control Studies10aFemale10aHumans10aMale10aProspective Studies10aSex Factors1 aTracy, R P1 aLemaitre, R, N1 aPsaty, B M1 aIves, D, G1 aEvans, R, W1 aCushman, M1 aMeilahn, E, N1 aKuller, L H uhttps://chs-nhlbi.org/node/148402781nas a2200337 4500008004100000022001400041245019200055210006900247260001300316300001200329490000700341520176600348653000902114653002202123653002402145653001402169653001102183653001102194653003102205653000902236653002702245100001602272700001702288700001802305700001802323700001402341700001502355700002002370700001702390856003602407 1997 eng d a0039-249900aSilent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group.0 aSilent brain infarction on magnetic resonance imaging and neurol c1997 Jun a1158-640 v283 aBACKGROUND AND PURPOSE: Infarctlike lesions are frequently detected in symptomatic and asymptomatic older persons undergoing cerebral MRI, but their significance in older adults has not been examined. We determined the prevalence of MRI infarcts in a population-based sample of men and women aged > or = 65 years and related these findings to demographic, cognitive, and neurological status.
METHODS: MRI scanning was performed in 3660 Cardiovascular Health Study (CHS) participants after brief neurological examinations and tests of cognitive function. MRIs were read centrally for the presence of an infarct > or = 3 mm in diameter or smaller infarctlike lesions.
RESULTS: MRI infarcts were detected in 1131 of 3647 participants with readable infarct information (31%) and in 961 of the subgroup of 3397 participants (28%) without known prior stroke ("silent" MRI infarcts). Smaller infarctlike lesions were found in 196 of 2516 participants who had no MRI infarcts > or = 3 mm. MRI infarcts were more common in participants who were older, had prior stroke, impaired cognition, visual field deficits, slowed repetitive finger tapping (all P < .0001), weakness on toe and heel walking, and history of memory loss, coma, or migraine headaches. Multivariate analysis in those without prior stroke showed strong associations of silent MRI infarcts with older age, history of migraines, lower digit symbol scores, and more abnormalities on neurological examination.
CONCLUSIONS: MRI evidence of brain infarction is common in older men and women without a clinical history of stroke. Their strong associations with impaired cognition and neurological deficits suggest that they are neither silent nor innocuous.
10aAged10aAged, 80 and over10aCerebral Infarction10aCognition10aFemale10aHumans10aMagnetic Resonance Imaging10aMale10aNeurologic Examination1 aPrice, T, R1 aManolio, T A1 aKronmal, R, A1 aKittner, S, J1 aYue, N, C1 aRobbins, J1 aAnton-Culver, H1 aO'Leary, D H uhttps://chs-nhlbi.org/node/148302375nas a2200409 4500008004100000022001400041245012700055210006900182260001300251300000900264490000800273520122000281653000901501653002201510653001001532653001001542653002801552653002401580653001901604653003401623653001101657653001101668653002501679653003101704653000901735653003101744653001601775100001401791700001701805700002001822700001701842700001901859700001701878700001801895700001601913856003601929 1997 eng d a0033-841900aSulcal, ventricular, and white matter changes at MR imaging in the aging brain: data from the cardiovascular health study.0 aSulcal ventricular and white matter changes at MR imaging in the c1997 Jan a33-90 v2023 aPURPOSE: To determine the distribution of changes in sulcal size, ventricular size, and white matter signal intensity depicted on cranial magnetic resonance (MR) images, with stratification according to age, race, and sex.
MATERIALS AND METHODS: Ventricular size, sulcal size, and white matter signal intensity changes were graded on cranial MR images of 3,660 community-living, elderly participants in the Cardiovascular Health Study. A healthier subgroup was also defined. Summary statistics for both groups were generated for age, race, and sex.
RESULTS: Regression models of the entire imaged cohort showed higher grades of all variables with increasing age, and higher ventricular and sulcal grades in men and in nonblack individuals. White matter grade was greater in women and in black individuals. Regression models of the healthier subgroup showed similar associations, except for a lack of association of sulcal and ventricular size with race.
CONCLUSION: Sulcal width, ventricular size, and white matter signal intensity change with age, sex, and race. Knowledge of these changes is important in appropriate interpretation of MR images of the elderly.
10aAged10aAged, 80 and over10aAging10aBrain10aCardiovascular Diseases10aCerebral Ventricles10aCohort Studies10aContinental Population Groups10aFemale10aHumans10aLongitudinal Studies10aMagnetic Resonance Imaging10aMale10aReproducibility of Results10aSex Factors1 aYue, N, C1 aArnold, A, M1 aLongstreth, W T1 aElster, A, D1 aJungreis, C, A1 aO'Leary, D H1 aPoirier, V, C1 aBryan, R, N uhttps://chs-nhlbi.org/node/146902708nas a2200361 4500008004100000022001400041245015500055210006900210260001300279300001100292490000700303520165900310653000901969653002401978653002902002653002102031653003002052653001902082653001102101653001102112653000902123653001502132653001702147653001202164653002902176100002002205700001702225700001702242700001702259700001602276700001802292856003602310 1998 eng d a0039-249900aAsymptomatic internal carotid artery stenosis defined by ultrasound and the risk of subsequent stroke in the elderly. The Cardiovascular Health Study.0 aAsymptomatic internal carotid artery stenosis defined by ultraso c1998 Nov a2371-60 v293 aBACKGROUND AND PURPOSE: We sought in this study to relate carotid ultrasound findings in asymptomatic older adults to the 5-year risk of various cerebrovascular outcomes used in the Asymptomatic Carotid Atherosclerosis Study (ACAS).
METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years and older. Analyses of internal carotid artery stenosis defined by multiple different cutoffs of peak systolic velocity, rather than one particular cutoff, were performed in the 5441 participants who underwent carotid ultrasound and lacked a history of transient ischemic attack or stroke. The 5-year risks of 7 cerebrovascular disease outcomes used in ACAS were estimated for each cutoff.
RESULTS: Associations with the 5-year risk of outcomes were substantially elevated only at cutoffs with high peak systolic velocities. In this population, the number of people with such high velocities was small. For example, with a cutoff of approximately 2.5 m/s, suggesting a stenosis of >70%, the 5-year risk of an ipsilateral fatal or nonfatal stroke was 5%, and only 0.5% of the group had velocities at least this high.
CONCLUSIONS: In a group of older adults likely to participate in a screening program, as evidenced by willingness to participate in CHS, high peak systolic velocities consistent with high-grade carotid stenosis were uncommon and risk of subsequent cerebrovascular disease outcomes was relatively low. These findings do not suggest that similar populations of older adults would benefit from a program using ultrasound to screen for asymptomatic carotid stenosis.
10aAged10aBlood Flow Velocity10aCarotid Artery, Internal10aCarotid Stenosis10aCerebrovascular Disorders10aCohort Studies10aFemale10aHumans10aMale10aPrevalence10aRisk Factors10aSystole10aUltrasonography, Doppler1 aLongstreth, W T1 aShemanski, L1 aLefkowitz, D1 aO'Leary, D H1 aPolak, J, F1 aWolfson, S, K uhttps://chs-nhlbi.org/node/151703016nas a2200325 4500008004100000022001400041245006000055210005600115260001700171300001200188490000700200520212400207653001002331653001802341653002402359653002302383653001102406653004002417653003102457653002702488100001902515700002002534700001502554700001702569700001402586700002102600700001702621700001602638856003602654 1998 eng d a0195-610800aA brain image database for structure/function analysis.0 abrain image database for structurefunction analysis c1998 Nov-Dec a1869-770 v193 aBACKGROUND AND PURPOSE: Lesion-deficit-based structure-function analysis has traditionally been empirical and nonquantitative. Our purpose was to establish a new brain image database (BRAID) that allows the statistical correlation of brain functional measures with anatomic lesions revealed by clinical brain images.
METHODS: Data on 303 participants in the MR Feasibility Study of the Cardiovascular Health Study were tested for lesion/deficit correlations. Functional data were derived from a limited neurologic examination performed at the time of the MR examination. Image data included 3D lesion descriptions derived from the MR examinations by hand segmentation. MR images were normalized in-plane using local, linear Talairach normalization. A database was implemented to support spatial data structures and associated geometric and statistical operations. The database stored the segmented lesions, patient functional scores, and several anatomic atlases. Lesion-deficit association was sought by contingency testing (chi2-test) for every possible combination of each neurologic variable and each labeled atlas structure. Significant associations that confirmed accepted lesion-deficit relationships were sought.
RESULTS: Two-hundred thirty-five infarctlike lesions in 117 subjects were viewed collectively after mapping into Talairach cartesian coordinates. Anatomic structures most strongly correlated with neurologic deficits tended to be situated in anatomically appropriate areas. For example, infarctlike lesions associated with visual field defects were correlated with structures in contralateral occipital structures, including the optic radiations and occipital gyri.
CONCLUSION: Known lesion-deficit correlations can be established by a database using a standard coordinate system for representing spatial data and incorporating functional and structural data together with appropriate query mechanisms. Improvements and further applications of this methodology may provide a powerful technique for uncovering new structure-function relationships.
10aBrain10aBrain Mapping10aCerebral Infarction10aDatabases as Topic10aHumans10aImage Processing, Computer-Assisted10aMagnetic Resonance Imaging10aNeurologic Examination1 aLetovsky, S, I1 aWhitehead, S, H1 aPaik, C, H1 aMiller, G, A1 aGerber, J1 aHerskovits, E, H1 aFulton, T, K1 aBryan, R, N uhttps://chs-nhlbi.org/node/151903022nas a2200337 4500008004100000022001400041245008300055210006900138260001300207300001100220490000700231520210300238653000902341653002202350653002002372653002802392653002102420653001102441653001102452653000902463653003502472653002602507100001802533700001402551700001502565700001702580700001802597700001802615700001502633856003602648 1998 eng d a0884-873400aCorrelates and prevalence of benzodiazepine use in community-dwelling elderly.0 aCorrelates and prevalence of benzodiazepine use in communitydwel c1998 Apr a243-500 v133 aOBJECTIVE: To describe the prevalence of benzodiazepine use, sociodemographic and physical health factors associated with use, dosages taken, and directions for use among individuals aged 65 years and older.
DESIGN: Cross-sectional analysis of baseline data from the community-based, prospective observational Cardiovascular Health Study.
PATIENTS/PARTICIPANTS: Medicare eligibility lists from four U.S. communities were used to recruit a representative sample of 5,201 community-dwelling elderly, of which 5,181 participants met all study criteria.
MEASUREMENTS AND MAIN RESULTS: Among participants, 511 (9.9%) were taking at least one benzodiazepine, primarily anxiolytics (73%). Benzodiazepines were often prescribed to be taken pro re nata (PRN "as needed"), and 36.5% of prescriptions with instructions to be taken regularly were taken at a dose lower than prescribed. Reported over-the-counter (OTC) sleep aid medication use was 39.2% in benzodiazepine users and 3.3% in nonusers. In a multivariate logistic model, the significant independent correlates of benzodiazepine use were being white (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.0, 3.4), female (OR 1.7; CI 1.4, 2.2), and living in Forsyth County, North Carolina, or Washington County, Maryland, compared with living in Sacramento County, California, or Allegheny County, Pennsylvania (OR 2.3; CI 1.4, 2.2); having coronary heart disease (OR 1.6; CI 1.2, 2.1), health status reported as poor or fair (OR 1.8; CI 1.4, 2.3), self-reported diagnosis of nervous or emotional disorder (OR 6.7; CI 5.1, 8.7), and reporting use of an OTC sleep aid medication (OR 18.7; CI 14.1, 24.7).
CONCLUSIONS: One in 10 participants reported taking a benzodiazepine, most frequently an anxiolytic, often at a lower dose than prescribed and usually PRN. The high prevalence of OTC sleep aid medication and benzodiazepine use may place the patient at increased risk of psychomotor impairment. Physicians should assess OTC sleep aid medication use when prescribing benzodiazepines.
10aAged10aAged, 80 and over10aBenzodiazepines10aCross-Sectional Studies10aDrug Utilization10aFemale10aHumans10aMale10aPractice Patterns, Physicians'10aSocioeconomic Factors1 aGleason, P, P1 aSchulz, R1 aSmith, N L1 aNewsom, J, T1 aKroboth, P, D1 aKroboth, F, J1 aPsaty, B M uhttps://chs-nhlbi.org/node/150302969nas a2200457 4500008004100000022001400041245009200055210006900147260001300216300001000229490000700239520177600246653000902022653002202031653002502053653001902078653002102097653001502118653002802133653002702161653001102188653001102199653001702210653000902227653001502236653001402251653001402265653002102279653001702300653001502317100001902332700001502351700001502366700001602381700001602397700002002413700001502433700001202448700001502460856003602475 1998 eng d a0340-624500aCorrelates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.0 aCorrelates of antithrombin protein C protein S and TFPI in a hea c1998 Jul a134-90 v803 aThe majority of fatal acute myocardial infarctions occur in the elderly. Since these events are predominantly thrombotic, we studied the cross-sectional associations of the anticoagulant proteins Antithrombin, Protein C, Protein S. and Tissue Factor Pathway Inhibitor (TFPI) in a subgroup (n = 400) of the Cardiovascular Health Study (a study of healthy men and women > or = 65 years) free of clinical cardiovascular disease (CVD). We did not observe any strong age-associated trends, although Protein C was lower in older women (p < or = 0.001), and TFPI was higher in older men (p < or = 0.01). The inhibitors were highly intercorrelated, and were associated with increased levels of inflammation-sensitive proteins (e.g., fibrinogen. plasminogen), lipids (especially total and LDL-cholesterol), and coagulation factors, such as Factors VIIc, IXc, and Xc. None was associated with the procoagulant markers Prothrombin Fragment F1-2 or Fibrinopeptide A. Only TFPI was associated with subclinical atherosclerosis: ankle-arm index and internal carotid artery stenosis, p trend < or = 0.01; and carotid wall thickness, p trend < or = 0.05. In multivariate analysis the independent predictors of TFPI were levels of fibrinogen; the fibrinolytic marker plasmin-antiplasmin complex; LDL-cholesterol; and carotid wall thickness (R2 for the model = 0.35). In summary, the inhibitors did not appear to increase with age, and were predominantly associated with inflammation markers and lipids. Since markers of thrombin production do increase with age, we hypothesize that an age-related hemostatic imbalance may ensue, with associated increased thrombotic risk. Only TFPI was associated with subclinical CVD, suggesting that it may more closely reflect endothelial damage.
10aAged10aAged, 80 and over10aAnalysis of Variance10aAnticoagulants10aAntithrombin III10aBiomarkers10aCross-Sectional Studies10aDisease Susceptibility10aFemale10aHumans10aLipoproteins10aMale10aPrevalence10aProtein C10aProtein S10aReference Values10aRisk Factors10aThrombosis1 aSakkinen, P, A1 aCushman, M1 aPsaty, B M1 aKuller, L H1 aBajaj, S, P1 aSabharwal, A, K1 aBoineau, R1 aMacy, E1 aTracy, R P uhttps://chs-nhlbi.org/node/157002980nas a2200349 4500008004100000022001400041245014500055210006900200260001600269300001100285490000800296520197300304653002202277653000902299653002202308653001902330653002202349653001102371653002702382653001102409653000902420653001502429653002302444653003002467100001402497700001702511700001502528700001802543700001802561700001502579856003602594 1998 eng d a0140-673600aDiabetes in older adults: comparison of 1997 American Diabetes Association classification of diabetes mellitus with 1985 WHO classification.0 aDiabetes in older adults comparison of 1997 American Diabetes As c1998 Sep 26 a1012-50 v3523 aBACKGROUND: We aimed to compare the prevalence of abnormal glucose tolerance identified by the 1985 WHO and the 1997 American Diabetes Association (ADA) diagnostic categories based on information collected in the Cardiovascular Health Study, an epidemiological study of elderly people.
METHODS: We measured glucose concentrations during fasting and 2 h after a 75 g oral glucose-tolerance test in participants aged 65-100 years in the Cardiovascular Health Study. From a 1989 cohort, we analysed the glucose measurements of 4515 individuals without a previous diagnosis of diabetes and of 262 additional measurements from an African-American cohort recruited in 1992-93.
FINDINGS: In the 1989 cohort, the prevalence of untreated diabetes with ADA diagnostic fasting criteria was 7.7% versus a prevalence of 14.8% by the WHO criteria. In the African-American cohort, the prevalence of untreated diabetes was 2.7% with ADA criteria and 11.8% with WHO criteria. 3509 (77.7%) of the 4515 participants in the 1989 cohort had normal glucose concentrations according to ADA fasting criteria, compared with 2401 (53.2%) according to WHO criteria. In the African-American cohort, the corresponding numbers were 239 (91.2%) versus 153 (58.4%). All differences in prevalence of abnormal glucose tolerance between ADA and WHO classifications were significant (p<0.0001).
INTERPRETATION: Among elderly individuals, there was a significant difference in the prevalence of diabetes identified by the WHO diagnostic criteria based on oral glucose-tolerance test and the ADA fasting criteria. Consequently, many individuals currently classified as non-diabetic according to ADA criteria would previously have had a diagnosis of diabetes according to WHO criteria. Longitudinal studies are needed to assess the value of the criteria in the identification of individuals at increased risk of diabetes-associated chronic complications.
10aAfrican Americans10aAged10aAged, 80 and over10aCohort Studies10aDiabetes Mellitus10aFemale10aGlucose Tolerance Test10aHumans10aMale10aPrevalence10aSocieties, Medical10aWorld Health Organization1 aWahl, P W1 aSavage, P, J1 aPsaty, B M1 aOrchard, T, J1 aRobbins, J, A1 aTracy, R P uhttps://chs-nhlbi.org/node/151501777nas a2200361 4500008004100000022001400041245013300055210006900188260001300257300001000270490000700280520082700287653001001114653001601124653000901140653001301149653001301162653001101175653001101186653000901197653001601206653001301222653001701235653001501252100001501267700002001282700001501302700001501317700001601332700001601348700001501364856003601379 1998 eng d a0340-624500aFactor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study.0 aFactor V Leiden is not a risk factor for arterial vascular disea c1998 May a912-50 v793 aCoagulation factor V Leiden is a risk marker for venous thrombosis. For arterial thrombosis no large study to date has included population-based elderly patients. The Cardiovascular Health Study is a longitudinal study of 5,201 men and women over age 65. With 3.4-year follow-up, we studied 373 incident cases of myocardial infarction (MI), angina, stroke. or transient ischemic attack (TIA), and 482 controls. The odds ratios for each event with heterozygous factor V Leiden were: MI, 0.46 (95% CI 0.17 to 1.25); angina, 1.0 (95% CI 0.45 to 2.23); stroke, 0.77 (95% CI 0.35 to 1.70): TIA, 1.33 (95% CI 0.5 to 3.55); any outcome, 0.83 (95% CI 0.48 to 1.44). Adjustment for cardiovascular risk factors did not change relationships. In older adults factor V Leiden is not a risk factor for future arterial thrombosis.
10aAdult10aAge Factors10aAged10aArteries10aFactor V10aFemale10aHumans10aMale10aMiddle Aged10aMutation10aRisk Factors10aThrombosis1 aCushman, M1 aRosendaal, F, R1 aPsaty, B M1 aCook, E, F1 aValliere, J1 aKuller, L H1 aTracy, R P uhttps://chs-nhlbi.org/node/150801825nas a2200217 4500008004100000022001400041245010300055210006900158260001300227300001000240490000600250520119600256100002001452700001401472700001701486700001901503700001701522700001901539700001401558856003501572 1998 eng d a1751-715X00aFactors Associated With Hospital Utilization in the Elderly: From the Cardiovascular Health Study.0 aFactors Associated With Hospital Utilization in the Elderly From c1998 May a27-350 v73 aOBJECTIVE: Analyze clinical, accepted biochemical, physiologic, and socioeconomic risk factors and correlate them with hospital utilization in an elderly population. DESIGN: Prospective, observational study in a defined, randomly recruited population. PARTICIPANTS: 5201 Medicare participants enrolled in the Cardiovascular Health Study (CHS). METHODS: Medicare recipients were randomly assigned to participate in an observational study. Baseline data were compared to hospital admissions and days of hospitalization over four years. DATA ANALYSIS: Data were grouped by type of risk factor and analyzed by Tobit analysis and logistic regression. RESULTS: Baseline variables associated with hospital use (p is less than 0.0001) were history of CHF, stroke, angina, hypertension, ln (timed walk), ln (blocks walked/week), age, gender, and clinic site. Factors not entering the model (p is greater than 0.05) were income, education, smoking, diabetes, weight, dietary fat, marital status, depression, and measures of mental function. CONCLUSIONS: In the elderly, existing health status is the major determinant of hospitalization and overwhelms many classic "risk factors" for morbidity.
1 aRobbins, J., A.1 aYanez, D.1 aPowe, N., R.1 aSavage, P., J.1 aIves, D., G.1 aGardin, J., M.1 aLyles, M. uhttps://chs-nhlbi.org/node/65002829nas a2200397 4500008004100000022001400041245016100055210006900216260001300285300001100298490000800309520163400317653000901951653002201960653002901982653002102011653003002032653001902062653001102081653001102092653003402103653000902137653003202146653000902178653003702187653004302224100001602267700001702283700001702300700001702317700001602334700001702350700001602367700001202383856003602395 1998 eng d a0033-841900aHypoechoic plaque at US of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study.0 aHypoechoic plaque at US of the carotid artery an independent ris c1998 Sep a649-540 v2083 aPURPOSE: To investigate the association between incident (first) stroke and the echogenicity of internal carotid arterial plaque at ultrasonography (US).
MATERIALS AND METHODS: A cohort of 4, 886 individuals who, at baseline, were 65 years of age or older and without symptoms of cerebrovascular disease was followed up for an average of 3.3 years. Baseline clinical findings were from color Doppler and duplex US studies of the carotid arteries and a record of traditional risk factors: age, sex, presence of diabetes mellitus, pack-years of cigarette smoking, presence of hypertension, elevated systolic and diastolic blood pressure, elevated low-density lipoprotein cholesterol level.
RESULTS: Incident strokes, excluding hemorrhagic strokes and strokes of cardiac origin, were seen in 104 individuals (2.1%) at risk. Age- and sex-adjusted odds ratios for incident stroke were significant for hypoechoic plaque (odds ratio, 2.53; 95% CI, 1,42,4.53). After controlling for risk factors in a Cox proportional hazards model, the relative risk (RR) of incident stroke was 1.72 (p = .015) for hypoechoic plaque and 2.32 (P = .004) for internal carotid arterial narrowing of at least 50%. In addition, hypoechoic plaque (RR, 2.78; CI, 1.36,5.69) and 50%-100% stenosis (RR, 3.08; CI, 1.28, 7.41) were associated with ipsilateral, nonfatal stroke.
CONCLUSION: In asymptomatic adults aged 65 years or older, that risk of incident stroke was associated with two US features: hypoechoic internal carotid arterial plaque and an estimated internal carotid arterial stenosis of 50%-100%.
10aAged10aAged, 80 and over10aCarotid Artery, Internal10aCarotid Stenosis10aCerebrovascular Disorders10aCohort Studies10aFemale10aHumans10aIntracranial Arteriosclerosis10aMale10aProportional Hazards Models10aRisk10aUltrasonography, Doppler, Duplex10aUltrasonography, Doppler, Transcranial1 aPolak, J, F1 aShemanski, L1 aO'Leary, D H1 aLefkowitz, D1 aPrice, T, R1 aSavage, P, J1 aBrant, W, E1 aReid, C uhttps://chs-nhlbi.org/node/151102759nas a2200313 4500008004100000022001400041245011600055210006900171260001300240300001200253490000700265520187400272653000902146653002402155653001102179653001102190653002502201653003102226653000902257653002602266653001702292100002002309700001502329700001702344700001302361700001902374700001602393856003602409 1998 eng d a0003-994200aLacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study.0 aLacunar infarcts defined by magnetic resonance imaging of 3660 e c1998 Sep a1217-250 v553 aOBJECTIVE: To identify risk factors for and functional consequences of lacunar infarct in elderly people.
METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years or older, in which 3660 participants underwent cranial magnetic resonance imaging (MRI). Neuroradiologists read scans in a standard fashion without any clinical information. Lacunes were defined as subcortical areas consistent with infarcts measuring 3 to 20 mm. In cross-sectional analyses, clinical correlates were contrasted among groups defined by MRI findings.
RESULTS: Of the 3660 subjects who underwent MRI, 2529 (69%) were free of infarcts of any kind and 841 (23%) had 1 or more lacunes without other types present, totaling 1270 lacunes. For most of these 841 subjects, their lacunes were single (66%) and silent (89%), namely without a history of transient ischemic attack or stroke. In multivariate analyses, factors independently associated with lacunes were increased age, diastolic blood pressure, creatinine, and pack-years of smoking (listed in descending order of strength of association; for all, P < .005), as well as maximum internal carotid artery stenosis of more than 50% (odds ratio [OR], 1.81; P < .005), male sex (OR, 0.74; P < .005), and history of diabetes at entrance into the study (OR, 1.33; P < .05). Models for subgroups of single, multiple, silent, and symptomatic lacunes differed only minimally. Those with silent lacunes had more cognitive, upper extremity, and lower extremity dysfunction not recognized as stroke than those whose MRIs were free of infarcts.
CONCLUSIONS: In this group of older adults, lacunes defined by MRI are common and associated with factors that likely promote or reflect small-vessel disease. Silent lacunes are also associated with neurologic dysfunction.
10aAged10aCerebral Infarction10aFemale10aHumans10aLongitudinal Studies10aMagnetic Resonance Imaging10aMale10aMultivariate Analysis10aRisk Factors1 aLongstreth, W T1 aBernick, C1 aManolio, T A1 aBryan, N1 aJungreis, C, A1 aPrice, T, R uhttps://chs-nhlbi.org/node/151402031nas a2200361 4500008004100000022001400041245006200055210006100117260001300178300001100191490000700202520109800209653000901307653002201316653002601338653001101364653001601375653002101391653001801412653001101430653002001441653001601461653000901477653001601486653003201502653001601534100001301550700001801563700001501581700001601596700002101612856003601633 1998 eng d a0895-435600aPredicting future years of healthy life for older adults.0 aPredicting future years of healthy life for older adults c1998 Apr a343-530 v513 aCost-effectiveness studies often need to compare the cost of a program to the lifetime benefits of the program, but estimates of lifetime benefits are not routinely available, especially for older adults. We used data from two large longitudinal studies of older adults (ages 65-100) to estimate transition probabilities from one health state to another, and used those probabilities to estimate the mean additional years of healthy life that an older adult of specified age, sex, and health status would experience. We found, for example, that 65-year-old women in excellent health can expect 16.8 years of healthy life in the future, compared to only 8.5 years for women in poor health. We also provide estimates of discounted years of healthy life and future life expectancy. These estimates may be used to extend the effective length of the study period in cost-effectiveness studies, to examine the impact of chronic diseases or risk factors on years of healthy life, or to investigate the relationship of years of life to years of healthy life. Several applications are described.
10aAged10aAged, 80 and over10aCost-Benefit Analysis10aFemale10aForecasting10aHealth Promotion10aHealth Status10aHumans10aLife Expectancy10aLife Tables10aMale10aProbability10aQuality-Adjusted Life Years10aSex Factors1 aDiehr, P1 aPatrick, D, L1 aBild, D, E1 aBurke, G, L1 aWilliamson, J, D uhttps://chs-nhlbi.org/node/150003834nas a2200409 4500008004100000022001400041245008800055210006900143260001600212300001100228490000800239520272800247653002202975653000902997653002203006653002803028653001903056653001103075653002203086653001903108653001103127653000903138653001403147653003203161653002403193653001703217653001803234100001503252700001803267700001703285700001503302700002103317700001603338700001803354700001603372856003603388 1998 eng d a0098-748400aRisk factors for 5-year mortality in older adults: the Cardiovascular Health Study.0 aRisk factors for 5year mortality in older adults the Cardiovascu c1998 Feb 25 a585-920 v2793 aCONTEXT: Multiple factors contribute to mortality in older adults, but the extent to which subclinical disease and other factors contribute independently to mortality risk is not known.
OBJECTIVE: To determine the disease, functional, and personal characteristics that jointly predict mortality in community-dwelling men and women aged 65 years or older.
DESIGN: Prospective population-based cohort study with 5 years of follow-up and a validation cohort of African Americans with 4.25-year follow-up.
SETTING: Four US communities.
PARTICIPANTS: A total of 5201 and 685 men and women aged 65 years or older in the original and African American cohorts, respectively.
MAIN OUTCOME MEASURES: Five-year mortality.
RESULTS: In the main cohort, 646 deaths (12%) occurred within 5 years. Using Cox proportional hazards models, 20 characteristics (of 78 assessed) were each significantly (P<.05) and independently associated with mortality: increasing age, male sex, income less than $50000 per year, low weight, lack of moderate or vigorous exercise, smoking for more than 50 pack-years, high brachial (>169 mm Hg) and low tibial (< or = 127 mm Hg) systolic blood pressure, diuretic use by those without hypertension or congestive heart failure, elevated fasting glucose level (>7.2 mmol/L [130 mg/dL]), low albumin level (< or = 37 g/L), elevated creatinine level (> or = 106 micromol/L [1.2 mg/dL]), low forced vital capacity (< or = 2.06 mL), aortic stenosis (moderate or severe) and abnormal left ventricular ejection fraction (by echocardiography), major electrocardiographic abnormality, stenosis of internal carotid artery (by ultrasound), congestive heart failure, difficulty in any instrumental activity of daily living, and low cognitive function by Digit Symbol Substitution test score. Neither high-density lipoprotein cholesterol nor low-density lipoprotein cholesterol was associated with mortality. After adjustment for other factors, the association between age and mortality diminished, but the reduction in mortality with female sex persisted. Finally, the risk of mortality was validated in the second cohort; quintiles of risk ranged from 2% to 39% and 0% to 26% for the 2 cohorts.
CONCLUSIONS: Objective measures of subclinical disease and disease severity were independent and joint predictors of 5-year mortality in older adults, along with male sex, relative poverty, physical activity, smoking, indicators of frailty, and disability. Except for history of congestive heart failure, objective, quantitative measures of disease were better predictors of mortality than was clinical history of disease.
10aAfrican Americans10aAged10aAged, 80 and over10aCardiovascular Diseases10aCohort Studies10aFemale10aFollow-Up Studies10aHealth Surveys10aHumans10aMale10aMortality10aProportional Hazards Models10aProspective Studies10aRisk Factors10aUnited States1 aFried, L P1 aKronmal, R, A1 aNewman, A, B1 aBild, D, E1 aMittelmark, M, B1 aPolak, J, F1 aRobbins, J, A1 aGardin, J M uhttps://chs-nhlbi.org/node/149802912nas a2200337 4500008004100000022001400041245015700055210006900212260001600281300001200297490000800309520192700317653000902244653004502253653002102298653001102319653001802330653001102348653002002359653000902379653001802388653002202406653001802428100001502446700001502461700001202476700001202488700002002500700001802520856003602538 1998 eng d a0003-992600aTemporal patterns in the medical treatment of congestive heart failure with angiotensin-converting enzyme inhibitors in older adults, 1989 through 1995.0 aTemporal patterns in the medical treatment of congestive heart f c1998 May 25 a1074-800 v1583 aBACKGROUND: Evidence from clinical trials in the past decade has consistently shown that angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in patients with congestive heart failure (CHF). The extent to which clinical practice has adopted ACE inhibitor therapy is unknown.
METHODS: The Cardiovascular Health Study is a prospective observational study of 5201 community-dwelling adults aged 65 years and older. Prevalent CHF cases were identified on study entry (from June 10, 1989, through May 31, 1990) and incident CHF cases were identified throughout 5 years of follow-up. Medication data were collected from annual medication inventories. The percentage of patients with CHF using ACE inhibitors was calculated at each annual examination. Temporal trends in CHF treatment with ACE inhibitors between June 10, 1989, through May 31, 1990, and June 1, 1994, through May 31, 1995, were analyzed.
RESULTS: Use of ACE inhibitors to treat CHF increased slightly over time among prevalent cases at each annual examination: 26% of prevalent CHF cases were treated in 1989-1990 compared with 36% of prevalent cases in 1994-1995. This 10% increase was statistically significant (P<.01). Participants with low ejection fractions were 2 times more likely to be treated with ACE inhibitors than were those with normal ejection fraction and this tendency did not change over time. Among cases newly diagnosed in the year before the 1990-1991 examination, 42% were using ACE inhibitors; among those newly diagnosed in the year before 1994-1995, 40% were using ACE inhibitors. This 2% decrease was not statistically significant (P=.68).
CONCLUSION: These findings suggest that, while the medical management of CHF with ACE inhibitors has increased modestly over time in prevalent cases, these drugs may still be underused, especially among incident cases.
10aAged10aAngiotensin-Converting Enzyme Inhibitors10aDrug Utilization10aFemale10aHeart Failure10aHumans10aLogistic Models10aMale10aStroke Volume10aTreatment Outcome10aUnited States1 aSmith, N L1 aPsaty, B M1 aPitt, B1 aGarg, R1 aGottdiener, J S1 aHeckbert, S R uhttps://chs-nhlbi.org/node/150703367nas a2200361 4500008004100000022001400041245010800055210006900163260001600232300001100248490000800259520237700267653000902644653002902653653002102682653001902703653001102722653001102733653002502744653000902769653001502778653001702793653001802810100001902828700001702847700001702864700001702881700001702898700002002915700001902935700001502954856003602969 1998 eng d a0003-992600aTime trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.0 aTime trends in the use of cholesterollowering agents in older ad c1998 Sep 14 a1761-80 v1583 aOBJECTIVES: To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older.
SUBJECTS AND METHODS: A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit.
RESULTS: The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy.
CONCLUSIONS: Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.
10aAged10aAnticholesteremic Agents10aCholesterol, LDL10aCohort Studies10aFemale10aHumans10aHypercholesterolemia10aMale10aPrevalence10aRisk Factors10aUnited States1 aLemaitre, R, N1 aFurberg, C D1 aNewman, A, B1 aHulley, S, B1 aGordon, D, J1 aGottdiener, J S1 aMcDonald, R, H1 aPsaty, B M uhttps://chs-nhlbi.org/node/151302285nas a2200445 4500008004100000022001400041245011300055210006900168260001300237300001100250490000800261520108000269653001001349653002101359653000901380653002201389653002301411653001101434653001801445653001101463653004101474653000901515653001601524653002001540653002101560653003101581653001801612100001601630700001801646700001701664700001401681700001701695700001601712700001501728700001401743700001301757700001501770700001801785856003601803 1998 eng d a0002-870300aUtilities for major stroke: results from a survey of preferences among persons at increased risk for stroke.0 aUtilities for major stroke results from a survey of preferences c1998 Oct a703-130 v1363 aBACKGROUND: Patient beliefs, values, and preferences are crucial to decisions involving health care. In a large sample of persons at increased risk for stroke, we examined attitudes toward hypothetical major stroke.
METHODS AND RESULTS: Respondents were obtained from the Academic Medical Center Consortium (n = 621), the Cardiovascular Health Study (n = 321 ), and United Health Care (n = 319). Preferences were primarily assessed by using the time trade off (TTO). Although major stroke is generally considered an undesirable event (mean TTO = 0.30), responses were varied: although 45% of respondents considered major stroke to be a worse outcome than death, 15% were willing to trade off little or no survival to avoid a major stroke.
CONCLUSIONS: Providers should speak directly with patients about beliefs, values, and preferences. Stroke-related interventions, even those with a high price or less than dramatic clinical benefits, are likely to be cost-effective if they prevent an outcome (major stroke) that is so undesirable.
10aAdult10aAge Distribution10aAged10aAged, 80 and over10aAttitude to Health10aFemale10aHealth Status10aHumans10aIntracranial Embolism and Thrombosis10aMale10aMiddle Aged10aQuality of Life10aSex Distribution10aSurveys and Questionnaires10aUnited States1 aSamsa, G, P1 aMatchar, D, B1 aGoldstein, L1 aBonito, A1 aDuncan, P, W1 aLipscomb, J1 aEnarson, C1 aWitter, D1 aVenus, P1 aPaul, J, E1 aWeinberger, M uhttps://chs-nhlbi.org/node/151602941nas a2200421 4500008004100000022001400041245015000055210006900205260001300274300001100287490000700298520175900305653002102064653000902085653002202094653001002116653000802126653003302134653002802167653001902195653001102214653001102225653001702236653000902253653003002262653001702292653002102309653002202330100001702352700001702369700001702386700001502403700001802418700001602436700001502452700001702467856003502484 1999 eng d a1079-564200aAnkle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group.0 aAnklearm index as a predictor of cardiovascular disease and mort c1999 Mar a538-450 v193 aPeripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.
10aAge Distribution10aAged10aAged, 80 and over10aAnkle10aArm10aBlood Pressure Determination10aCardiovascular Diseases10aCohort Studies10aFemale10aHumans10aHypertension10aMale10aPredictive Value of Tests10aRisk Factors10aSex Distribution10aSurvival Analysis1 aNewman, A, B1 aShemanski, L1 aManolio, T A1 aCushman, M1 aMittelmark, M1 aPolak, J, F1 aPowe, N, R1 aSiscovick, D uhttps://chs-nhlbi.org/node/58602852nas a2200409 4500008004100000022001400041245012300055210006900178260001300247300001100260490000700271520173400278653000902012653001802021653002802039653001902067653002202086653001702108653001102125653002202136653001102158653002402169653001202193653000902205653002402214653001702238653001702255653001802272100001502290700001802305700001802323700001702341700001902358700001502377700001502392856003502407 1999 eng d a0149-599200aAntidiabetic treatment trends in a cohort of elderly people with diabetes. The cardiovascular health study, 1989-1997.0 aAntidiabetic treatment trends in a cohort of elderly people with c1999 May a736-420 v223 aOBJECTIVE: This study characterizes the pharmaceutical treatment of type 2 diabetes from 1989-1990 to 1996-1997 in an elderly cohort.
RESEARCH DESIGN AND METHODS: A total of 5,888 adults aged > or = 65 years were recruited and attended a baseline clinic visit in 1989-1990 (n = 5,201, original cohort) or 1992-1993 (n = 687. African-American [new] cohort) as participants of the Cardiovascular Health Study. Fasting serum glucose (FSG) was measured at baseline. Medication use was ascertained by drug inventory at all annual clinic visits. Diabetes was defined at baseline as insulin or oral hypoglycemic agent (OHA) use or as having an FSG > or = 7.0 mmol/l (126 mg/dl), the current consensus definition of diabetes.
RESULTS: A total of 387 (7%) original (FSG = 9.8 mmol/l [177 mg/dl]) and 115 (17%) new (FSG = 10.6 mmol/l [191 mg/dl]) cohort members had pharmacologically treated diabetes at baseline. Among those in the original and in the new cohorts who survived follow-up, respectively, OHA use decreased from 80 to 48% (P < 0.001) and from 67 to 50% (P < 0.003) and insulin use increased from 20 to 33% (P = 0.001) and from 33 to 37% (P = 0.603). There were 396 (8%) original (FSG = 8.8 mmol/l [159 mg/dl]) and 45 (7%) new (FSG = 10.0 mmol/l [181 mg/dl]) cohort members with diabetes untreated at baseline. Among them, respectively, OHA use reached 38 and 30% and insulin use reached 6 and 16% in 1996-1997.
CONCLUSIONS: Diabetes was common in this elderly cohort, and > 80% of treated patients with diabetes at baseline were not achieving fasting glucose goals of < or = 6.7 mmol/l (120 mg/dl). Many untreated at baseline remained untreated after 7 years of follow-up.
10aAged10aBlood Glucose10aCardiovascular Diseases10aCohort Studies10aDiabetes Mellitus10aDrug Therapy10aFemale10aFollow-Up Studies10aHumans10aHypoglycemic Agents10aInsulin10aMale10aProspective Studies10aRisk Factors10aTime Factors10aUnited States1 aSmith, N L1 aHeckbert, S R1 aBittner, V, A1 aSavage, P, J1 aBarzilay, J, I1 aDobs, A, S1 aPsaty, B M uhttps://chs-nhlbi.org/node/59103458nas a2200469 4500008004100000022001400041245016100055210006900216260001600285300001000301490000800311520210300319653001602422653000902438653001802447653002802465653002802493653002702521653002202548653001202570653001102582653002402593653001102617653002502628653000902653653002402662653001702686653003202703653002302735653001802758653003002776100001902806700002102825700001402846700001602860700001502876700001702891700001202908700001602920700001702936856003502953 1999 eng d a0140-673600aCardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria.0 aCardiovascular disease in older adults with glucose disorders co c1999 Aug 21 a622-50 v3543 aBACKGROUND: The new fasting American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus rely mainly on fasting blood glucose concentrations and use a lower cut-off value for diagnosis than the WHO criteria. We aimed to assess the sensitivity of these criteria for the detection of cardiovascular disease, the main complication of diabetes mellitus in the elderly.
METHODS: We did a cross-sectional and prospective analysis of 4515 participants of the Cardiovascular Health Study, an 8 year longitudinal study designed to identify factors related to the onset and course of cardiovascular disease in adults aged at least 65 years. We calculated the prevalence and incidence of cardiovascular disease for the ADA and WHO criteria.
FINDINGS: There was a higher prevalence of cardiovascular disease among individuals with impaired glucose or newly diagnosed diabetes by both criteria than among those with normal glucose concentrations. However, because fewer individuals had abnormal glucose states by the fasting ADA criteria (22.3%) than by the WHO criteria (46.8%), the number of cases of cardiovascular disease attributable to abnormal glucose states was a third of that attributable by the WHO criteria (53 vs 159 cases per 10,000). For the two sets of criteria, the relative risk for incident cardiovascular disease (mean follow-up 5.9 years) was higher in individuals with impaired glucose and newly diagnosed diabetes than in those with normal glucose. Individuals classified as normal by the fasting ADA criteria had a higher absolute number of incident events (455 of 581 events) than those classified as normal by the WHO criteria (269 of 581 events). Fasting ADA criteria were therefore less sensitive than the WHO criteria for predicting cardiovascular disease among individuals with abnormal glucose (sensitivity, 28% vs 54%).
INTERPRETATION: The new fasting ADA criteria seem to be less predictive than the WHO criteria for the burden of cardiovascular disease associated with abnormal glucose in the elderly.
10aAge Factors10aAged10aBlood Glucose10aCardiovascular Diseases10aCross-Sectional Studies10aDiabetes Complications10aDiabetes Mellitus10aFasting10aFemale10aGlucose Intolerance10aHumans10aLongitudinal Studies10aMale10aProspective Studies10aRisk Factors10aSensitivity and Specificity10aSocieties, Medical10aUnited States10aWorld Health Organization1 aBarzilay, J, I1 aSpiekerman, C, F1 aWahl, P W1 aKuller, L H1 aCushman, M1 aFurberg, C D1 aDobs, A1 aPolak, J, F1 aSavage, P, J uhttps://chs-nhlbi.org/node/60003311nas a2200385 4500008004100000022001400041245017500055210006900230260001600299300001000315490000800325520216900333653000902502653002102511653003002532653002602562653001102588653001102599653001402610653000902624653002602633653003202659653002402691653001702715653001802732653001702750653002002767100001702787700001602804700001802820700001702838700001602855700001802871856003602889 1999 eng d a0028-479300aCarotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group.0 aCarotidartery intima and media thickness as a risk factor for my c1999 Jan 07 a14-220 v3403 aBACKGROUND: The combined thickness of the intima and media of the carotid artery is associated with the prevalence of cardiovascular disease. We studied the associations between the thickness of the carotid-artery intima and media and the incidence of new myocardial infarction or stroke in persons without clinical cardiovascular disease.
METHODS: Noninvasive measurements of the intima and media of the common and internal carotid artery were made with high-resolution ultrasonography in 5858 subjects 65 years of age or older. Cardiovascular events (new myocardial infarction or stroke) served as outcome variables in subjects without clinical cardiovascular disease (4476 subjects) over a median follow-up period of 6.2 years.
RESULTS: The incidence of cardiovascular events correlated with measurements of carotid-artery intima-media thickness. The relative risk of myocardial infarction or stroke increased with intima-media thickness (P<0.001). The relative risk of myocardial infarction or stroke (adjusted for age and sex) for the quintile with the highest thickness as compared with the lowest quintile was 3.87 (95 percent confidence interval, 2.72 to 5.51). The association between cardiovascular events and intima-media thickness remained significant after adjustment for traditional risk factors, showing increasing risks for each quintile of combined intima-media thickness, from the second quintile (relative risk, 1.54; 95 percent confidence interval, 1.04 to 2.28), to the third (relative risk, 1.84; 95 percent confidence interval, 1.26 to 2.67), fourth (relative risk, 2.01; 95 percent confidence interval, 1.38 to 2.91), and fifth (relative risk, 3.15; 95 percent confidence interval, 2.19 to 4.52). The results of separate analyses of myocardial infarction and stroke paralleled those for the combined end point.
CONCLUSIONS: Increases in the thickness of the intima and media of the carotid artery, as measured noninvasively by ultrasonography, are directly associated with an increased risk of myocardial infarction and stroke in older adults without a history of cardiovascular disease.
10aAged10aCarotid Arteries10aCerebrovascular Disorders10aDisease-Free Survival10aFemale10aHumans10aIncidence10aMale10aMyocardial Infarction10aProportional Hazards Models10aProspective Studies10aRisk Factors10aTunica Intima10aTunica Media10aUltrasonography1 aO'Leary, D H1 aPolak, J, F1 aKronmal, R, A1 aManolio, T A1 aBurke, G, L1 aWolfson, S, K uhttps://chs-nhlbi.org/node/152002817nas a2200397 4500008004100000022001400041245011500055210006900170260001300239300001000252490000700262520171300269653001601982653000901998653002002007653001502027653001102042653004302053653001702096653001702113653002202130653001702152653001102169653000902180653002602189653003802215653001702253100001502270700001902285700001602304700001502320700001502335700001902350700001502369856003502384 1999 eng d a1079-564200aFibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study.0 aFibrinolytic activation markers predict myocardial infarction in c1999 Mar a493-80 v193 aCoagulation factor levels predict arterial thrombosis in epidemiological studies, but studies of older persons are needed. We studied 3 plasma antigenic markers of fibrinolysis, viz, plasminogen activator inhibitor-1 (PAI-1), fibrin fragment D-dimer, and plasmin-antiplasmin complex (PAP) for the prediction of arterial thrombosis in healthy elderly persons over age 65. The study was a nested case-control study in the Cardiovascular Health Study cohort of 5201 men and women >/=65 years of age who were enrolled from 1989 to 1990. Cases were 146 participants without baseline clinical vascular disease who developed myocardial infarction, angina, or coronary death during a follow-up of 2.4 years. Controls remained free of cardiovascular events and were matched 1:1 to cases with respect to sex, duration of follow-up, and baseline subclinical vascular disease status. With increasing quartile of D-dimer and PAP levels but not of PAI-1, there was an independent increased risk of myocardial infarction or coronary death, but not of angina. The relative risk for D-dimer above versus below the median value (>/=120 microg/L) was 2.5 (95% confidence interval, 1.1 to 5.9) and for PAP above the median (>/=5.25 nmol/L), 3.1 (1.3 to 7.7). Risks were independent of C-reactive protein and fibrinogen concentrations. There were no differences in risk by sex or presence of baseline subclinical disease. D-dimer and PAP, but not PAI-1, predicted future myocardial infarction in men and women over age 65. Relationships were independent of other risk factors, including inflammation markers. Results indicate a major role for these markers in identifying a high risk of arterial disease in this age group.
10aAge Factors10aAged10aAngina Pectoris10aBiomarkers10aFemale10aFibrin Fibrinogen Degradation Products10aFibrinolysin10aFibrinolysis10aFollow-Up Studies10aHeart Arrest10aHumans10aMale10aMyocardial Infarction10aPlasminogen Activator Inhibitor 110aRisk Factors1 aCushman, M1 aLemaitre, R, N1 aKuller, L H1 aPsaty, B M1 aMacy, E, M1 aSharrett, A, R1 aTracy, R P uhttps://chs-nhlbi.org/node/58402974nas a2200373 4500008004100000022001400041245008000055210006900135260001300204300001000217490000700227520198600234653000902220653001502229653002502244653002802269653001402297653001102311653001502322653003202337653001102369653001702380653001502397653002202412653001902434653001802453100001502471700001802486700001502504700001602519700001502535700001502550856003502565 1999 eng d a1079-564200aHormone replacement therapy, inflammation, and hemostasis in elderly women.0 aHormone replacement therapy inflammation and hemostasis in elder c1999 Apr a893-90 v193 aLipid-lowering by postmenopausal hormone therapy (HRT) explains only partly the assumed coronary risk reduction associated with therapy. To explore other possible mechanisms, we studied associations of HRT use with inflammation and hemostasis risk markers in women >/=65 years of age. Subjects were selected from 3393 participants in the fourth year examination of the Cardiovascular Health Study, an observational study of vascular disease risk factors. After excluding women with vascular disease, we compared levels of inflammation and hemostasis variables in the 230 women using unopposed estrogen and 60 using estrogen/progestin, with those of 196 nonusers selected as controls. Compared with nonusers, unopposed estrogen use was associated with 59% higher mean C-reactive protein (P<0.001), but with modestly lower levels of other inflammation indicators, fibrinogen, and alpha-1 acid glycoprotein (P<0.001). Factor VIIc was 16% higher among estrogen users (P<0.001), but this was not associated with higher thrombin production (prothrombin fragment 1-2), or increased fibrin breakdown (D-dimer). Concentration of plasminogen activator inhibitor-1 was 50% lower in both using groups (P<0.001) compared with nonusers, and this was associated with higher plasmin-antiplasmin complex: 8% higher in estrogen and 18% higher in estrogen/progestin users (P<0. 05). Relationships between the markers and hormone use were less pronounced in estrogen/progestin users, with no association for C-reactive protein except in women in upper 2 tertiles of body mass index (P for interaction, 0.02). The direction and strength of the associations of HRT use with inflammation markers differed depending on the protein, so it is not clear whether HRT confers coronary risk reduction through an inflammation-sensitive mechanism. Associations with hemostasis markers indicated no association with evidence of procoagulation and a possible association with increased fibrinolytic activity.
10aAged10aBiomarkers10aCase-Control Studies10aCross-Sectional Studies10aEstrogens10aFemale10aHemostasis10aHormone Replacement Therapy10aHumans10aInflammation10aProgestins10aRandom Allocation10aUnited Kingdom10aUnited States1 aCushman, M1 aMeilahn, E, N1 aPsaty, B M1 aKuller, L H1 aDobs, A, S1 aTracy, R P uhttps://chs-nhlbi.org/node/58802885nas a2200421 4500008004100000022001400041245016500055210006900220260001300289300001000302490000700312520165200319653000901971653001001980653002801990653002402018653002802042653001102070653001102081653003102092653003102123653000902154653001502163653002802178653003002206653001502236653002402251653001702275653001802292100001902310700001602329700001602345700001702361700001702378700001502395700001702410856003602427 1999 eng d a0039-249900aPrevalence and associations of MRI-demonstrated brain infarcts in elderly subjects with a history of transient ischemic attack. The Cardiovascular Health Study.0 aPrevalence and associations of MRIdemonstrated brain infarcts in c1999 Feb a383-80 v303 aBACKGROUND AND PURPOSE: MRI is more sensitive than CT, but the significance of brain abnormalities seen on MR images obtained in older subjects with transient ischemic attack (TIA) is not clear. We studied the prevalence and risk factors associated with MRI-demonstrated infarcts in elderly subjects with a history of TIA.
METHODS: Participants of the Cardiovascular Health Study, aged 65 years or more and without prior stroke, were studied with brain MRI (n=3456). The prevalence of brain infarcts (>/=3 mm) on MRI was determined in subjects with and without TIA. The cardiovascular risk factors and clinical and subclinical cardiovascular disease associated with MRI infarcts were studied in subjects with TIA.
RESULTS: Subjects with TIA (n=100) had a higher prevalence of MRI infarcts than subjects without TIA (46% versus 28%; P<0.001). The unadjusted odds ratio for having MRI infarcts in subjects with TIA was 2.20 (95% CI, 1.47 to 3.30) and remained significantly elevated after adjustments for risk factors and cerebrovascular disease (odds ratio, 1.86; 95% CI, 1.23 to 2.83). In subjects with TIA, diastolic blood pressure (P=0.01) and internal carotid artery intima-media thickness (P=0.01) were the only factors predictive of the presence of MRI infarcts by stepwise logistic regression analysis.
CONCLUSIONS: MRI infarcts are imaging manifestations of clinically important cerebrovascular disease in subjects with a history of TIA, given their increased prevalence and positive association with increased diastolic blood pressure and internal carotid artery intima-media thickness.
10aAged10aBrain10aCardiovascular Diseases10aCerebral Infarction10aCross-Sectional Studies10aFemale10aHumans10aIschemic Attack, Transient10aMagnetic Resonance Imaging10aMale10aOdds Ratio10aPopulation Surveillance10aPredictive Value of Tests10aPrevalence10aProspective Studies10aRisk Factors10aUnited States1 aBhadelia, R, A1 aAnderson, M1 aPolak, J, F1 aManolio, T A1 aBeauchamp, N1 aKnepper, L1 aO'Leary, D H uhttps://chs-nhlbi.org/node/152403503nas a2200445 4500008004100000022001400041245010400055210006900159260001300228300001200241490000700253520222500260653000902485653002202494653002402516653002802540653003702568653001902605653002102624653003002645653004002675653001102715653001702726653001702743653001102760653002302771653000902794653002602803653002602829653003802855653001702893100001902910700001502929700001502944700001702959700001502976700001602991700001503007856003503022 1999 eng d a1079-564200aRelationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.0 aRelationship of plasmin generation to cardiovascular disease ris c1999 Mar a499-5040 v193 aPlasmin-alpha2-antiplasmin complex (PAP) marks plasmin generation and fibrinolytic balance. We recently observed that elevated levels of PAP predict acute myocardial infarction in the elderly, yet little is known about the correlates of PAP. We measured PAP in 800 elderly subjects who were free of clinical cardiovascular disease in 2 cohort studies: the Cardiovascular Health Study and the Honolulu Heart Program. Median PAP levels did not differ between the Cardiovascular Health Study (6.05+/-1.46 nmol/L) and the Honolulu Heart Program (6.11+/-1.44 nmol/L), and correlates of PAP were similar in both cohorts. In CHS, PAP levels increased with age (r=0. 30), procoagulant factors (eg, factor VIIc, r=0.15), thrombin activity (prothrombin fragment F1+2, r=0.29), and inflammation-sensitive proteins (eg, fibrinogen, r=0.44; factor VIIIc, r=0.37). PAP was associated with increased atherosclerosis as measured by the ankle-arm index (AAI) (P for trend, =0.001). PAP was negatively related to factors associated with the insulin resistance syndrome (IRS) (eg, fasting insulin, r=-0.26; body mass index, r=-0.26), possibly reflecting an association with plasminogen activator inhibitor-1 (r=-0.29). Although our study did not have sufficient power to detect a significant interaction, PAP and AAI appeared to be more weakly associated in subjects with more manifestations of the IRS: PAP appeared more strongly associated with AAI in the subgroup with 0 or 1 metabolic disorders (P=0.001; slope estimate, -0.14) compared with the subgroup with 2 or more metabolic disorders (P=0.10; slope estimate, -0.08) and in those with non-insulin-dependent diabetes mellitus (P=0.46; slope estimate, -0.04). Although PAP reflects reactive fibrinolysis and is associated with subclinical atherosclerosis, this relationship may be weaker in populations with characteristics of the IRS, possibly reflecting the inhibitory effects of plasminogen activator inhibitor-1 on PAP. Decreased fibrinolysis in the presence of subclinical disease in subjects with hyperinsulinemia or glucose intolerance is consistent with the premise that depressed plasmin generation may enhance the progression of atherosclerosis in these people.
10aAged10aAged, 80 and over10aalpha-2-Antiplasmin10aAntifibrinolytic Agents10aAsian Continental Ancestry Group10aCohort Studies10aCoronary Disease10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aFibrinolysin10aFibrinolysis10aHumans10aInsulin Resistance10aMale10aMultivariate Analysis10aMyocardial Infarction10aPlasminogen Activator Inhibitor 110aRisk Factors1 aSakkinen, P, A1 aCushman, M1 aPsaty, B M1 aRodriguez, B1 aBoineau, R1 aKuller, L H1 aTracy, R P uhttps://chs-nhlbi.org/node/58502570nas a2200301 4500008004100000022001400041245011700055210006900172260001300241300001000254490000700264520171700271653000901988653001201997653002602009653001202035653001102047653002402058653002302082653001602105653003102121100001502152700001502167700001802182700001502200700001802215856003502233 1999 eng d a0895-435600aThe reliability of medication inventory methods compared to serum levels of cardiovascular drugs in the elderly.0 areliability of medication inventory methods compared to serum le c1999 Feb a143-60 v523 aMedication inventory is more reliable than self-report in assessing prescription drug use in elderly populations. It is not known how strongly medication inventory reflects actual medication use as measured by serum drug levels. In the Cardiovascular Health Study, medication data were collected annually by study interviewers from medication containers brought to the clinic visit. At the fourth clinic visit, venipuncture was performed under 12-hour fasting conditions. Participants were told to take medications as usual. Based on medication inventory results, we randomly selected 55 users and 55 non-users of four cardiovascular drugs: aspirin, propranolol, hydrochlorothiazide, and digoxin. All 110 blood samples for each of the four drugs were analyzed; cut points were based on detectable levels given laboratory limitations. Kappa statistics (K) tested degree of agreement between medication inventory findings and serum detection. Assays were completed on 400 samples (91%). Agreement for aspirin (n=102) was poor: K=0.16 (95% CI: 0.0-0.32). Agreement for propranolol (n = 98) was fair: K=0.43 (95% CI: 0.27-0.59). Agreement for hydrochlorothiazide (n=100) was good: K=0.62 (95% CI: 0.53-0.91). Agreement for digoxin (n=100) was excellent: K=0.94 (95% CI: 0.74-1.0). For four all drugs, lack of agreement was confined primarily to participants who reported use but did not have detectable levels. Excluding aspirin users, only one non-user (0.7%) had drug detected in serum. The medication inventory is a reasonably sensitive and a fairly reliable method for ascertaining non-aspirin cardiovascular drug use in the elderly even though this method may overestimate use as assessed by serum level.
10aAged10aAspirin10aCardiovascular Agents10aDigoxin10aHumans10aHydrochlorothiazide10aPatient Compliance10aPropranolol10aReproducibility of Results1 aSmith, N L1 aPsaty, B M1 aHeckbert, S R1 aTracy, R P1 aCornell, E, S uhttps://chs-nhlbi.org/node/58902278nas a2200361 4500008004100000022001400041245008600055210006900141260001300210300001100223490000700234520128400241653000901525653002001534653001101554653002201565653001801587653001101605653002001616653000901636653003201645653004201677653002001719653001601739653002201755653001701777653002201794100001301816700001801829700001601847700001801863856003501881 1999 eng d a0197-245600aSurvival versus years of healthy life: which is more powerful as a study outcome?0 aSurvival versus years of healthy life which is more powerful as c1999 Jun a267-790 v203 aStudies of interventions that are intended to improve patients' health are often evaluated with survival as the primary outcome, even when a measure adjusted for quality of survival, such as years of healthy life (YHL), would seem more appropriate. The purpose of this article is to determine whether studies based on survival are more or less powerful than studies based on YHL in clinical trials where either measure might be appropriate. We used data from the Cardiovascular Health Study (CHS) to estimate the sample size that would be needed in studies of 156 different health conditions, for the two outcome measures. The median sample size for a 5-year study was 687 if survival was the endpoint and 484 for YHL. YHL usually required lower sample sizes than survival, although survival was more powerful for some health conditions. We also found that lengthy studies, and studies with many follow-up measures per person, did not have appreciably higher power than less intensive studies. We conclude that clinical investigations in which the goal is to improve health may often be performed more efficiently with YHL rather than survival as the primary outcome measure. Such studies can be short in duration, with relatively few measures per person of health status.
10aAged10aAngina Pectoris10aFemale10aFollow-Up Studies10aHealth Status10aHumans10aLife Expectancy10aMale10aQuality-Adjusted Life Years10aRandomized Controlled Trials as Topic10aResearch Design10aSample Size10aSurvival Analysis10aTime Factors10aTreatment Outcome1 aDiehr, P1 aPatrick, D, L1 aBurke, G, L1 aWilliamson, J uhttps://chs-nhlbi.org/node/59202834nas a2200385 4500008004100000022001400041245009400055210006900149260001600218300001100234490000800245520182100253653000902074653001902083653001202102653002402114653003002138653001702168653002402185653001102209653001102220653001402231653000902245653001502254653002202269653001302291100001502304700001502319700001702334700001302351700001502364700001702379700001702396856003502413 1999 eng d a0003-992600aTemporal trends in the use of anticoagulants among older adults with atrial fibrillation.0 aTemporal trends in the use of anticoagulants among older adults c1999 Jul 26 a1574-80 v1593 aBACKGROUND: Several recent randomized clinical trials have demonstrated that warfarin sodium treatment, and to a lesser extent aspirin, reduces risk of stroke and death compared with placebo in persons with atrial fibrillation. Insufficient documentation exists on the extent to which the use of these therapies following trial publications has continued to increase in the elderly with atrial fibrillation.
METHODS: We used data from the Cardiovascular Health Study, a study of 5888 community-dwelling adults aged 65 years or older, to determine the prevalence of warfarin and aspirin use in persons with electrocardiogram-identified atrial fibrillation. Electrocardiogram examinations were conducted at baseline from 1989 through 1990, and at 6 subsequent annual examinations through 1995-1996. Medication data were collected by inventory methods at each examination. Temporal change in use of anticoagulants was analyzed by comparing percentage use in 1990 to use in each year through 1996.
RESULTS: The use of warfarin increased 4-fold from 13% in 1990 to 50% in 1996 among participants with prevalent atrial fibrillation (P<.001). Daily use of aspirin did not increase over time. Participants younger than 80 years were 4 times more likely to use warfarin in 1996 (P<.001) than those 80 years and older. Use of aspirin did not vary significantly with age.
CONCLUSIONS: Warfarin use in community-dwelling elderly persons with electrocardiogram-documented atrial fibrillation increased steadily following the first publication of its treatment benefit, reaching 50% by 1996. In contrast, use of aspirin was unchanged during this same period. Continued efforts to promote appropriate anticoagulation therapy to physicians and their patients may still be needed.
10aAged10aAnticoagulants10aAspirin10aAtrial Fibrillation10aCerebrovascular Disorders10aDrug Therapy10aElectrocardiography10aFemale10aHumans10aIncidence10aMale10aPrevalence10aTreatment Outcome10aWarfarin1 aSmith, N L1 aPsaty, B M1 aFurberg, C D1 aWhite, R1 aLima, J, A1 aNewman, A, B1 aManolio, T A uhttps://chs-nhlbi.org/node/59903636nas a2200397 4500008004100000022001400041245015700055210006900212260001600281300001200297490000800309520249400317653002102811653000902832653001102841653002202852653001102874653001402885653000902899653002602908653002602934653003002960653003202990653000903022653001703031653002103048100001503069700001703084700001603101700001503117700002103132700001603153700001403169700002003183856003503203 1999 eng d a0003-992600aTraditional risk factors and subclinical disease measures as predictors of first myocardial infarction in older adults: the Cardiovascular Health Study.0 aTraditional risk factors and subclinical disease measures as pre c1999 Jun 28 a1339-470 v1593 aBACKGROUND: Risk factors for myocardial infarction (MI) have not been well characterized in older adults, and in estimating risk, we sought to assess the individual and joint contributions made by both traditional risk factors and measures of subclinical disease.
METHODS: In the Cardiovascular Health Study, we recruited 5888 adults aged 65 years and older from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination that included traditional risk factors such as blood pressure and fasting glucose level and measures of subclinical disease as assessed by electrocardiography, carotid ultrasonography, echocardiography, pulmonary function, and ankle-arm index. Participants were followed up with semiannual contacts, and all cardiovascular events were classified by the Morbidity and Mortality Committee. The main analytic technique was the Cox proportional hazards model.
RESULTS: At baseline, 1967 men and 2979 women had no history of an MI. After follow-up for an average of 4.8 years, there were 302 coronary events, which included 263 patients with MI and 39 with definite fatal coronary disease. The incidence was higher in men (20.7 per 1000 person-years) than women (7.9 per 1000 person-years). In all subjects, the incidence was strongly associated with age, increasing from 7.8 per 1000 person-years in subjects aged 65 to 69 years to 25.6 per 1000 person-years in subjects aged 85 years and older. Glucose level and systolic blood pressure were associated with the incidence of MI, but smoking and lipid measures were not. After adjustment for age and sex, the significant subclinical disease predictors of MI were borderline or abnormal ejection fraction by echocardiography, high levels of intimal-medial thickness of the internal carotid artery, and a low ankle-arm index. Forced vital capacity and electrocardiographic left ventricular mass did not enter the stepwise model. Excluding subjects with clinical cardiovascular diseases such as prior angina or congestive heart failure at baseline had little effect on these results. Risk factors were generally similar in men and women.
CONCLUSIONS: After follow-up of 4.8 years, systolic blood pressure, fasting glucose level, and selected subclinical disease measures were important predictors of the incidence of MI in older adults. Uncontrolled high blood pressure may explain about one quarter of the coronary events in this population.
10aAge Distribution10aAged10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aMultivariate Analysis10aMyocardial Infarction10aPredictive Value of Tests10aProportional Hazards Models10aRisk10aRisk Factors10aSex Distribution1 aPsaty, B M1 aFurberg, C D1 aKuller, L H1 aBild, D, E1 aRautaharju, P, M1 aPolak, J, F1 aBovill, E1 aGottdiener, J S uhttps://chs-nhlbi.org/node/59303847nas a2200421 4500008004100000022001400041245013700055210006900192260001600261300001200277490000800289520270400297653001003001653000903011653001903020653002803039653001103067653001103078653001703089653002003106653000903126653001603135653001203151653002003163653002603183653001203209100001603221700001603237700001503253700001403268700001603282700001503298700002103313700001703334700001903351700002003370856003503390 2000 eng d a0098-748400aAssociation of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study.0 aAssociation of sleepdisordered breathing sleep apnea and hyperte c2000 Apr 12 a1829-360 v2833 aCONTEXT: Sleep-disordered breathing (SDB) and sleep apnea have been linked to hypertension in previous studies, but most of these studies used surrogate information to define SDB (eg, snoring) and were based on small clinic populations, or both.
OBJECTIVE: To assess the association between SDB and hypertension in a large cohort of middle-aged and older persons.
DESIGN AND SETTING: Cross-sectional analyses of participants in the Sleep Heart Health Study, a community-based multicenter study conducted between November 1995 and January 1998.
PARTICIPANTS: A total of 6132 subjects recruited from ongoing population-based studies (aged > or = 40 years; 52.8% female).
MAIN OUTCOME MEASURES: Apnea-hypopnea index (AHI, the average number of apneas plus hypopneas per hour of sleep, with apnea defined as a cessation of airflow and hypopnea defined as a > or = 30% reduction in airflow or thoracoabdominal excursion both of which are accompanied by a > or = 4% drop in oxyhemoglobin saturation) [corrected], obtained by unattended home polysomnography. Other measures include arousal index; percentage of sleep time below 90% oxygen saturation; history of snoring; and presence of hypertension, defined as resting blood pressure of at least 140/90 mm Hg or use of antihypertensive medication.
RESULTS: Mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing SDB measures, although some of this association was explained by body mass index (BMI). After adjusting for demographics and anthropometric variables (including BMI, neck circumference, and waist-to-hip ratio), as well as for alcohol intake and smoking, the odds ratio for hypertension, comparing the highest category of AHI (> or = 30 per hour) with the lowest category (< 1.5 per hour), was 1.37 (95% confidence interval [CI], 1.03-1.83; P for trend = .005). The corresponding estimate comparing the highest and lowest categories of percentage of sleep time below 90% oxygen saturation (> or = 12% vs < 0.05%) was 1.46 (95% CI, 1.12-1.88; P for trend <.001). In stratified analyses, associations of hypertension with either measure of SDB were seen in both sexes, older and younger ages, all ethnic groups, and among normal-weight and overweight individuals. Weaker and nonsignificant associations were observed for the arousal index or self-reported history of habitual snoring.
CONCLUSION: Our findings from the largest cross-sectional study to date indicate that SDB is associated with systemic hypertension in middle-aged and older individuals of different sexes and ethnic backgrounds.
10aAdult10aAged10aCohort Studies10aCross-Sectional Studies10aFemale10aHumans10aHypertension10aLogistic Models10aMale10aMiddle Aged10aObesity10aPolysomnography10aSleep Apnea Syndromes10aSnoring1 aNieto, F, J1 aYoung, T, B1 aLind, B, K1 aShahar, E1 aSamet, J, M1 aRedline, S1 aD'Agostino, R, B1 aNewman, A, B1 aLebowitz, M, D1 aPickering, T, G uhttps://chs-nhlbi.org/node/61302915nas a2200457 4500008004100000022001400041245019400055210006900249260001600318300001200334490000800346520158700354653001001941653001601951653000901967653002601976653002202002653002502024653002902049653002102078653002002099653001102119653002502130653001902155653001102174653002102185653000902206653002602215653001702241100002002258700001902278700001302297700001902310700001402329700001502343700001502358700001502373700001602388700001802404856003502422 2000 eng d a1524-453900aChlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults : the Cardiovascular Health Study.0 aChlamydia pneumoniae herpes simplex virus type 1 and cytomegalov c2000 Nov 07 a2335-400 v1023 aBACKGROUND: Whether serological evidence of prior infection with Chlamydia pneumoniae, herpes simplex virus type 1 (HSV-1), and cytomegalovirus (CMV) is associated with myocardial infarction (MI) and coronary heart disease (CHD) death remains a source of controversy.
METHODS AND RESULTS: We conducted a nested case-control study among participants in the Cardiovascular Health Study, a cohort study of persons aged >/=65 years. Cases experienced an incident MI and CHD death (n=213). Control subjects were matched to cases by age, sex, clinic, year of enrollment, and month of blood draw (n=405). Serum was analyzed for IgG antibodies to C pneumoniae, HSV-1, and CMV. After adjustment for other risk factors, the risk of MI and CHD death was associated with the presence of IgG antibodies to HSV-1 (odds ratio [OR] 2.0, 95% CI 1.1 to 3.6) but was not associated with the presence of IgG antibodies to either C pneumoniae (OR 1.1, 95% CI 0.7 to 1.8) or CMV (OR 1.2, 95% CI 0.7 to 1.9). Although there was little association with low to moderate C pneumoniae antibody titers (=1:512), high-titer (1:1024) C pneumoniae antibody was associated with an increased risk (OR 2.2, 95% CI 1.1 to 4.4).
CONCLUSIONS: Among older adults, the presence of IgG antibodies to HSV-1 was associated with a 2-fold increase in the risk of incident MI and CHD death. For C pneumoniae, only high-titer IgG antibodies were associated with an increased risk of MI and CHD death. The presence of IgG antibodies to CMV was not associated with risk among the elderly.
10aAdult10aAge Factors10aAged10aAntibodies, Bacterial10aAntibodies, Viral10aCase-Control Studies10aChlamydophila pneumoniae10aCoronary Disease10aCytomegalovirus10aFemale10aHerpesvirus 1, Human10aHIV Antibodies10aHumans10aImmunoglobulin G10aMale10aMyocardial Infarction10aRisk Factors1 aSiscovick, D, S1 aSchwartz, S, M1 aCorey, L1 aGrayston, J, T1 aAshley, R1 aWang, S, P1 aPsaty, B M1 aTracy, R P1 aKuller, L H1 aKronmal, R, A uhttps://chs-nhlbi.org/node/62503361nas a2200421 4500008004100000022001400041245008200055210006900137260001300206300000900219490000700228520217000235653000902405653002202414653001002436653001902446653001702465653001702482653001802499653002302517653003002540653001102570653001502581653002702596653002802623653001102651653002502662653000902687653002202696653003402718653005702752100001902809700002402828700002202852700001602874700001402890856003502904 2000 eng d a0012-179700aEvidence of islet cell autoimmunity in elderly patients with type 2 diabetes.0 aEvidence of islet cell autoimmunity in elderly patients with typ c2000 Jan a32-80 v493 aIn light of an occurring growth of elderly people affected by type 2 diabetes and recent observations indicating that type 2 diabetes may be a disease of the innate immune system, we evaluated whether signs of islet cell autoimmunity are associated with an abnormal glucose control, the presence of insulin requirement, or an activation of the acute-phase response in older individuals with type 2 diabetes. GAD65 and IA-2 autoantibodies along with the acute-phase response markers fibrinogen and C-reactive protein were tested in 196 serum samples from patients with type 2 diabetes and in 94 nondiabetic control subjects over the age of 65 years from the Pittsburgh cohort of the Cardiovascular Health Study. Of the diabetic patients, 12% (24 of 196) had autoantibodies against GAD65 and/or IA-2, a prevalence significantly higher than that found in nondiabetic individuals (1 of 94, 1.1%; P = 0.001). Type 2 diabetic patients who were positive for GAD65 and/or IA-2 autoantibodies (Ab+), as compared with those negative for these autoantibodies (Ab-), had an abnormal oral glucose tolerance test (OGTT) (P = 0.03) before and a higher frequency of oral hypoglycemic treatment (P = 0.003) at the time of autoantibody testing. No differences were seen in the percentage of insulin requirement in the two groups. Moreover, a statistically significant increase in fibrinogen (P = 0.005) and C-reactive protein levels (P = 0.025) was found in type 2 diabetic patients with high levels of GAD65 and/or IA-2 autoantibodies as compared with Ab-patients and control subjects. In conclusion, in type 2 diabetic subjects > or =65 years old, the presence of islet cell autoimmunity is associated with an impairment of the acute-phase insulin secretion, as revealed by an OGTT. A pronounced activation of the acute-phase response, found to be associated with islet cell autoimmunity, may in part explain this defect in insulin secretion. These findings not only have direct implications for adequate classification and treatment of diabetes in the elderly, but also for understanding the autoimmune/inflammatory mechanisms involved in the pathogenesis of hyperglycemia.
10aAged10aAged, 80 and over10aAging10aAutoantibodies10aAutoantigens10aAutoimmunity10aBlood Glucose10aC-Reactive Protein10aDiabetes Mellitus, Type 210aFemale10aFibrinogen10aGlucose Tolerance Test10aGlutamate Decarboxylase10aHumans10aIslets of Langerhans10aMale10aMembrane Proteins10aProtein Tyrosine Phosphatases10aReceptor-Like Protein Tyrosine Phosphatases, Class 81 aPietropaolo, M1 aBarinas-Mitchell, E1 aPietropaolo, S, L1 aKuller, L H1 aTrucco, M uhttps://chs-nhlbi.org/node/60603300nas a2200385 4500008004100000022001400041245009200055210006900147260001300216300001200229490000700241520225600248653000902504653002202513653002102535653001102556653002502567653001802592653001102610653003102621653000902652653002402661653001702685653001802702100002002720700001702740700002002757700001602777700001502793700001802808700001602826700001902842700001802861856003502879 2000 eng d a0735-109700aPredictors of congestive heart failure in the elderly: the Cardiovascular Health Study.0 aPredictors of congestive heart failure in the elderly the Cardio c2000 May a1628-370 v353 aOBJECTIVES: We sought to characterize the predictors of incident congestive heart failure (CHF), as determined by central adjudication, in a community-based elderly population.
BACKGROUND: The elderly constitute a growing proportion of patients admitted to the hospital with CHF, and CHF is a leading source of morbidity and mortality in this group. Elderly patients differ from younger individuals diagnosed with CHF in terms of biologic characteristics.
METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of 5,888 elderly people >65 years old (average 73 +/- 5, range 65 to 100) at four locations. Multiple laboratory measures of cardiovascular structure and function, blood chemistries and functional assessments were obtained.
RESULTS: During an average follow-up of 5.5 years (median 6.3), 597 participants developed incident CHF (rate 19.3/1,000 person-years). The incidence of CHF increased progressively across age groups and was greater in men than in women. On multivariate analysis, other independent predictors included prevalent coronary heart disease, stroke or transient ischemic attack at baseline, diabetes, systolic blood pressure (BP), forced expiratory volume 1 s, creatinine >1.4 mg/dl, C-reactive protein, ankle-arm index <0.9, atrial fibrillation, electrocardiographic (ECG) left ventricular (LV) mass, ECG ST-T segment abnormality, internal carotid artery wall thickness and decreased LV systolic function. Population-attributable risk, determined from predictors of risk and prevalence, was relatively high for prevalent coronary heart disease (13.1%), systolic BP > or =140 mm Hg (12.8%) and a high level of C-reactive protein (9.7%), but was low for subnormal LV function (4.1%) and atrial fibrillation (2.2%).
CONCLUSIONS: The incidence of CHF is high in the elderly and is related mainly to age, gender, clinical and subclinical coronary heart disease, systolic BP and inflammation. Despite the high relative risk of subnormal systolic LV function and atrial fibrillation, the actual population risk of these for CHF is small because of their relatively low prevalence in community-dwelling elderly people.
10aAged10aAged, 80 and over10aCoronary Disease10aFemale10aGeriatric Assessment10aHeart Failure10aHumans10aIschemic Attack, Transient10aMale10aProspective Studies10aRisk Factors10aSurvival Rate1 aGottdiener, J S1 aArnold, A, M1 aAurigemma, G, P1 aPolak, J, F1 aTracy, R P1 aKitzman, D, W1 aGardin, J M1 aRutledge, J, E1 aBoineau, R, C uhttps://chs-nhlbi.org/node/61502927nas a2200385 4500008004100000022001400041245020200055210006900257260001300326300001100339490000700350520174100357653003902098653001602137653000902153653001802162653002402180653004002204653001102244653001102255653003402266653000902300653003002309653001502339653001602354653002002370100002102390700001502411700002002426700001702446700001502463700001302478700001502491856003502506 2000 eng d a0022-073600aRace- and sex-specific ECG models for left ventricular mass in older populations. Factors influencing overestimation of left ventricular hypertrophy prevalence by ECG criteria in African-Americans.0 aRace and sexspecific ECG models for left ventricular mass in old c2000 Jul a205-180 v333 aThe validity of the reported high prevalence of left ventricular hypertrophy (LVH) among African-American men and women has been questioned owing to conflicting echocardiographic evidence. We used echocardiographic left ventricular mass (LVM) from M-mode measurements to evaluate associations between LVM, body size, and electrocardiographic (ECG) variables in 3,627 white and African-American men and women 65 years of age and older who were participants of the Cardiovascular Health Study (CHS), a multicenter cohort study of risk factors for coronary heart disease and stroke. ECG amplitudes used in LVH criteria were substantially higher in African-Americans, with apparent LVH prevalence 2 to 3 times higher in African American men and women than in white men and women, although there was no significant racial difference in echocardiographic LVM. The higher apparent LVH prevalence by Sokolow-Lyon criteria in African-American men is in part owing to smaller lateral chest diameter. In women, reasons for racial differences in ECG LVH prevalence remain largely unexplained although a small part of the excess LVH in African-American women by the Sokolow-Lyon criteria appears to be owing to a larger lateral chest semidiameter in white women. ECG variables alone were too inaccurate for LVM prediction, and it was necessary to incorporate in all ECG models body weight that was properly adjusted for race and sex. This resulted in modest LVM prediction accuracy, with R-square values ranging from .22 to .36. Race- and sex-specific ECG models introduced for LVM estimation with an appropriate adjustment for body size differences are expected to facilitate evaluation of LVH status in contrasting racial population groups.
10aAfrican Continental Ancestry Group10aAge Factors10aAged10aAnthropometry10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aHumans10aHypertrophy, Left Ventricular10aMale10aPredictive Value of Tests10aPrevalence10aSex Factors10aUltrasonography1 aRautaharju, P, M1 aPark, L, P1 aGottdiener, J S1 aSiscovick, D1 aBoineau, R1 aSmith, V1 aPowe, N, R uhttps://chs-nhlbi.org/node/62103508nas a2200433 4500008004100000022001400041245012900055210006900184260001300253300001200266490000700278520228200285653001002567653003002577653002802607653001502635653002302650653003302673653001102706653001102717653001802728653001602746653001702762653001702779653002302796653002602819653003002845653001802875653001702893100002002910700001602930700001702946700001202963700001802975700001602993700001603009700001403025856003503039 2001 eng d a1047-279700aArea characteristics and individual-level socioeconomic position indicators in three population-based epidemiologic studies.0 aArea characteristics and individuallevel socioeconomic position c2001 Aug a395-4050 v113 aPURPOSE: There is growing interest in incorporating area indicators into epidemiologic analyses. Using data from the 1990 U.S. Census linked to individual-level data from three epidemiologic studies, we investigated how different area indicators are interrelated, how measures for different sized areas compare, and the relation between area and individual-level social position indicators.
METHODS: The interrelations between 13 area indicators of wealth/income, education, occupation, and other socioenvironmental characteristics were investigated using correlation coefficients and factor analyses. The extent to which block-group measures provide information distinct from census tract measures was investigated using intraclass correlation coefficients. Loglinear models were used to investigate associations between area and individual-level indicators.
RESULTS: Correlations between area measures were generally in the 0.5--0.8 range. In factor analyses, six indicators of income/wealth, education, and occupation loaded on one factor in most geographic sites. Correlations between block-group and census tract measures were high (correlation coefficients 0.85--0.96). Most of the variability in block-group indicators was between census tracts (intraclass correlation coefficients 0.72--0.92). Although individual-level and area indicators were associated, there was evidence of important heterogeneity in area of residence within individual-level income or education categories. The strength of the association between individual and area measures was similar in the three studies and in whites and blacks, but blacks were much more likely to live in more disadvantaged areas than whites.
CONCLUSIONS: Area measures of wealth/income, education, and occupation are moderately to highly correlated. Differences between using census tract or block-group measures in contextual investigations are likely to be relatively small. Area and individual-level indicators are far from perfectly correlated and provide complementary information on living circumstances. Differences in the residential environments of blacks and whites may need to be taken into account in interpreting race differences in epidemiologic studies.
10aAdult10aBlack or African American10aCardiovascular Diseases10aDemography10aEducational Status10aFactor Analysis, Statistical10aHumans10aIncome10aLinear Models10aOccupations10aRisk Factors10aSocial Class10aSocial Environment10aSocioeconomic Factors10aStatistics, Nonparametric10aUnited States10aWhite People1 aDiez-Roux, A, V1 aKiefe, C, I1 aJacobs, D, R1 aHaan, M1 aJackson, S, A1 aNieto, F, J1 aPaton, C, C1 aSchulz, R uhttps://chs-nhlbi.org/node/65703312nas a2200409 4500008004100000022001400041245014600055210006900201260001600270300001200286490000800298520218500306653000902491653001902500653001102519653001102530653000902541653002602550653001402576653003202590653002402622653001702646653001102663653001802674653001802692100001502710700001702725700001602742700001502758700001702773700001402790700001702804700001602821700001602837700001402853856003502867 2001 eng d a0003-992600aAssociation between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.0 aAssociation between blood pressure level and the risk of myocard c2001 May 14 a1183-920 v1613 aBACKGROUND: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure.
METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified.
RESULTS: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension.
CONCLUSION: In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.
10aAged10aBlood Pressure10aFemale10aHumans10aMale10aMyocardial Infarction10aPrognosis10aProportional Hazards Models10aProspective Studies10aRisk Factors10aStroke10aSurvival Rate10aUnited States1 aPsaty, B M1 aFurberg, C D1 aKuller, L H1 aCushman, M1 aSavage, P, J1 aLevine, D1 aO'Leary, D H1 aBryan, R, N1 aAnderson, M1 aLumley, T uhttps://chs-nhlbi.org/node/64702679nas a2200385 4500008004100000022001400041245010300055210006900158260001600227300001100243490000800254520164800262653000901910653002501919653001501944653002301959653002801982653001602010653001102026653001502037653001102052653001702063653002002080653000902100653002202109653001602131653001202147100001802159700001502177700001602192700001602208700001902224700001502243856003502258 2001 eng d a0002-926200aAssociation between physical activity and markers of inflammation in a healthy elderly population.0 aAssociation between physical activity and markers of inflammatio c2001 Feb 01 a242-500 v1533 aHigher levels of physical activity are associated with lower risk of cardiovascular disease. There is growing evidence that the development of the atherosclerotic plaque is associated with inflammation. In this study, the authors investigated the cross-sectional association between physical activity and markers of inflammation in a healthy elderly population. Data obtained in 1989-1990 and 1992-1993 from the Cardiovascular Health Study, a cohort of 5,888 men and women aged >/=65 years, were analyzed. Concentrations of the inflammation markers-C-reactive protein, fibrinogen, Factor VIII activity, white blood cells, and albumin-were compared cross-sectionally by quartile of self-reported physical activity. Compared with persons in the lowest quartile, those in the highest quartile of physical activity had 19%, 6%, 4%, and 3% lower concentrations of C-reactive protein, white blood cells, fibrinogen, and Factor VIII activity, respectively, after adjustment for gender, the presence of cardiovascular disease, age, race, smoking, body mass index, diabetes, and hypertension. Multivariate regression models suggested that the association of higher levels of physical activity with lower levels of inflammation markers may be mediated by body mass index and glucose. There was no association between physical activity and albumin. Higher levels of physical activity were associated with lower concentrations of four out of five inflammation markers in this elderly cohort. These data suggest that increased exercise is associated with reduced inflammation. Prospective studies will be required for verification of these findings.
10aAged10aAnalysis of Variance10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aFactor VIII10aFemale10aFibrinogen10aHumans10aInflammation10aLeukocyte Count10aMale10aPhysical Exertion10aSex Factors10aSmoking1 aGeffken, D, F1 aCushman, M1 aBurke, G, L1 aPolak, J, F1 aSakkinen, P, A1 aTracy, R P uhttps://chs-nhlbi.org/node/62803119nas a2200457 4500008004100000022001400041245015400055210006900209260001300278300001100291490000600302520185400308653001502162653001002177653001602187653000902203653002202212653002202234653002002256653001102276653001102287653000902298653001602307653002302323653002802346653003102374653001602405653001702421653002302438100002102461700001102482700001202493700001602505700001702521700001702538700001602555700001902571700001702590700001902607856003502626 2001 eng d a1350-627700aBrachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter.0 aBrachial flowmediated vasodilator responses in populationbased r c2001 Oct a319-280 v83 aBACKGROUND: Brachial artery ultrasound has been proposed as an inexpensive, accurate way to assess cardiovascular risk in populations. However, analysis and interpretation of these data are not uniform.
METHODS: We analysed the relationship between relative and absolute changes in brachial artery diameter in response to flow-mediated dilation and age, gender and baseline diameter among 4,040 ultrasound examinations from subjects aged 14 to 98 years.
RESULTS: Reproducibility studies demonstrated intra- and interreader and intrasubject correlations from 0.67 to 0.84 for repeated measures of per cent change in diameter. Per cent change in diameter after flow stimulus was 3.58 +/- 0.10% (mean +/- standard deviation). Corresponding values for baseline diameter and absolute change in diameter were 4.43 +/- 0.87 mm and 0.15 +/- 0.01 mm, respectively. Baseline diameter and its variance were inversely related to per cent change in diameter (P< 0.001). In contrast, absolute change in diameter was more uniform throughout the range of baseline diameters. Baseline diameter was directly related, and per cent change in diameter inversely related, to age (P < 0.001 for all three measures). Time to maximum vasodilator response increased with age (P < 0.001). Women (n=2,315) had significantly larger per cent change in diameter than men (n=1,725) (P < 0.001). However, after adjustment for age and baseline diameter, per cent and absolute change were 5% smaller in women than men (P < 0.05 for both). In multivariate analysis, age was overwhelmingly the most important determinant of absolute change in diameter (P < 0.001).
CONCLUSIONS: Automated analysis of brachial flow-mediated vasodilator responses is both feasible and reproducible in large-scale clinical and population-based research.
10aAdolescent10aAdult10aAge Factors10aAged10aAged, 80 and over10aBlood Circulation10aBrachial Artery10aFemale10aHumans10aMale10aMiddle Aged10aObserver Variation10aPopulation Surveillance10aReproducibility of Results10aSex Factors10aVasodilation10aVasodilator Agents1 aHerrington, D, M1 aFan, L1 aDrum, M1 aRiley, W, A1 aPusser, B, E1 aCrouse, J, R1 aBurke, G, L1 aMcBurnie, M, A1 aMorgan, T, M1 aEspeland, M, A uhttps://chs-nhlbi.org/node/66502409nas a2200337 4500008004100000022001400041245011900055210006900174260001300243300001000256490000700266520148600273653002101759653000901780653003001789653002101819653001101840653001801851653001101869653001401880653000901894653003001903100001801933700001601951700001301967700001501980700001201995700001202007700001702019856003502036 2001 eng d a0027-968400aIncidence and predictors of coronary heart disease among older African Americans--the Cardiovascular Health Study.0 aIncidence and predictors of coronary heart disease among older A c2001 Nov a423-90 v933 aAlthough coronary heart disease (CHD) is the leading cause of death and morbidity in older African Americans, relatively little is known about the incidence and predictors of CHD in this population. This study was undertaken to determine the incidence and predictors of CHD in African-American men and women aged 65 years and older. The participants in this study included a total of 924 African-American men and women aged 65 years of age and older who participated in the Cardiovascular Health Study (CHS). The overall CHD incidence was 26.6 per 1,000 person-years of risk. Rates were higher in men than women (35.3 vs. 21.6) and in those 75 years or older than in those less than 75 years (31.3 vs. 24.5). In multivariate analysis, factors associated with higher risk of incident disease were male gender [relative risk (RR) = 1.8, 95% confidence interval (CI) = 1.1, 2.7], diabetes mellitus (RR = 1.9, 95% CI = 1.2, 2.9), total cholesterol (RR for 40 mg/dL increment = 1.3, 95% CI = 1.0, 1.5), and low (i.e., <0.9) ankle-arm index (RR = 2.1, 95% CI = 1.3, 3.4) after adjusting for age. Within this cohort of older African Americans, male gender, diabetes mellitus, total cholesterol, and low ankle-arm index and were independently predictive of incident events. These results suggest that the ankle-arm index, a measure of advanced atherosclerosis, should be further evaluated for its efficacy in identifying older African Americans at risk for incident clinical events.
10aAge Distribution10aAged10aBlack or African American10aCoronary Disease10aFemale10aHealth Status10aHumans10aIncidence10aMale10aPredictive Value of Tests1 aJackson, S, A1 aBurke, G, L1 aThach, C1 aCushman, M1 aIves, D1 aPowe, N1 aManolio, T A uhttps://chs-nhlbi.org/node/66802959nas a2200385 4500008004100000022001400041245009100055210006900146260001300215300001000228490000700238520192700245653000902172653002802181653001902209653001002228653001102238653002202249653001802271653002902289653001802318653002002336653001102356653001802367653002502385653000902410653002202419653001702441100001302458700001802471700001802489700001502507700001602522856003502538 2001 eng d a0002-861400aPatterns of self-rated health in older adults before and after sentinel health events.0 aPatterns of selfrated health in older adults before and after se c2001 Jan a36-440 v493 aOBJECTIVES: To describe and compare patterns of change in self-rated health for older adults before death and before and after stroke, myocardial infarction, congestive heart failure, cardiac procedure, hospital admission for cancer, and hip fracture.
DESIGN: "Event cohort," measuring time in months before and after the event.
SETTING: Four U.S. communities.
PARTICIPANTS: 5888 participants in the Cardiovascular Health Study (CHS), sampled from Medicare rolls and followed up to 8 years. Mean age at baseline was 73.
MEASUREMENTS: Self-rated health, including a category for death, assessed at 6-month intervals, and ascertainment of events.
METHODS: We examined the percentage that was healthy each month in the 5 years before death and in the 2 years before and after the other events, and compared the patterns to a "no event" group and to one another, using graphs and linear regression.
RESULTS: For people who died, health status declined slowly until about 9 months before death, when it dropped steeply. Comparing persons equally far from death, health was unrelated to age, but men and whites were healthier than women and blacks. Health for other events declined before the event, dropped steeply at the event, showed some recovery, and then declined further after the event. About 65% to 80% of the subjects were healthy 2 years before their event, but only 35% to 65% were healthy two years afterwards. Patterns were similar although less extreme for the "no event" group.
CONCLUSION: Visualizing trajectories of health helps us understand how serious health events changes health. Conclusions about change must be drawn with care because of a variety of possible biases. We have described the trajectories in detail. Work is now needed to explain, predict, and possibly prevent such changes in health.
10aAged10aCardiovascular Diseases10aCohort Studies10aDeath10aFemale10aFollow-Up Studies10aHealth Status10aHealth Status Indicators10aHip Fractures10aHospitalization10aHumans10aLinear Models10aLongitudinal Studies10aMale10aRandom Allocation10aTime Factors1 aDiehr, P1 aWilliamson, J1 aPatrick, D, L1 aBild, D, E1 aBurke, G, L uhttps://chs-nhlbi.org/node/63402371nas a2200373 4500008004100000022001400041245010300055210006900158260001300227300001000240490000800250520135500258653000901613653001801622653001701640653002001657653002801677653003301705653001101738653001101749653002001760653001801780653001501798653001401813653001701827653002201844653001701866100001501883700001501898700001801913700001501931700001601946856003501962 2001 eng d a0007-104800aPost-menopausal hormone therapy and concentrations of protein C and antithrombin in elderly women.0 aPostmenopausal hormone therapy and concentrations of protein C a c2001 Jul a162-80 v1143 aThe effects of post-menopausal hormone therapy (HRT) on blood coagulation in elderly women are not well defined. We studied associations of HRT use with levels of natural anticoagulant proteins in a cross-sectional study of 3393 women > or = 65 years of age participating in the Cardiovascular Health Study. Protein C antigen and antithrombin were measured in all users (n = 230 unopposed oestrogen; 60 oestrogen/progestin) and a comparison group of 196 age- and race-matched non-users. Compared with non-users, oestrogen use was associated with higher protein C (4.80 vs. 4.30 microg/ml, P < 0.01). Results were similar for oestrogen/progestin (P > 0.05). In both user groups, antithrombin was lower than in non-users (109% for each vs. 115% in non-users, P < 0.001). Adjustment for factors related to prescription of HRT and to anticoagulant protein levels had little impact on the results. For antithrombin, associations with HRT were larger for thinner Caucasian women and black women. Venous thrombosis from HRT may be mediated partly by alterations in antithrombin, but not protein C concentrations. This study extends previous observations to older women, the group at highest risk of venous thromboembolism. Studies of HRT-induced alterations in anticoagulant function in relation to the occurrence of thrombosis with HRT are required.
10aAged10aAntithrombins10aBlack People10aBody Mass Index10aCross-Sectional Studies10aEstrogen Replacement Therapy10aFemale10aHumans10aLogistic Models10aPostmenopause10aProgestins10aProtein C10aRisk Factors10aVenous Thrombosis10aWhite People1 aCushman, M1 aPsaty, B M1 aMeilahn, E, N1 aDobs, A, S1 aKuller, L H uhttps://chs-nhlbi.org/node/65902203nas a2200289 4500008004100000022001400041245007000055210006900125260000900194300001100203490000700214520146600221653001601687653000901703653001001712653001101722653001801733653001101751653000901762653001601771653002001787653002401807653001601831100001301847700001801860856003501878 2001 eng d a0962-934300aProbabilities of transition among health states for older adults.0 aProbabilities of transition among health states for older adults c2001 a431-420 v103 aGOAL: To estimate the probabilities of transition among self-rated health states for older adults, and examine how they vary by age and sex.
METHODS: We used self-rated health (excellent, very good, good, fair, poor, dead) collected in two longitudinal studies of older adults (mean age 75) to estimate the probability of transition in 2 years. We used the estimates to project future health for selected cohorts.
FINDINGS: These older adults were most likely to be in the same health state 2 years later, but a substantial proportion changed in both directions. Transition probabilities varied by initial health state, age and sex. Men were more likely than women to transition to excellent or dead. Women were more likely than men to transition to good or fair health. Although women aged 70 will have more years of life and more years of healthy life than men, they also have more years of unhealthy life, and the proportion of remaining life that is healthy is slightly higher for men. When observed and predicted years of healthy life (YHL) were compared in various subgroups, the YHL of persons with less favorable baseline characteristics was lower than predicted, and vice-versa. Differences, however, were small (about 5%).
CONCLUSIONS: These transition probability estimates can be used to predict the future health of individuals or groups as a function of current age, sex, and self-rated health.
10aAge Factors10aAged10aAging10aFemale10aHealth Status10aHumans10aMale10aProbability10aQuality of Life10aRegression Analysis10aSex Factors1 aDiehr, P1 aPatrick, D, L uhttps://chs-nhlbi.org/node/67302542nas a2200421 4500008004100000022001400041245011300055210006900168260001600237300000900253490000800262520136000270653001001630653000901640653002501649653002801674653002801702653002801730653001101758653001101769653001801780653002501798653000901823653001601832653002001848653001701868653002601885653001801911100001701929700001601946700001401962700001501976700001501991700002002006700001502026710004402041856003502085 2001 eng d a0002-926200aRelation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study.0 aRelation of sleepdisordered breathing to cardiovascular disease c2001 Jul 01 a50-90 v1543 aAssociations between sleep-disordered breathing and cardiovascular disease (CVD) may be mediated by higher cardiovascular risk factor levels in those with sleep-disordered breathing. The authors examined these relations in the Sleep Heart Health Study, a multiethnic cohort of 6,440 men and women over age 40 years conducted from October 1995 to February 1998 and characterized by home polysomnography. In 4,991 participants who were free of self-reported CVD at the time of the sleep study, moderate levels of sleep-disordered breathing were common, with a median Respiratory Disturbance Index (RDI) of 4.0 (interquartile range, 1.25-10.7). The level of RDI was associated cross-sectionally with age, body mass index, waist-to-hip ratio, hypertension, diabetes, and lipid levels. These relations were more pronounced in those under age 65 years than in those over age 65. Women under age 65 years with RDI in the higher quartiles were more obese than men with similar RDI. Although the pattern of associations was consistent with greater obesity in those with higher RDI, higher body mass index did not explain all of these associations. If sleep-disordered breathing is shown in future follow-up to increase the risk for incident CVD events, part of the risk is likely to be due to the higher cardiovascular risk factors in those with higher RDI.
10aAdult10aAged10aAnalysis of Variance10aCardiovascular Diseases10aChi-Square Distribution10aCross-Sectional Studies10aFemale10aHumans10aLinear Models10aLongitudinal Studies10aMale10aMiddle Aged10aPolysomnography10aRisk Factors10aSleep Apnea Syndromes10aUnited States1 aNewman, A, B1 aNieto, F, J1 aGuidry, U1 aLind, B, K1 aRedline, S1 aPickering, T, G1 aQuan, S, F1 aSleep Heart Health Study Research Group uhttps://chs-nhlbi.org/node/65403470nas a2200469 4500008004100000022001400041245012400055210006900179260001300248300001100261490000700272520212500279653003102404653002102435653000902456653002202465653004402487653001902531653001202550653002802562653001102590653003202601653002002633653001102653653001402664653000902678653002602687653003002713653003202743653002402775653001702799653001202816653001802828100001702846700001802863700001902881700001702900700001602917700001702933700001502950856003502965 2001 eng d a0002-861400aRisk factors for hospitalized gastrointestinal bleeding among older persons. Cardiovascular Health Study Investigators.0 aRisk factors for hospitalized gastrointestinal bleeding among ol c2001 Feb a126-330 v493 aOBJECTIVES: We sought to estimate the incidence of hospitalization for upper and lower gastrointestinal bleeding among older persons and to identify independent risk factors.
DESIGN: Prospective cohort study.
SETTING: The Cardiovascular Health Study (CHS).
PARTICIPANTS: 5,888 noninstitutionalized men and women age 65 years or older in four U.S. communities enrolled in the CHS.
MEASUREMENTS: Gastrointestinal bleeding events during the period 1989 through 1998 were identified using hospital discharge diagnosis codes and confirmed by medical records review. Risk-factor information was collected in a standardized fashion at study baseline and annually during follow-up.
RESULTS: Among CHS participants (mean baseline age 73.3 years, 42% male), the incidence of hospitalized gastrointestinal bleeding was 6.8/1,000 person-years. In multivariate analyses, advanced age, male sex, unmarried status, cardiovascular disease, difficulty with daily activities, use of multiple medications, and use of oral anticoagulants were independent risk factors. Compared with nonsmokers, subjects who smoked more than half a pack per day had a multivariate-adjusted hazard ratio (HR) of 2.14 (95% confidence interval [CI] = 1.22-3.75) for upper gastrointestinal bleeding and a multivariate-adjusted HR of 0.21 (95% CI = 0.03-1.54) for lower gastrointestinal bleeding. Aspirin users did not have an elevated risk of upper gastrointestinal bleeding (HR = 0.76, 95% CI = 0.52-1.11), and users of other nonsteroidal anti-inflammatory drugs had a HR of 1.54 (95 % CI = 0.99-2.36). Low ankle-arm systolic blood pressure index was associated with higher risk of gastrointestinal bleeding among subjects with clinical cardiovascular disease but not among those without clinical cardiovascular disease.
CONCLUSION: This study identifies risk factors for gastrointestinal bleeding, such as disability, that may be amenable to modification. The findings will help clinicians to identify older persons who are at high risk for gastrointestinal bleeding.
10aActivities of Daily Living10aAge Distribution10aAged10aAged, 80 and over10aAnti-Inflammatory Agents, Non-Steroidal10aAnticoagulants10aAspirin10aCardiovascular Diseases10aFemale10aGastrointestinal Hemorrhage10aHospitalization10aHumans10aIncidence10aMale10aMultivariate Analysis10aPredictive Value of Tests10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSmoking10aUnited States1 aKaplan, R, C1 aHeckbert, S R1 aKoepsell, T, D1 aFurberg, C D1 aPolak, J, F1 aSchoen, R, E1 aPsaty, B M uhttps://chs-nhlbi.org/node/63502111nas a2200385 4500008004100000022001400041245009200055210006900147260001300216300001200229490000700241520101100248653000901259653002001268653003201288653003001320653001901350653001601369653002201385653001101407653001101418653003001429653000801459653000901467653001501476653003201491653003101523100001701554700001801571700002201589700001601611700001601627710004701643856003501690 2001 eng d a0895-435600aThe role of comorbidity in the assessment of intermittent claudication in older adults.0 arole of comorbidity in the assessment of intermittent claudicati c2001 Mar a294-3000 v543 aThe prevalence of intermittent claudication (IC) in older adults by questionnaire is less than 5% while the prevalence of peripheral arterial disease (PAD) by non-invasive testing is 2-4-fold higher. Comorbid conditions may result in under-reporting intermittent claudication (IC) as assessed by the Rose Questionnaire. We examined characteristics of those who report leg pain in relationship to other comorbid conditions and disability in 5888 participants of the Cardiovascular Health Study (CHS). Older adults with exertional leg pain, not meeting criteria for IC, had a higher prevalence of PAD on non-invasive testing with the ankle-arm index than those without pain, as well as a higher prevalence of arthritis. The pattern of responses suggested that pain for both conditions was reported together. The Rose Questionnaire for IC is specific for PAD, but a negative questionnaire does not indicate a lack of symptoms, rather the presence of PAD along with other conditions that can cause pain.
10aAged10aAngina Pectoris10aArterial Occlusive Diseases10aCerebrovascular Disorders10aCohort Studies10aComorbidity10aDiabetes Mellitus10aFemale10aHumans10aIntermittent Claudication10aLeg10aMale10aPrevalence10aSensitivity and Specificity10aSurveys and Questionnaires1 aNewman, A, B1 aNaydeck, B, L1 aSutton-Tyrrell, K1 aPolak, J, F1 aKuller, L H1 aCardiovascular Health Study Research Group uhttps://chs-nhlbi.org/node/63802720nas a2200373 4500008004100000022001400041245008800055210006900143260001600212300001100228490000700239520168800246653000901934653002401943653001901967653001101986653002201997653001102019653001402030653003102044653000902075653003002084653001702114653001102131100001502142700001402157700001502171700002002186700001502206700001702221700001302238710006002251856003502311 2001 eng d a0028-387800aSilent MRI infarcts and the risk of future stroke: the cardiovascular health study.0 aSilent MRI infarcts and the risk of future stroke the cardiovasc c2001 Oct 09 a1222-90 v573 aBACKGROUND: Silent infarcts are commonly discovered on cranial MRI in the elderly.
OBJECTIVE: To examine the association between risk of stroke and presence of silent infarcts, alone and in combination with other stroke risk factors.
METHODS: Participants (3,324) in the Cardiovascular Health Study (CHS) without a history of stroke underwent cranial MRI scans between 1992 and 1994. Silent infarcts were defined as focal lesions greater than 3 mm that were hyperintense on T2 images and, if subcortical, hypointense on T1 images. Incident strokes were identified and classified over an average follow-up of 4 years. The authors evaluated the risk of subsequent symptomatic stroke and how it was modified by other potential stroke risk factors among those with silent infarcts.
RESULTS: Approximately 28% of CHS participants had evidence of silent infarcts (n = 923). The incidence of stroke was 18.7 per 1,000 person-years in those with silent infarcts (n = 67) compared with 9.5 per 1,000 person-years in the absence of silent infarcts. The adjusted relative risk of incident stroke increased with multiple (more than one) silent infarcts (hazard ratio 1.9 [1.2 to 2.8]). Higher values of diastolic and systolic blood pressure, common and internal carotid wall thickness, and the presence of atrial fibrillation were associated with an increased risk of strokes in those with silent infarcts (n = 53 strokes).
CONCLUSION: The presence of silent cerebral infarcts on MRI is an independent predictor of the risk of symptomatic stroke over a 4-year follow- up in older individuals without a clinical history of stroke.
10aAged10aCerebral Infarction10aCohort Studies10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMagnetic Resonance Imaging10aMale10aPredictive Value of Tests10aRisk Factors10aStroke1 aBernick, C1 aKuller, L1 aDulberg, C1 aLongstreth, W T1 aManolio, T1 aBeauchamp, N1 aPrice, T1 aCardiovascular Health Study Collaborative Reseach Group uhttps://chs-nhlbi.org/node/66302704nas a2200373 4500008004100000022001400041245010300055210006900158260001300227300001100240490000700251520168500258653000901943653003701952653001001989653002001999653001102019653001802030653001102048653002002059653002502079653000902104653002402113653002002137653001402157653003102171100001302202700001802215700001502233700001602248700001602264700001502280856003502295 2001 eng d a0025-707900aTransforming self-rated health and the SF-36 scales to include death and improve interpretability.0 aTransforming selfrated health and the SF36 scales to include dea c2001 Jul a670-800 v393 aBACKGROUND: Most measures of health-related quality of life are undefined for people who die. Longitudinal analyses are often limited to a healthier cohort (survivors) that cannot be identified prospectively, and that may have had little change in health.
OBJECTIVE: To develop and evaluate methods to transform a single self-rated health item (excellent to poor; EVGGFP) and the physical component score of the SF-36 (PCS) to new variables that include a defensible value for death.
METHODS: Using longitudinal data from two large studies of older adults, health variables were transformed to the probability of being healthy in the future, conditional on the current observed value; death then has the value of 0. For EVGGFP, the new transformations were compared with some that were published earlier, based on different data. For the PCS, how well three different transformations, based on different definitions of being healthy, discriminated among groups of patients, and detected change in time were assessed.
RESULTS: The new transformation for EVGGFP was similar to that published previously. Coding the 5 categories as 95, 90, 80, 30, and 15, and coding dead as 0 is recommended. The three transformations of the PCS detected group differences and change at least as well as the standard PCS.
CONCLUSION: These easily interpretable transformed variables permit keeping persons who die in the analyses. Using the transformed variables for longitudinal analyses of health when deaths occur, either for secondary or primary analysis, is recommended. This approach can be applied to other measures of health.
10aAged10aData Interpretation, Statistical10aDeath10aDecision Making10aFemale10aHealth Status10aHumans10aLogistic Models10aLongitudinal Studies10aMale10aModels, Statistical10aQuality of Life10aROC Curve10aSurveys and Questionnaires1 aDiehr, P1 aPatrick, D, L1 aSpertus, J1 aKiefe, C, I1 aMcDonell, M1 aFihn, S, D uhttps://chs-nhlbi.org/node/65801903nas a2200301 4500008004100000022001400041245006600055210006100121260001300182300001100195490000700206520112000213653000901333653001001342653001001352653001101362653002901373653001101402653001801413653002501431653000901456653002101465100001701486700002101503700002201524700002001546856003501566 2002 eng d a0895-435600aThe aging and dying processes and the health of older adults.0 aaging and dying processes and the health of older adults c2002 Mar a269-780 v553 aIt is difficult to distinguish changes in health due to aging from those related to dying, because the two processes are highly related. Some potentially treatable conditions may mistakenly be dismissed as due to old age. The goal of this article was to examine the relationships of aging and of dying to changes in 10 health-related variables: self-rated health, depression, ADLs, IADLs, minimental state examination, body mass index, blocks walked per week, bed days, hospitalization, and walking speed (all coded so that higher values were better). We used longitudinal data from the Cardiovascular Health Study to estimate the changes in the variables associated with 5 years of aging and also in the 5 years before death, controlling for years from death and for age, respectively. All 10 health variables declined as death approached, and most of them also declined with age. The "effect" of the dying process was usually significantly larger than the effect of aging. Large declines in these health measures are probably not due to aging, and should be taken seriously by patients and their providers.
10aAged10aAging10aDeath10aFemale10aHealth Status Indicators10aHumans10aLinear Models10aLongitudinal Studies10aMale10aMuscular Atrophy1 aDiehr, Paula1 aWilliamson, Jeff1 aBurke, Gregory, L1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/68002960nas a2200409 4500008004100000022001400041245015100055210006900206260001300275300001100288490000700299520170300306653003902009653000902048653001902057653002802076653004002104653001102144653001902155653001102174653001702185653000902202653002602211653003402237653002702271653001802298100002302316700002302339700001902362700001902381700002002400700002202420700002402442700002402466700002502490856003502515 2002 eng d a0895-706100aAngiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events.0 aAngiotensin II type 1 receptor polymorphisms in the cardiovascul c2002 Dec a1050-60 v153 aBACKGROUND: The angiotensin II type 1 receptor A1166C polymorphism has been associated with increased risks of hypertension and myocardial infarction in several small studies. We examined the association between this polymorphism and new-onset hypertension, blood pressure (BP) control, and incident cardiovascular events in a large population-based cohort of older adults.
METHODS: Eight hundred self-identified African Americans and 1,371 randomly selected white participants in the Cardiovascular Health Study were genotyped. The median duration of follow-up was 8.1 years.
RESULTS: The A1166C polymorphism was not associated with new-onset hypertension, with BP control, or with incident cardiovascular events in the overall population. In white participants, the CC genotype was associated with higher baseline systolic BP and pulse pressure, compared to the AC or AA genotype. In whites with treated hypertension at baseline, compared to the AA genotype, the CC genotype was associated with increased risks of incident congestive heart failure (hazard ratio = 2.5, 95% confidence interval [CI] 1.3-4.9) and incident ischemic stroke (hazard ratio = 2.6, 95% CI 1.1-6.0). These associations were not observed among white participants without treated hypertension, but the interaction of genotype with treated hypertension on ischemic stroke and heart failure was only marginally significant.
CONCLUSIONS: On the whole, in this large cohort of older adults, the A1166C polymorphism was not associated with BP control or incident cardiovascular events. The subgroup findings in treated hypertensives need to be confirmed in additional studies.
10aAfrican Continental Ancestry Group10aAged10aBlood Pressure10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aHumans10aHypertension10aMale10aPolymorphism, Genetic10aReceptor, Angiotensin, Type 110aReceptors, Angiotensin10aUnited States1 aHindorff, Lucia, A1 aHeckbert, Susan, R1 aTracy, Russell1 aTang, Zhonghua1 aPsaty, Bruce, M1 aEdwards, Karen, L1 aSiscovick, David, S1 aKronmal, Richard, A1 aNazar-Stewart, Valle uhttps://chs-nhlbi.org/node/71101042nas a2200337 4500008004100000022001400041245008800055210006900143260001300212300001000225490000700235653000900242653002800251653002900279653003200308653002500340653003300365653001100398653001700409653002400426653001700450100002200467700002300489700002400512700002400536700002100560700002200581700002000603710004600623856003500669 2002 eng d a0002-072900aCalcium channel blocker use and gastrointestinal tract bleeding among older adults.0 aCalcium channel blocker use and gastrointestinal tract bleeding c2002 May a217-80 v3110aAged10aAntihypertensive Agents10aCalcium Channel Blockers10aGastrointestinal Hemorrhage10aGeriatric Assessment10aHealth Services for the Aged10aHumans10aHypertension10aProspective Studies10aRisk Factors1 aKaplan, Robert, C1 aHeckbert, Susan, R1 aKoepsell, Thomas, D1 aRosendaal, Frits, R1 aFurberg, Curt, D1 aCooper, Lawton, S1 aPsaty, Bruce, M1 aCardiovascular Health Study Investigators uhttps://chs-nhlbi.org/node/68903261nas a2200397 4500008004100000022001400041245008400055210006900139260001300208300001300221490000700234520216800241653002102409653000902430653002102439653002102460653002102481653001502502653002802517653001102545653001102556653002802567653000902595653001502604653002402619653001702643100002402660700002002684700001702704700002302721700002102744700002202765700002102787700002002808856003502828 2002 eng d a0085-253800aCardiovascular disease risk status in elderly persons with renal insufficiency.0 aCardiovascular disease risk status in elderly persons with renal c2002 Sep a997-10040 v623 aBACKGROUND: Renal insufficiency has been independently associated with incident cardiovascular disease events in some, but not all, prospective studies. We determined the prevalence of elevated cardiovascular disease risk status among elderly persons with renal insufficiency.
METHODS: This study is a cross-sectional analysis using data collected at the baseline visit of the Cardiovascular Health Study, which enrolled 5888 community dwelling adults aged 65 years or older from four clinical centers in the United States. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. The outcomes of this study included prevalent cardiovascular disease [prior coronary heart disease (CHD) or stroke], subclinical cardiovascular disease (abnormal values of ankle-arm index, carotid ultrasound, and echocardiography) and elevated cardiovascular risk based upon a diagnosis of diabetes and the Framingham equations. The association between renal insufficiency and cardiovascular risk status was estimated with and without adjustment for other cardiovascular predictors.
RESULTS: Among the 5808 participants with creatinine levels measured at entry, 15.9% of men (N = 394), and 7.6% of women (N = 254) had renal insufficiency. The prevalence of either clinical or subclinical cardiovascular disease was 64% in persons with renal insufficiency compared with 43% in those without it [odds ratio (OR) 2.34; 95% confidence interval (95% CI), 1.96, 2.80]. After adjustment for other cardiovascular risk factors, renal insufficiency remained significantly associated with clinical and subclinical cardiovascular disease (adjusted OR 1.43; 95% CI, 1.18, 1.75), but the magnitude of association was substantially reduced. After combining clinical and subclinical cardiovascular disease, diabetes, and an estimated risk>20% by the Framingham equations, 78% of men and 61% of women with renal insufficiency had elevated cardiovascular risk status.
CONCLUSIONS: Renal insufficiency is a marker for elevated cardiovascular disease risk in community dwelling elderly adults.
10aAge Distribution10aAged10aCholesterol, HDL10aCholesterol, LDL10aCoronary Disease10aCreatinine10aCross-Sectional Studies10aFemale10aHumans10aKidney Failure, Chronic10aMale10aPrevalence10aProspective Studies10aRisk Factors1 aShlipak, Michael, G1 aFried, Linda, F1 aCrump, Casey1 aBleyer, Anthony, J1 aManolio, Teri, A1 aTracy, Russell, P1 aFurberg, Curt, D1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/69702765nas a2200373 4500008004100000022001400041245013000055210006900185260001600254300001100270490000800281520168800289653000901977653002101986653001102007653001102018653001402029653000902043653001602052653002602068653003202094653002402126653002302150653001702173653001802190653002202208100002002230700001802250700002302268700002302291700002102314700002102335856003502356 2002 eng d a0003-992600aCardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology.0 aCardiovascular risk factors and venous thromboembolism incidence c2002 May 27 a1182-90 v1623 aBACKGROUND: The association between traditional cardiovascular risk factors and risk of venous thromboembolism (VTE) has not been extensively examined in prospective studies.
METHODS: To determine whether atherosclerotic risk factors are also associated with increased incidence of VTE, we conducted a prospective study of 19 293 men and women without previous VTE in 6 US communities between 1987 and 1998.
RESULTS: There were 215 validated VTE events (1.45 per 1000 person-years) during a median of 8 years of follow-up. The age-adjusted hazard ratio was 1.4 (95% confidence interval [CI], 1.1-1.9) for men vs women, 1.6 (95% CI, 1.2-2.2) for blacks vs whites, and 1.7 (95% CI, 1.5-2.0) per decade of age. Cigarette smoking, hypertension, dyslipidemia, physical inactivity, and alcohol consumption were not associated with risk of VTE. Age-, race-, and sex-adjusted hazard ratios for body mass index categories (calculated as the weight in kilograms divided by the height in meters squared) of less than 25, 25 to less than 30, 30 to less than 35, 35 to less than 40, and 40 or more were 1.0, 1.5, 2.2, 1.5, and 2.7, respectively (P<.001 for the trend). Diabetes was also associated with an increased risk of VTE (adjusted hazard ratio, 1.5 [95% CI, 1.0-2.1]).
CONCLUSIONS: Our data showing no relationship of some arterial risk factors with VTE corroborate the view that the etiology of VTE differs from atherosclerotic cardiovascular disease. In addition, the findings suggest a hypothesis that avoidance of obesity and diabetes or vigilance in prophylaxis in patients with those conditions may prevent some venous thromboses.
10aAged10aArteriosclerosis10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aMultivariate Analysis10aProportional Hazards Models10aProspective Studies10aPulmonary Embolism10aRisk Factors10aUnited States10aVenous Thrombosis1 aTsai, Albert, W1 aCushman, Mary1 aRosamond, Wayne, D1 aHeckbert, Susan, R1 aPolak, Joseph, F1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/69103016nas a2200397 4500008004100000022001400041245015200055210006900207260001600276300001100292490000800303520182700311653000902138653001802147653002802165653001202193653001102205653002702216653001102243653000902254653002602263653003002289653003202319653002002351653001102371100002302382700002402405700002102429700002102450700002302471700002102494700002402515700002402539700002002563856003502583 2002 eng d a0003-992600aFasting and 2-hour postchallenge serum glucose measures and risk of incident cardiovascular events in the elderly: the Cardiovascular Health Study.0 aFasting and 2hour postchallenge serum glucose measures and risk c2002 Jan 28 a209-160 v1623 aBACKGROUND: The contributions of fasting and 2-hour postchallenge glucose level to cardiovascular events remain ill-defined, especially for nondiabetic adults. This study examined the relative predictive power of fasting and 2-hour glucose level on cardiovascular event risk.
METHODS: A total of 4014 community-dwelling adults 65 years or older who participated in the baseline visit of the Cardiovascular Health Study and who were without treated diabetes or previous myocardial infarction or stroke were eligible for analyses. Participants with treated diabetes at baseline were excluded. Incident myocardial infarction or stroke, or coronary death, was the outcome of interest. Age-, sex-, and race-adjusted proportional hazards regression models described individual and joint associations between baseline measures of fasting and 2-hour postchallenge glucose level and event risk.
RESULTS: There were 764 incident cardiovascular events during 8.5 years of follow-up. Fasting glucose level of 115 mg/dL (6.4 mmol/L) or more was associated with an increased cardiovascular risk (hazard ratio [HR], 1.66 [95% confidence interval (CI), 1.39-1.98]) in adjusted analyses compared with fasting glucose level less than 115 mg/dL. Two-hour glucose level was associated with a linear risk (HR, 1.02 [95% CI, 1.00-1.04] per 10 mg/dL [0.6 mmol/L]) that included an additional increase in risk for 2-hour glucose level of 154 mg/dL (8.5 mmol/L) or more (HR, 1.29 [95% CI, 1.04-1.59]) in adjusted analyses. In joint fasting and 2-hour glucose models, only 2-hour glucose level remained predictive of event risk.
CONCLUSIONS: Two-hour glucose level was better than fasting glucose level alone at identifying older adults at increased risk of major incident cardiovascular events.
10aAged10aBlood Glucose10aCardiovascular Diseases10aFasting10aFemale10aGlucose Tolerance Test10aHumans10aMale10aMyocardial Infarction10aPredictive Value of Tests10aProportional Hazards Models10aRisk Assessment10aStroke1 aSmith, Nicholas, L1 aBarzilay, Joshua, I1 aShaffer, Douglas1 aSavage, Peter, J1 aHeckbert, Susan, R1 aKuller, Lewis, H1 aKronmal, Richard, A1 aResnick, Helaine, E1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/67503238nas a2200397 4500008004100000022001400041245013200055210006900187260001300256300001100269490000700280520209000287653001602377653000902393653001802402653001902420653002802439653002102467653002802488653002702516653002202543653001102565653001102576653000902587653001502596653002402611653001702635100002302652700002102675700002302696700002402719700002102743700002102764700002002785856003502805 2002 eng d a0002-861400aGlucose, blood pressure, and lipid control in older people with and without diabetes mellitus: the Cardiovascular Health Study.0 aGlucose blood pressure and lipid control in older people with an c2002 Mar a416-230 v503 aOBJECTIVES: To determine the prevalence of cardiovascular risk-factor treatment and control in older adults with normal fasting glucose, impaired fasting glucose, and diabetes mellitus and whether those with diabetes mellitus had better risk factor control than older adults with normal fasting glucose.
DESIGN: Secondary analysis of data from population-based, prospective cohort study of risk factors for cardio-vascular and cerebrovascular disease in older people (Cardiovascular Health Study).
SETTING: Community-based.
PARTICIPANTS: Community-dwelling adults aged 65 and older.
MEASUREMENTS: Fasting plasma glucose, serum cholesterol and its subfractions, systolic and diastolic blood pressures, and body mass index.
RESULTS: There were 579 (18%) cohort members with diabetes mellitus (77% receiving antidiabetic medication, 23% with fasting glucose > or =126 mg/dL and no treatment), 213 (6%) with impaired fasting glucose, and 2,582 (77%)with normal fasting glucose. Of diabetic participants, 12% had recommended fasting glucose levels of less than 110 mg/dL. Of participants with hypertension, a larger proportion of diabetic participants than nondiabetic participants (89% versus 75%, P < .01) was treated with antihypertensive agents, but a smaller proportion of diabetic participants had recommended blood pressure levels of 129/85 mmHg or lower than nondiabetic participants had recommended blood pressure levels of 139/89 mmHg or lower (27% vs 48%, P < .01). Diabetic dyslipidemic participants were treated less often with lipid-lowering therapy (26% versus 55%, P < .01) and achieved recommended low-density lipoprotein goals less often (8%versus 54%, P < .01) than nondiabetic dyslipidemic participants.
CONCLUSIONS: Overall, treatment and control of cardiovascular risk factors were suboptimal in this older population, especially among those with diabetes mellitus. Optimizing risk-factor control can improve health outcomes in older adults with and without diabetes mellitus.
10aAge Factors10aAged10aBlood Glucose10aBlood Pressure10aCardiovascular Diseases10aCholesterol, LDL10aCross-Sectional Studies10aDiabetes Complications10aDiabetes Mellitus10aFemale10aHumans10aMale10aPrevalence10aProspective Studies10aRisk Factors1 aSmith, Nicholas, L1 aSavage, Peter, J1 aHeckbert, Susan, R1 aBarzilay, Joshua, I1 aBittner, Vera, A1 aKuller, Lewis, H1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/68503032nas a2200445 4500008004100000022001400041245013100055210006900186260001600255300001200271490000700283520175100290653000902041653001002050653002602060653002502086653001902111653002102130653001102151653001802162653001102180653002202191653002202213653002302235653003602258653000902294653004502303653001702348653001602365100001802381700001802399700001902417700001702436700001602453700001702469700002102486700002302507700002102530856003502551 2002 eng d a1524-463600aNuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study.0 aNuclear magnetic resonance spectroscopy of lipoproteins and risk c2002 Jul 01 a1175-800 v223 aOBJECTIVES: Relationships between incident cardiovascular disease and lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy were evaluated in the Cardiovascular Health Study (CHS) in a nested case-cohort analysis.
METHODS AND RESULTS: The case group consisted of 434 participants with incident myocardial infarction (MI) and angina diagnosed after entry to the study (1990 to 1995) and the comparison group, 249 "healthy" participants with no prevalent clinical or subclinical disease. By univariate analysis, the median levels for healthy participants versus participants with incident MI and angina were 0 versus 7 mg% for small low density lipoprotein (LDL), 1501 versus 1680 nmol/L for the number of LDL particles, and 21.6 versus 21.3 for LDL size, and these values were significantly different between "healthy" participants and those with incident MI and angina for women but not men. The levels of less dense LDL, which is most of the total LDL cholesterol among women, was not related to incident MI and angina. For women, large high density lipoprotein cholesterol (HDLc), but not small HDLc, levels were significantly higher for healthy participants compared with levels for participants with MI and angina. For men and women, levels of total and very low density lipoprotein triglycerides were higher for the case group than for the healthy group. In multivariate models for women that included triglycerides and HDLc, the number of LDL particles (but not LDL size) remained significantly related to MI and angina.
CONCLUSIONS: Small LDL, the size of LDL particles, and the greater number of LDL particles are related to incident coronary heart disease among older women.
10aAged10aAging10aCardiovascular System10aCase-Control Studies10aCohort Studies10aCoronary Disease10aFemale10aHealth Status10aHumans10aLipoproteins, HDL10aLipoproteins, LDL10aLipoproteins, VLDL10aMagnetic Resonance Spectroscopy10aMale10aNuclear Magnetic Resonance, Biomolecular10aRisk Factors10aSex Factors1 aKuller, Lewis1 aArnold, Alice1 aTracy, Russell1 aOtvos, James1 aBurke, Greg1 aPsaty, Bruce1 aSiscovick, David1 aFreedman, David, S1 aKronmal, Richard uhttps://chs-nhlbi.org/node/69603533nas a2200457 4500008004100000022001400041245014200055210006900197260001600266300001000282490000800292520220800300653000902508653001902517653002102536653001102557653001802568653001102586653002502597653000902622653002602631653001502657653001402672653001702686653001102703653003502714653003102749100002402780700002502804700002102829700002002850700002102870700002302891700001802914700001802932700002202950700002202972700002502994700002103019856003503040 2002 eng d a1539-370400aOutcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study.0 aOutcome of congestive heart failure in elderly persons influence c2002 Oct 15 a631-90 v1373 aBACKGROUND: Most persons with congestive heart failure are elderly, and many elderly persons with congestive heart failure have normal left ventricular systolic function.
OBJECTIVE: To evaluate the relationship between left ventricular systolic function and outcome of congestive heart failure in elderly persons.
DESIGN: Population-based longitudinal study of coronary heart disease and stroke.
SETTING: Four U.S. sites: Forsyth County, North Carolina; Sacramento County, California; Allegheny County, Pennsylvania; and Washington County, Maryland.
PARTICIPANTS: 5888 persons who were at least 65 years of age and were recruited from the community.
MEASUREMENTS: Total mortality and cardiovascular morbidity and mortality.
RESULTS: Of 5532 participants, 269 (4.9%) had congestive heart failure. Among these, left ventricular function was normal in 63%, borderline decreased in 15%, and overtly impaired in 22%. The mortality rate was 25 deaths per 1000 person-years in the reference group (no congestive heart failure and normal left ventricular function at baseline); 154 deaths per 1000 person-years in participants with congestive heart failure and impaired left ventricular systolic function; 87 and 115 deaths per 1000 person-years in participants with congestive heart failure and normal or borderline systolic function, respectively; and 89 deaths per 1000 person-years in persons with impaired left ventricular function but no congestive heart failure. Although the risk for death from congestive heart failure was lower in persons with normal systolic function than in those with impaired function, more deaths were associated with normal systolic function because more persons with heart failure fall into this category.
CONCLUSIONS: Community-dwelling elderly persons, especially those with impaired left ventricular function, have a substantial risk for death from congestive heart failure. However, more deaths occur from heart failure in persons with normal systolic function because left ventricular function is more often normal than impaired in elderly persons with heart failure.
10aAged10aCause of Death10aEchocardiography10aFemale10aHeart Failure10aHumans10aLongitudinal Studies10aMale10aMyocardial Infarction10aPrevalence10aPrognosis10aRisk Factors10aStroke10aVentricular Dysfunction, Right10aVentricular Function, Left1 aGottdiener, John, S1 aMcClelland, Robyn, L1 aMarshall, Robert1 aShemanski, Lynn1 aFurberg, Curt, D1 aKitzman, Dalane, W1 aCushman, Mary1 aPolak, Joseph1 aGardin, Julius, M1 aGersh, Bernard, J1 aAurigemma, Gerard, P1 aManolio, Teri, A uhttps://chs-nhlbi.org/node/70501489nas a2200289 4500008004100000022001400041245008500055210006900140260001300209300000900222490000700231520067800238653000900916653000900925653002100934653001100955653001700966653002400983653002401007653001701031100001701048700002401065700002301089700002001112710003201132856003501164 2002 eng d a1047-279700aA regression model for longitudinal change in the presence of measurement error.0 aregression model for longitudinal change in the presence of meas c2002 Jan a34-80 v123 aPURPOSE: The analysis of change in measured variables has become quite popular in studies where data are collected repeatedly over time. The authors describe some of the potential pitfalls in the analysis of change when the variable for change is measured with error. They show that regression analysis is often biased, possibly leading to erroneous results.
METHODS: A simple method to correct for measurement error bias in regression models that model change is presented.
RESULTS AND CONCLUSIONS: The two examples illustrate how measurement error can adversely affect an analysis. The bias-corrected approach yields valid results.
10aAged10aBias10aCoronary Disease10aHumans10aLipoproteins10aModels, Statistical10aRegression Analysis10aRisk Factors1 aYanez, David1 aKronmal, Richard, A1 aShemanski, Lynn, R1 aPsaty, Bruce, M1 aCardiovascular Health Study uhttps://chs-nhlbi.org/node/67203590nas a2200469 4500008004100000022001400041245013400055210006900189260001300258300001000271490000700281520225800288653001702546653000902563653002202572653002102594653001702615653001902632653001902651653003002670653002502700653001102725653001102736653002502747653000902772653001502781653002402796653002402820653001702844653001702861653001702878100001802895700002102913700002102934700002102955700002202976700002402998700002203022700002203044700001903066856003503085 2002 eng d a0007-116100aThe relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study.0 arelation of atherosclerotic cardiovascular disease to retinopath c2002 Jan a84-900 v863 aAIMS: To describe the association of retinopathy with atherosclerosis and atherosclerotic risk factors in people with diabetes.
METHODS: 296 of the 558 people classified as having diabetes by the American Diabetes Association criteria, from a population based cohort of adults (ranging in age from 69 to 102 years) living in four United States communities (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were studied from 1997 to 1998. Lesions typical of diabetic retinopathy were determined by grading a 45 degrees colour fundus photograph of one eye of each participant, using a modification of the Airlie House classification system.
RESULTS: Retinopathy was present in 20% of the diabetic cohort, with the lowest prevalence (16%), in those 80 years of age or older. Retinopathy was detected in 20.3% of the 296 people with diabetes; 2.7% of the 296 had signs of proliferative retinopathy and 2.1% had signs of macular oedema. The prevalence of diabetic retinopathy was higher in black people (35.4%) than white (16.0%). Controlling for age, sex, and blood glucose, retinopathy was more frequent in black people than white (odds ratio (OR) 2.26, 95% confidence interval (CI) 1.01, 5.05), in those with longer duration of diabetes (OR (per 5 years of diabetes) 1.42, 95% CI 1.18, 1.70), in those with subclinical cardiovascular disease (OR 1.49, 95% CI 0.51, 4.31), or coronary heart disease or stroke (OR 3.23, 95% CI 1.09, 9.56) than those without those diseases, in those with higher plasma low density lipoprotein (LDL) cholesterol (OR (per 10 mg/dl of LDL cholesterol) 1.12, 95% CI 1.02, 1.23), and in those with gross proteinuria (OR 4.76, 95% CI 1.53, 14.86).
CONCLUSION: Data from this population based study suggest a higher prevalence of retinopathy in black people than white people with diabetes and the association of cardiovascular disease, elevated plasma LDL cholesterol, and gross proteinuria with diabetic retinopathy. However, any conclusions or explanations regarding associations described here must be made with caution because only about one half of those with diabetes mellitus were evaluated.
10aAge of Onset10aAged10aAged, 80 and over10aArteriosclerosis10aBlack People10aBlood Pressure10aCohort Studies10aDiabetes Mellitus, Type 210aDiabetic Retinopathy10aFemale10aHumans10aLongitudinal Studies10aMale10aOdds Ratio10aProspective Studies10aRegression Analysis10aRisk Factors10aTime Factors10aWhite People1 aKlein, Ronald1 aMarino, Emily, K1 aKuller, Lewis, H1 aPolak, Joseph, F1 aTracy, Russell, P1 aGottdiener, John, S1 aBurke, Gregory, L1 aHubbard, Larry, D1 aBoineau, Robin uhttps://chs-nhlbi.org/node/67402789nas a2200241 4500008004100000022004300041024003600084245009200120210006900212260001500281300000800296490000700304520208500311653001202396653001202408653001602420653001802436100001302454700001402467700001602481700001402497856003602511 2002 eng d a1606-6359 print: ISSN 1476-7392 online aDOI 10.1080/160663502100001028900aReproducibility of two approaches for assessing alcohol consumption among older adults.0 aReproducibility of two approaches for assessing alcohol consumpt c2002-01-01 a3850 v103 aObjectives: In this study, we hypothesized that there is greater disclosure in self reports of alcohol intake when details of quantity-frequency measures of alcohol consumption are ascertained in the context of a general health and life style questionnaire as compared to a directed interview on usual drinking habits.
Methods: Data are from the 1993 to 1994 follow-up of the Washington County cohort of men and women 65 years and older, participating in the Cardiovascular Health Study. A total of 918 subjects completed a questionnaire evaluation of their usual alcohol consumption by two separate approaches: (1) alcohol intake was derived from responses to questions contained within a medical and personal history questionnaire; (2) the same questions were within a medical and personal history questionnaire.
Results: The mean alcohol intake for the entire cohort, and for drinkers alone were almost identical when assessed by either questionnaire, with high correlation between the two estimates, irrespective of beverage type. There was 89% agreement classifying drinkers versus nondrinkers by both approaches, with the strength of the agreement good (k=0.76). This agreement became moderate if drinkers were further categorized into three levels of alcohol intake. Predictors of the differences in alcohol intake between the two questionnaires were explored by multiple regression. Differences were largest for those who stated that the reason they drank was because they were no longer working, and for those drinking on average more than 24g (greater than approximately 2 drinks) of alcohol daily.
Discussion: Although agreement between the two approaches was generally comparable, some findings may indicate that older adults who are problem drinkers or drink heavily report lower consumption patterns when administered a more directed questionnaire specifically focusing on drinking behavior. These findings have implications in the design of studies measuring alcohol consumption among elderly persons with a relatively low background alcohol intake. 10aalcohol10aelderly10ameasurement10aquestionnaire1 aCrum, RM1 aPuddey, I1 aGilbert, CG1 aFried, LP uhttps://chs-nhlbi.org/node/152902696nas a2200361 4500008004100000022001400041245008300055210006900138260001600207300001100223490000700234520171800241653000901959653001901968653002501987653001402012653001102026653001802037653000902055653001402064653002302078653003202101653002402133653001702157653001102174100001602185700001702201700001802218700001502236700001602251710003202267856003502299 2002 eng d a0028-387800aSerum potassium level and dietary potassium intake as risk factors for stroke.0 aSerum potassium level and dietary potassium intake as risk facto c2002 Aug 13 a314-200 v593 aBACKGROUND: Numerous studies have found that low potassium intake and low serum potassium are associated with increased stroke mortality, but data regarding stroke incidence have been limited. Serum potassium levels, dietary potassium intake, and diuretic use in relation to risk for stroke in a prospectively studied cohort were investigated.
METHODS: The study comprised 5,600 men and women older than 65 years who were free of stroke at enrollment. Baseline data included serum potassium level, dietary potassium intake, and diuretic use. Participants were followed for 4 to 8 years, and the incidence and types of strokes were recorded. Low serum potassium was defined as less than 4.1 mEq/L, and low potassium intake as less than 2.4 g/d.
RESULTS: Among diuretic users, there was an increased risk for stroke associated with lower serum potassium (relative risk [RR]: 2.5, p < 0.0001). Among individuals not taking diuretics, there was an increased risk for stroke associated with low dietary potassium intake (RR: 1.5, p < 0.005). The small number of diuretic users with lower serum potassium and atrial fibrillation had a 10-fold greater risk for stroke compared with those with higher serum potassium and normal sinus rhythm.
CONCLUSIONS: A lower serum potassium level in diuretic users, and low potassium intake in those not taking diuretics were associated with increased stroke incidence among older individuals. Lower serum potassium was associated with a particularly high risk for stroke in the small number of diuretic users with atrial fibrillation. Further study is required to determine if modification of these factors would prevent strokes.
10aAged10aCohort Studies10aConfidence Intervals10aDiuretics10aHumans10aLinear Models10aMale10aPotassium10aPotassium, Dietary10aProportional Hazards Models10aProspective Studies10aRisk Factors10aStroke1 aGreen, D, M1 aRopper, A, H1 aKronmal, R, A1 aPsaty, B M1 aBurke, G, L1 aCardiovascular Health Study uhttps://chs-nhlbi.org/node/69803096nas a2200385 4500008004100000022001400041245019900055210006900254260001600323300001300339490000800352520187000360653000902230653002102239653002102260653001102281653002202292653001102314653005102325653002502376653002502401653001402426653000902440653002602449653003202475653001702507653001802524100002402542700002002566700002302586700002402609700002002633700002202653856003502675 2002 eng d a0003-992600aTherapy with hydroxymethylglutaryl coenzyme a reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study.0 aTherapy with hydroxymethylglutaryl coenzyme a reductase inhibito c2002 Jun 24 a1395-4000 v1623 aBACKGROUND: Recommendations to treat older adults with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) for the primary prevention of coronary heart disease events are supported by a single clinical trial restricted to adults 73 years or younger with low levels of high-density lipoprotein cholesterol.
METHODS: We investigated the association of statin use with incident cardiovascular disease and all-cause mortality during up to 7.3 years' follow-up of 1250 women and 664 men from the Cardiovascular Health Study. Study participants were 65 years and older and free of cardiovascular disease at baseline. They received drug therapy to lower cholesterol levels at baseline or no treatment with a recommendation for therapy according to the National Cholesterol Education Program guidelines. Use of these drugs was assessed annually. We used proportional-hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for confounding variables.
RESULTS: We found 382 incident cardiovascular events (159 myocardial infarctions, 159 strokes, and 64 deaths due to coronary heart disease) and 362 total deaths from June 1, 1989, to May 31, 1997. Compared with no use of drugs to lower cholesterol levels, statin use was associated with decreased risk of cardiovascular events (multivariate HR, 0.44; 95% CI, 0.27-0.71) and all-cause mortality (HR, 0.56; 95% CI, 0.36-0.88). Similar associations were observed among participants 74 years or older at baseline.
CONCLUSIONS: Use of statins was associated with decreased risk of incident cardiovascular events among elderly adults. These findings lend support to the National Cholesterol Education Program guidelines, which recommend therapy for the lowering of cholesterol levels for older adults with hypercholesterolemia.
10aAged10aCholesterol, LDL10aCoronary Disease10aFemale10aFollow-Up Studies10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aHypercholesterolemia10aHypolipidemic Agents10aIncidence10aMale10aMultivariate Analysis10aProportional Hazards Models10aRisk Factors10aUnited States1 aLemaitre, Rozenn, N1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aKronmal, Richard, A1 aNewman, Anne, B1 aBurke, Gregory, L uhttps://chs-nhlbi.org/node/69503826nas a2200433 4500008004100000022001400041245014100055210006900196260001600265300001200281490000800293520256400301653001602865653000902881653002802890653001402918653001902932653001702951653001102968653004202979653001103021653001703032653000903049653002403058653001703082100002003099700002103119700002303140700002303163700002403186700002203210700002003232700001803252700001903270700001503289700002103304710003203325856003503357 2002 eng d a0003-992600aTime trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study.0 aTime trends in high blood pressure control and the use of antihy c2002 Nov 11 a2325-320 v1623 aBACKGROUND: Control of high blood pressure (BP) in older adults is an important part of public health efforts at prevention.
OBJECTIVE: To assess recent time trends in the awareness, treatment, and control of high BP and in the use of medications to treat high BP.
METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline, participants underwent an extensive examination that included the measurement of BP, use of medications, and other risk factors. Participants were followed up with annual visits that assessed BP and medication use from baseline in 1989-1990 through the examination in 1998-1999. The primary outcome measures were control of BP to levels lower than than 140/90 mm Hg and the prevalence of use of various classes of antihypertensive medications.
RESULTS: The awareness, treatment, and control of high BP improved during the 1990s. The proportions aware and treated were higher among blacks than whites, though control prevalences were similar. For both groups combined, the control of high BP to lower than 140/90 mm Hg increased from 37% at baseline to 49% in 1999. The 51% whose BP was not controlled generally had isolated mild to moderate elevations in systolic BP. Among treated persons, the improvement in control was achieved in part by a mean increase of 0.2 antihypertensive medications per person over the course of 9 years. Improved control was also achieved by increasing the proportion of the entire Cardiovascular Health Study population that was treated for hypertension, from 34.5% in 1990 to 51.1% in 1999. Time trends in antihypertensive drug use were pronounced. Among those without coronary disease, the use of low-dose diuretics and beta-blockers decreased, while the use of newer agents, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers increased.
CONCLUSIONS: While control of high BP improved in the 1990s, about half the participants with hypertension had uncontrolled BP, primarily mild to moderate elevations in systolic BP. Low-dose diuretics and beta-blockers--the preferred agents since 1993 according to the recommendations of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure--remained underused. More widespread use of these agents will be an important intervention to prevent the devastating complications of hypertension, including stroke, myocardial infarction, and heart failure.
10aAge Factors10aAged10aAntihypertensive Agents10aAwareness10aCohort Studies10aDrug Therapy10aFemale10aHealth Knowledge, Attitudes, Practice10aHumans10aHypertension10aMale10aProspective Studies10aTime Factors1 aPsaty, Bruce, M1 aManolio, Teri, A1 aSmith, Nicholas, L1 aHeckbert, Susan, R1 aGottdiener, John, S1 aBurke, Gregory, L1 aWeissfeld, Joel1 aEnright, Paul1 aLumley, Thomas1 aPowe, Neil1 aFurberg, Curt, D1 aCardiovascular Health Study uhttps://chs-nhlbi.org/node/70802322nas a2200193 4500008004100000022001400041245008400055210006900139260001600208300000600224490000600230520176400236100001702000700002002017700002302037700001802060700001502078856003502093 2002 eng d a1468-670800aWeight-modification trials in older adults: what should the outcome measure be?0 aWeightmodification trials in older adults what should the outcom c2002 Jan 07 a10 v33 aBACKGROUND: Overweight older adults are often counseled to lose weight, even though there is little evidence of excess mortality in that age group. Overweight and underweight may be more associated with health status than with mortality, but few clinical trials of any kind have been based on maximizing years of healthy life (YHL), as opposed to years of life (YOL). OBJECTIVE: This paper examines the relationship of body mass index (BMI) to both YHL and YOL. Results were used to determine whether clinical trials of weight-modification based on improving YHL would be more powerful than studies based on survival. DESIGN: We used data from a cohort of 4,878 non-smoking men and women aged 65-100 at baseline (mean age 73) and followed 7 years. We estimated mean YHL and YOL in four categories of BMI: underweight, normal, overweight, and obese. RESULTS: Subjects averaged 6.3 YOL and 4.6 YHL of a possible 7 years. Both measures were higher for women and whites. For men, none of the BMI groups was significantly different from the normal group on either YOL or YHL. For women, the obese had significantly lower YHL (but not YOL) than the normals, and the underweight had significantly lower YOL and YHL. The overweight group was not significantly different from the normal group on either measure. CONCLUSIONS: Clinical trials of weight loss interventions for obese older women would require fewer participants if YHL rather than YOL was the outcome measure. Interventions for obese men or for the merely overweight are not likely to achieve differences in either YOL or YHL. Evaluations of interventions for the underweight (which would presumably address the causes of their low weight) may be conducted efficiently using either outcome measure.
1 aDiehr, Paula1 aNewman, Anne, B1 aJackson, Sharon, A1 aKuller, Lewis1 aPowe, Neil uhttps://chs-nhlbi.org/node/68702492nas a2200349 4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520147800257653000901735653002101744653002801765653002801793653002801821653001101849653001901860653001101879653002501890653000901915653002401924100002401948700002401972700002501996700002302021700002102044700001802065700002402083856003502107 2003 eng d a1524-463600aAlcohol consumption and carotid atherosclerosis in older adults: the Cardiovascular Health Study.0 aAlcohol consumption and carotid atherosclerosis in older adults c2003 Dec a2252-90 v233 aOBJECTIVE: The association of alcohol use with atherosclerosis is inconsistent in previous studies.
METHODS AND RESULTS: For the Cardiovascular Health Study, 5888 adults aged 65 years and older underwent a standardized interview and examination. They reported beer, wine, and liquor use individually and underwent B-mode ultrasonography to determine internal and common carotid intima-media thickness (IMT). We compared composite carotid IMT values cross-sectionally using linear regression to adjust for demographic and clinical characteristics. Among 4247 participants free of cardiovascular disease, consumers of 1 to 6 drinks per week had 0.07+/-0.04-mm lower composite IMT and consumers of 14 or more drinks per week had 0.07+/-0.05-mm higher IMT than abstainers (P quadratic trend=0.02). We found similar relationships using internal and common carotid thickness measures and among men and women. The higher IMT associated with heavier alcohol use was particularly strong among 1592 participants with confirmed cardiovascular disease (0.24+/-0.09 mm greater than abstainers). Controlling for HDL cholesterol levels reduced the effect on composite IMT among consumers of 1 to 6 drinks per week by 22%.
CONCLUSIONS: Relative to older adults who abstain from alcohol, consumption of 1 to 6 drinks per week had an inverse association with carotid atherosclerosis whereas consumption of 14 or more drinks had a positive association.
10aAged10aAlcohol Drinking10aCardiovascular Diseases10aCarotid Artery Diseases10aCross-Sectional Studies10aFemale10aHealth Surveys10aHumans10aLongitudinal Studies10aMale10aProspective Studies1 aMukamal, Kenneth, J1 aKronmal, Richard, A1 aMittleman, Murray, A1 aO'Leary, Daniel, H1 aPolak, Joseph, F1 aCushman, Mary1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/75302922nas a2200373 4500008004100000022001400041245011800055210006900173260001300242300001000255490000700265520188100272653000902153653001902162653002802181653001902209653001102228653001102239653001102250653001602261653000902277653002402286653002402310653001702334653001702351100002302368700002002391700001902411700001902430700001702449700002302466700002402489856003502513 2003 eng d a0002-861400aThe association between time since last meal and blood pressure in older adults: the cardiovascular health study.0 aassociation between time since last meal and blood pressure in o c2003 Jun a824-80 v513 aOBJECTIVES: To demonstrate a postprandial hypotensive (PPH) phenomenon in older adults.
DESIGN: Observational, prospective cohort study composed of baseline and nine follow-up visits.
SETTING: Cardiovascular Health Study, an epidemiological study of risk factors for cardiovascular disease in older adults.
PARTICIPANTS: Five thousand eight hundred eighty-eight community-dwelling adults aged 65 and older.
MEASUREMENTS: Blood pressure and time since last meal were recorded synchronously at baseline and at follow-up clinic visits. Generalized estimating equations were used to estimate associations between time since last meal and blood pressure and to adjust variance estimates to account for repeated blood pressure measures within subjects across fasting times.
RESULTS: Mean systolic and diastolic blood pressures were lower in the first hour after the last meal and were progressively higher through the fourth hour after the last meal than blood pressures measured immediately after the last meal (0 hour: 133.7/68.8 mmHg; 1st hour: 130.1/66.6 mmHg; 4th hour: 136.5/71.1 mmHg). Changes were significant for systolic and diastolic measures (P <.001 for both). Exploratory analyses suggested that the systolic PPH association was more pronounced in women. Little evidence was found that the degree of systolic or diastolic PPH varied by age, race, prevalent cardiovascular disease, heart rate, ejection fraction, treated hypertension or diabetes mellitus, or body mass index.
CONCLUSION: These data support previous observations that there is a significant drop in blood pressure within 1 hour after a meal in older adults. Time since last meal may be an important factor to consider when measuring blood pressure in older adults, and perhaps national standards need to be set.
10aAged10aBlood Pressure10aCardiovascular Diseases10aCohort Studies10aEating10aFemale10aHumans10aHypotension10aMale10aPostprandial Period10aProspective Studies10aRisk Factors10aTime Factors1 aSmith, Nicholas, L1 aPsaty, Bruce, M1 aRutan, Gale, H1 aLumley, Thomas1 aYanez, David1 aChaves, Paulo, H M1 aKronmal, Richard, A uhttps://chs-nhlbi.org/node/73802636nas a2200481 4500008004100000022001400041245010300055210006900158260001600227300001100243490000800254520123900262653003901501653000901540653001201549653001901561653002801580653001901608653001601627653002101643653004001664653002201704653001901726653001101745653001401756653002701770653002601797653003401823653002001857653001101877653001801888100002301906700002301929700002201952700002001974700001901994700002402013700001902037700001702056700002402073700002202097856003502119 2003 eng d a1524-453900aBeta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly.0 aBeta2adrenergic receptor polymorphisms and risk of incident card c2003 Apr 22 a2021-40 v1073 aBACKGROUND: Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study.
METHODS AND RESULTS: A total of 808 black and 4441 white participants (mean age, 73 years) were genotyped for the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenergic receptor. There were 702 incident coronary events, 438 ischemic strokes, and 1136 combined cardiovascular events during 7 to 10 years of follow-up. Allele frequencies differed by race but not by age or hypertension status. Glu27 carriers had a lower risk of coronary events than Gln27 homozygotes (hazard ratio, 0.82; 95% CI, 0.70 to 0.95), and there was a suggestion of decreased risk among Gly16 carriers compared with Arg16 homozygotes (hazard ratio, 0.88; 95% CI, 0.72 to 1.07). There was no association of beta2-adrenergic receptor genotype with ischemic stroke or combined cardiovascular events.
CONCLUSIONS: The Glu27 allele of the beta2-adrenergic receptor was associated with a lower risk of incident coronary events in this elderly population.
10aAfrican Continental Ancestry Group10aAged10aAlleles10aBrain Ischemia10aCardiovascular Diseases10aCohort Studies10aComorbidity10aCoronary Disease10aEuropean Continental Ancestry Group10aFollow-Up Studies10aGene Frequency10aHumans10aIncidence10aLinkage Disequilibrium10aPolymorphism, Genetic10aReceptors, Adrenergic, beta-210aRisk Assessment10aStroke10aUnited States1 aHeckbert, Susan, R1 aHindorff, Lucia, A1 aEdwards, Karen, L1 aPsaty, Bruce, M1 aLumley, Thomas1 aSiscovick, David, S1 aTang, Zhonghua1 aDurda, Peter1 aKronmal, Richard, A1 aTracy, Russell, P uhttps://chs-nhlbi.org/node/73303113nas a2200553 4500008004100000022001400041245013800055210006900193260001600262300001100278490000800289520158800297653000901885653001901894653002301913653001501936653002101951653001901972653001601991653001102007653002202018653001102040653001402051653002502065653000902090653001302099653001902112653001502131653001702146653003202163653002002195653001702215653001102232653001802243653001702261653002002278100001602298700001602314700002102330700002002351700002102371700002302392700002102415700002402436700002502460700002102485700001802506856003502524 2003 eng d a1524-453900aC-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study.0 aCreactive protein carotid intimamedia thickness and incidence of c2003 Jul 15 a166-700 v1083 aBACKGROUND: Increased carotid artery intima-media thickness (IMT) and elevated C-reactive protein (CRP) are both associated with the occurrence of stroke. We investigated whether elevated CRP is a risk factor for ischemic stroke independent of carotid IMT and studied the interaction between CRP and IMT.
METHODS AND RESULTS: We studied 5417 participants aged 65 years or older without preexisting stroke or chronic atrial fibrillation who were participants in the Cardiovascular Health Study. The hazard ratio of incident ischemic stroke was estimated by Cox proportional hazards regression. During 10.2 years of follow-up, 469 incident ischemic strokes occurred. The adjusted hazard ratios for ischemic stroke in the 2nd to 4th quartiles of baseline CRP, relative to the 1st quartile, were 1.19 (95% CI 0.92 to 1.53), 1.05 (95% CI 0.81 to 1.37), and 1.60 (95% CI 1.23 to 2.08), respectively. With additional adjustment for carotid IMT, there was little confounding. The association of CRP with stroke was significantly different depending on IMT (P<0.02), with no association of CRP with stroke among those in the lowest IMT tertile and a significant association among those with higher levels of IMT.
CONCLUSIONS: We conclude that elevated CRP is a risk factor for ischemic stroke, independent of atherosclerosis severity as measured by carotid IMT. The association of CRP with stroke is more apparent in the presence of a higher carotid IMT. CRP and carotid IMT may each be independent integrals in determining the risk of ischemic stroke.
10aAged10aBrain Ischemia10aC-Reactive Protein10aCalifornia10aCarotid Arteries10aCohort Studies10aComorbidity10aFemale10aFollow-Up Studies10aHumans10aIncidence10aLongitudinal Studies10aMale10aMaryland10aNorth Carolina10aOdds Ratio10aPennsylvania10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aStroke10aTunica Intima10aTunica Media10aUltrasonography1 aCao, Jie, J1 aThach, Chau1 aManolio, Teri, A1 aPsaty, Bruce, M1 aKuller, Lewis, H1 aChaves, Paulo, H M1 aPolak, Joseph, F1 aSutton-Tyrrell, Kim1 aHerrington, David, M1 aPrice, Thomas, R1 aCushman, Mary uhttps://chs-nhlbi.org/node/74103943nas a2200397 4500008004100000022001400041245008100055210006900136260001300205300001000218490000700228520285600235653000903091653002203100653001103122653001103133653002003144653000903164653001603173653002603189653001503215653001703230653002603247653002903273100002403302700001903326700001703345700001803362700001703380700001903397700001903416700002303435700002303458710002903481856003503510 2003 eng d a0149-599200aDiabetes and sleep disturbances: findings from the Sleep Heart Health Study.0 aDiabetes and sleep disturbances findings from the Sleep Heart He c2003 Mar a702-90 v263 aOBJECTIVE: To test the hypothesis that diabetes is independently associated with sleep-disordered breathing (SDB), and in particular that diabetes is associated with sleep abnormalities of a central, rather than obstructive, nature.
RESEARCH DESIGN AND METHODS: Using baseline data from the Sleep Heart Health Study (SHHS), we related diabetes to 1). the respiratory disturbance index (RDI; number of apneas plus hypopneas per h of sleep); 2). obstructive apnea index (OAI; >or=3 apneas/h of sleep associated with obstruction of the upper airway); 3). percent of sleep time < 90% O(2) saturation; 4). central apnea index (CAI; >or=3 apneas [without respiratory effort]/h sleep); 5). occurrence of a periodic breathing (Cheyne Stokes) pattern; and 6) sleep stages. Initial analyses excluding persons with prevalent cardiovascular disease (CVD) were repeated including these participants.
RESULTS: Of the 5874 participants included in this report, 692 (11.8%) reported diabetes or were taking oral hypoglycemic medications or insulin and 1002 had prevalent CVD. Among the 4872 persons without CVD, 470 (9.6%) had diabetes. Diabetic participants had worse CVD risk factor profiles than their nondiabetic counterparts, including higher BMI, waist and neck circumferences, triglycerides, higher prevalence of hypertension, and lower HDL cholesterol (P < 0.001, all). Descriptive analyses indicated differences between diabetic and nondiabetic participants in RDI, sleep stages, sleep time <90% O(2) saturation, CAI, and periodic breathing (P < 0.05, all). However, multivariable regression analyses that adjusted for age, sex, BMI, race, and neck circumference eliminated these differences for all sleep measures except percent time in rapid eye movement (REM) sleep (19.0% among diabetic vs. 20.1% among nondiabetic subjects, P < 0.001) and prevalence of periodic breathing (odds ratio [OR] for diabetic subjects versus nondiabetic subjects 1.80, 95% CI 1.02-3.15). Additionally, adjusted analyses showed diabetes was associated with nonstatistically significant elevations in the odds of an increased central breathing index (OR 1.42, 95% CI 0.80-2.55). Addition to the analysis of the 1002 persons with prevalent CVD (including 222 people with diabetes) did not materially change these results.
CONCLUSIONS: These data suggest that diabetes is associated with periodic breathing, a respiratory abnormality associated with abnormalities in the central control of ventilation. Some sleep disturbances may result from diabetes through the deleterious effects of diabetes on central control of respiration. The high prevalence of SDB in diabetes, although largely explained by obesity and other confounders, suggests the presence of a potentially treatable risk factor for CVD in the diabetic population.
10aAged10aDiabetes Mellitus10aFemale10aHumans10aLogistic Models10aMale10aMiddle Aged10aMultivariate Analysis10aPrevalence10aRisk Factors10aSleep Apnea Syndromes10aSleep Apnea, Obstructive1 aResnick, Helaine, E1 aRedline, Susan1 aShahar, Eyal1 aGilpin, Adele1 aNewman, Anne1 aWalter, Robert1 aEwy, Gordon, A1 aHoward, Barbara, V1 aPunjabi, Naresh, M1 aSleep Heart Health Study uhttps://chs-nhlbi.org/node/72703344nas a2200469 4500008004100000022001400041245010400055210006900159260001600228300001000244490000800254520201200262653000902274653002402283653001502307653003002322653002302352653002802375653001902403653001502422653002802437653001102465653004302476653001502519653001702534653001102551653001702562653001802579653000902597653002402606653002402630653001702654100002402671700002002695700001702715700002302732700002102755700002202776700002102798700002002819856003502839 2003 eng d a1524-453900aElevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency.0 aElevations of inflammatory and procoagulant biomarkers in elderl c2003 Jan 07 a87-920 v1073 aBACKGROUND: Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease.
METHODS AND RESULTS: The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged > or =65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P<0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar.
CONCLUSION: Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.
10aAged10aalpha-2-Antiplasmin10aBiomarkers10aBlood Coagulation Factors10aC-Reactive Protein10aCardiovascular Diseases10aCohort Studies10aCreatinine10aCross-Sectional Studies10aFemale10aFibrin Fibrinogen Degradation Products10aFibrinogen10aFibrinolysin10aHumans10aInflammation10aInterleukin-610aMale10aProspective Studies10aRenal Insufficiency10aRisk Factors1 aShlipak, Michael, G1 aFried, Linda, F1 aCrump, Casey1 aBleyer, Anthony, J1 aManolio, Teri, A1 aTracy, Russell, P1 aFurberg, Curt, D1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/71903151nas a2200493 4500008004100000022001400041245011600055210006900171260001300240300001100253490000700264520176200271653000902033653002202042653002002064653001902084653003302103653001102136653001802147653001102165653001402176653001502190653001602205653002602221653001202247653003302259653003202292653002402324653000902348653001702357653001802374653001902392100001902411700002002430700002302450700001802473700002002491700001902511700002402530700002302554700002202577700002302599856003502622 2003 eng d a1540-999600aHormone replacement therapy and the risk of incident congestive heart failure: the Cardiovascular Health Study.0 aHormone replacement therapy and the risk of incident congestive c2003 May a341-500 v123 aBACKGROUND: The development of congestive heart failure (CHF) in older persons is related to a variety of mechanisms. Hormone replacement therapy (HRT) affects several of the pathways that may be important in the development of CHF. We hypothesized that HRT would be associated with a decreased risk of incident CHF.
METHODS: Using Cox proportional-hazards regression, we assessed the risk of incident CHF (n = 304) associated with time-dependent past and current use of HRT compared to never use. The Cardiovascular Health Study is a prospective cohort study of community-dwelling adults aged 65 years and older. This analysis included female participants without a history of CHF at baseline (n = 3223).
RESULTS: At baseline, 62% were never users, 26% were past users, and 12% were current users of HRT. Compared with never users, the multivariable relative risk (RR) of CHF was 1.01 (95% confidence interval [95% CI] 0.76,1.34) for past users and 1.34 (0.93,1.94) for current users. Results were similar among most treatment and clinical subgroups, except that the association of current HRT with CHF appeared to depend on body mass index (BMI) or osteoporosis status. The RR was 0.82 (0.43,1.60) for normal weight women, 1.65 (0.95,2.88) for overweight women, and 2.22 (1.06,4.67) for obese women (p = 0.01 for interaction). Similarly, the RR was 0.15 (0.04,0.65) for women with osteoporosis and 1.82 (1.25,2.65) for women without osteoporosis (p = 0.001 for interaction).
CONCLUSIONS: Overall, HRT was not associated with the risk of incident CHF, although BMI and osteoporosis appeared to modify the association of HRT with CHF. The risk of CHF was lower in patients with lower BMI or osteoporosis.
10aAged10aAged, 80 and over10aBody Mass Index10aCohort Studies10aEstrogen Replacement Therapy10aFemale10aHeart Failure10aHumans10aIncidence10aLife Style10aMiddle Aged10aMultivariate Analysis10aObesity10aOsteoporosis, Postmenopausal10aProportional Hazards Models10aProspective Studies10aRisk10aRisk Factors10aUnited States10aWomen's Health1 aRea, Thomas, D1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aCushman, Mary1 aMeilahn, Elaine1 aOlson, Jean, L1 aLemaitre, Rozenn, N1 aSmith, Nicholas, L1 aSotoodehnia, Nona1 aChaves, Paulo, H M uhttps://chs-nhlbi.org/node/74002623nas a2200385 4500008004100000022001400041245005900055210005800114260001600172300001200188490000800200520156500208653000901773653002401782653002301806653002801829653001101857653001101868653001701879653002501896653000901921653001701930100002301947700002101970700002901991700002602020700002302046700002402069700002202093700002602115700002002141700002202161700001902183856003502202 2003 eng d a1524-453900aInflammation as a risk factor for atrial fibrillation.0 aInflammation as a risk factor for atrial fibrillation c2003 Dec 16 a3006-100 v1083 aBACKGROUND: The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort.
METHODS AND RESULTS: CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P<0.001).
CONCLUSIONS: CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.
10aAged10aAtrial Fibrillation10aC-Reactive Protein10aCross-Sectional Studies10aFemale10aHumans10aInflammation10aLongitudinal Studies10aMale10aRisk Factors1 aAviles, Ronnier, J1 aMartin, David, O1 aApperson-Hansen, Carolyn1 aHoughtaling, Penny, L1 aRautaharju, Pentti1 aKronmal, Richard, A1 aTracy, Russell, P1 aVan Wagoner, David, R1 aPsaty, Bruce, M1 aLauer, Michael, S1 aChung, Mina, K uhttps://chs-nhlbi.org/node/75803786nas a2200445 4500008004100000022001400041245012600055210006900181260001300250300001100263490000800274520252700282653000902809653002202818653001902840653002802859653002802887653001102915653001102926653001702937653000902954653001502963653002102978653002002999653001703019653001803036100002003054700001803074700002103092700002103113700002203134700002103156700001803177700001903195700002203214700002103236700002403257700002403281856003503305 2003 eng d a0161-642000aThe prevalence and risk factors of retinal microvascular abnormalities in older persons: The Cardiovascular Health Study.0 aprevalence and risk factors of retinal microvascular abnormaliti c2003 Apr a658-660 v1103 aPURPOSE: To describe the prevalence of retinal microvascular characteristics and their associations with atherosclerosis in elderly, nondiabetic persons.
DESIGN AND PARTICIPANTS: Population-based, cross-sectional study comprising 2050 men and women aged 69 to 97 years without diabetes, living in four communities.
METHODS: Participants underwent retinal photography and standardized grading of retinal microvascular characteristics, including retinopathy (e.g., microaneurysms, retinal hemorrhages), focal arteriolar narrowing, and arteriovenous nicking. In addition, calibers of retinal arterioles and venules were measured on digitized photographs to obtain an estimate of generalized arteriolar narrowing. Atherosclerosis and its risk factors were obtained from clinical examination and laboratory investigations.
MAIN OUTCOME MEASURES: Prevalence of retinal microvascular abnormalities and their associations with measures of atherosclerosis.
RESULTS: The prevalence of retinal microvascular abnormalities was 8.3% for retinopathy, 9.6% for focal arteriolar narrowing, and 7.7% for arteriovenous nicking. All retinal lesions were associated with hypertension (odds ratios [OR] were 1.8 for retinopathy, 2.1 for focal arteriolar narrowing, 1.5 for arteriovenous nicking, and 1.7 for generalized arteriolar narrowing). After controlling for age, gender, race, mean arterial blood pressure, and antihypertensive medication use, retinopathy was associated with prevalent coronary heart disease (OR, 1.7), prevalent myocardial infarction (OR, 1.7), prevalent stroke (OR, 2.0), presence of carotid artery plaque (OR, 1.9), and increased intima-media thickness of the common carotid (OR, 2.3; fourth vs. first quartile) and internal carotid (OR, 1.8; fourth vs. first quartile) arteries. In contrast, focal arteriolar narrowing, arteriovenous nicking, and generalized arteriolar narrowing were not associated with any measures of atherosclerosis.
CONCLUSIONS: Retinal microvascular abnormalities are common in older persons without diabetes and are related to hypertension. Retinopathy is associated with prevalent coronary heart disease, stroke, and carotid artery thickening, but focal and generalized arteriolar narrowing and arteriovenous nicking are not related to most measures of atherosclerosis. These data suggest that retinal microvascular abnormalities reflect processes associated with hypertension but distinct from atherosclerosis.
10aAged10aAged, 80 and over10aBlood Pressure10aCoronary Artery Disease10aCross-Sectional Studies10aFemale10aHumans10aHypertension10aMale10aPrevalence10aRetinal Diseases10aRetinal Vessels10aRisk Factors10aUnited States1 aWong, Tien, Yin1 aKlein, Ronald1 aSharrett, Richey1 aManolio, Teri, A1 aHubbard, Larry, D1 aMarino, Emily, K1 aKuller, Lewis1 aBurke, Gregory1 aTracy, Russell, P1 aPolak, Joseph, F1 aGottdiener, John, S1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/73402477nas a2200481 4500008004100000022001400041245018500055210006900240260001300309300001200322490000700334520104600341653000901387653001001396653001201406653002501418653001901443653001301462653001101475653001301486653001701499653001101516653002501527653000901552653004901561653001601610653001501626653004901641653002601690653002401716653001701740653002201757100002001779700001801799700002101817700002301838700002301861700001801884700001701902700002001919700002101939856003501960 2003 eng d a0361-860900aSerum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).0 aSerum homocysteine thermolabile variant of methylene tetrahydrof c2003 Mar a192-2000 v723 aWe sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.
10aAged10aAging10aAnimals10aCase-Control Studies10aCohort Studies10aFactor V10aFemale10aGenotype10aHomocysteine10aHumans10aLongitudinal Studies10aMale10aMethylenetetrahydrofolate Reductase (NADPH2)10aMiddle Aged10aOdds Ratio10aOxidoreductases Acting on CH-NH Group Donors10aPolymorphism, Genetic10aProspective Studies10aRisk Factors10aVenous Thrombosis1 aTsai, Albert, W1 aCushman, Mary1 aTsai, Michael, Y1 aHeckbert, Susan, R1 aRosamond, Wayne, D1 aAleksic, Nena1 aYanez, David1 aPsaty, Bruce, M1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/72603188nas a2200433 4500008004100000022001400041245010300055210006900158260001600227300000900243490000800252520195400260653000902214653001902223653001102242653002902253653001102282653000902293653001602302653001902318653002002337653002402357653004302381653001002424653002902434653001502463653001902478100002102497700002002518700002702538700001902565700002202584700002002606700002402626700002302650700001702673710002902690856003502719 2003 eng d a1073-449X00aSleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease.0 aSleep and sleepdisordered breathing in adults with predominantly c2003 Jan 01 a7-140 v1673 aNeither the association between obstructive airways disease (OAD) and sleep apnea-hypopnea (SAH) nor the sleep consequences of each disorder alone and together have been characterized in an adult community setting. Our primary aims were (1) to determine if there is an association between OAD and SAH and (2) identify predictors of oxyhemoglobin desaturation during sleep in persons having OAD with and without SAH. Polysomnography and spirometry results from 5,954 participants in the Sleep Heart Health Study were analyzed. OAD was defined by a FEV1/FVC value less than 70%. Assessment of SAH prevalence in OAD was performed using thresholds of respiratory disturbance index (RDI) greater than 10 and greater than 15. A total of 1,132 participants had OAD that was predominantly mild (FEV1/FVC 63.81 +/- 6.56%, mean +/- SD). SAH was not more prevalent in participants with OAD than in those without OAD (22.32 versus 28.86%, with and without OAD, respectively, at RDI threshold values greater than 10; and 13.97 versus 18.63%, with and without OAD, respectively, at RDI threshold value greater than 15). In the absence of SAH, the adjusted odds ratio for sleep desaturation (> 5% total sleep time with saturation < 90%) was greater than 1.9 when FEV1/FVC was less than 65%. Participants with both OAD and SAH had greater sleep perturbation and desaturation than those with one disorder. Generally mild OAD alone was associated with minimally altered sleep quality. We conclude that (1) there is no association between generally mild OAD and SAH; (2) exclusive of SAH and after adjusting for demographic factors and awake oxyhemoglobin saturation, an FEV1/FVC value less than 65% is associated with increased risk of sleep desaturation; (3) desaturation is greater in persons with both OAD and SAH compared with each of these alone; and (4) individuals with generally mild OAD and without SAH in the community have minimally perturbed sleep.
10aAged10aCohort Studies10aFemale10aForced Expiratory Volume10aHumans10aMale10aMiddle Aged10aOxyhemoglobins10aPolysomnography10aProspective Studies10aPulmonary Disease, Chronic Obstructive10aSleep10aSleep Apnea, Obstructive10aSpirometry10aVital Capacity1 aSanders, Mark, H1 aNewman, Anne, B1 aHaggerty, Catherine, L1 aRedline, Susan1 aLebowitz, Michael1 aSamet, Jonathan1 aO'Connor, George, T1 aPunjabi, Naresh, M1 aShahar, Eyal1 aSleep Heart Health Study uhttps://chs-nhlbi.org/node/71501693nas a2200253 4500008004100000022001400041245008300055210006900138260001600207300001100223490000800234520099200242653000901234653001001243653001001253653002501263653002901288653001901317653001101336653001701347100001701364700002301381856003501404 2003 eng d a1539-370400aTrajectories of health for older adults over time: accounting fully for death.0 aTrajectories of health for older adults over time accounting ful c2003 Sep 02 a416-200 v1393 aThe process of healthy aging can best be described by plotting the trajectory of health-related variables over time. Unfortunately, graphs including data only from survivors may be misleading because they may confuse patterns of mortality with patterns of change in health. Two approaches for creating graphs that account for death in such situations are 1) to incorporate a category or value for death into the longitudinal health variable and 2) to measure time in years before death or some other event. The first approach has been applied to self-rated health (excellent to poor) and the 36-Item Short-Form Health Survey (SF-36). It allows for flexible and interpretable analyses and may be appropriate for other variables as well. The second approach also accounts fully for death, but the questions it can address are limited. Both approaches are useful and should be used at a minimum for supporting analyses in longitudinal studies in which persons die during observation.
10aAged10aAging10aDeath10aGeriatric Assessment10aHealth Status Indicators10aHealth Surveys10aHumans10aTime Factors1 aDiehr, Paula1 aPatrick, Donald, L uhttps://chs-nhlbi.org/node/74602144nas a2200313 4500008004100000022001400041245008300055210006900138260001600207300001200223490000700235520128900242653001001531653000901541653002201550653002501572653002401597653002401621653001101645653002101656653001101677653000901688653001601697100002601713700002001739700001701759700001901776856003501795 2004 eng d a0002-914900aAssessment of prolonged QT and JT intervals in ventricular conduction defects.0 aAssessment of prolonged QT and JT intervals in ventricular condu c2004 Apr 15 a1017-210 v933 aThe JT interval or Bazett's QTc - QRS has been advocated for detection of prolonged repolarization in ventricular conduction defects (VCDs). However, the use of neither JT nor QTc - QRS has been validated, and normal limits for rate-adjusted JT have not been established for VCDs or for normal ventricular conduction. Functional relations among RR, JT, and QT intervals were evaluated in 11,739 adult men and women with normal ventricular conduction and in 1,251 subjects with major VCD. The results showed that JT adjustment obtained as QTc - QRS retained a strong residual correlation with ventricular rate (r = 0.54), making its use ill-advised. In contrast, QT adjustment as a linear function of the RR interval for VCD as QT(RR,QRS) = QT - 155 x (60/heart rate - 1) - 0.93 x (QRS - 139) + k, with k = -22 ms for men and -34 ms for women, removed the rate dependence and produced upper 2% and 5% normal limits at 460 and 450 ms, respectively, which are identical to those in normal conduction. As an alternative, equally effective linear JT adjustment formulas were derived, including newly required normal standards. Thus, detection of prolonged repolarization in VCD requires the use of the JT interval or a bivariate model for QT with RR and QRS intervals as covariates.
10aAdult10aAged10aAged, 80 and over10aArrhythmias, Cardiac10aBundle-Branch Block10aElectrocardiography10aFemale10aHeart Ventricles10aHumans10aMale10aMiddle Aged1 aRautaharju, Pentti, M1 aZhang, Zhu-Ming1 aPrineas, Ron1 aHeiss, Gerardo uhttps://chs-nhlbi.org/node/77403017nas a2200457 4500008004100000022001400041245015200055210006900207260001300276300001200289490000700301520171100308653002202019653003902041653000902080653001102089653001902100653001102119653001402130653001102144653000902155653001402164653002602178653002802204653002402232653001702256653001102273653001802284100002002302700002202322700002402344700002202368700002002390700002002410700001902430700001802449700001602467700002002483700002102503856003502524 2004 eng d a0002-861400aThe association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: The Cardiovascular Health Study.0 aassociation between lipid levels and the risks of incident myoca c2004 Oct a1639-470 v523 aOBJECTIVES: To assess the association between lipid levels and cardiovascular events in older adults.
DESIGN: A prospective population-based study.
SETTING: Four field centers in U.S. communities.
PARTICIPANTS: A total of 5,201 adults aged 65 and older living in U.S. communities, plus a recruitment of 687 African Americans 3 years later.
MEASUREMENTS: Fasting lipid measures included low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, and triglycerides.
RESULTS: At baseline, 1,954 men and 2,931 women were at risk for an incident myocardial infarction (MI) or stroke. During an average 7.5-year follow-up, 436 subjects had a coronary event, 332 had an ischemic stroke, 104 a hemorrhagic stroke, and 1,096 died. After adjustment, lipid measures were not major predictors of the outcomes of MI, ischemic stroke, hemorrhagic stroke, and total mortality. For total cholesterol and LDL-C, the associations with MI and ischemic stroke were only marginally significant. HDL-C was inversely associated with MI risk (hazard ratio=0.85 per standard deviation of 15.7 mg/dL, 95% confidence interval=0.76-0.96). For the outcome of ischemic stroke, high levels of HDL-C were associated with a decreased risk in men but not women. Lipid measures were generally only weakly associated with the risks of hemorrhagic stroke or total mortality.
CONCLUSION: In this population-based study of older adults, most lipid measures were weakly associated with cardiovascular events. The association between low HDL-C and increased MI risk was nonetheless strong and consistent.
10aAfrican Americans10aAfrican Continental Ancestry Group10aAged10aFemale10aHealth Surveys10aHumans10aIncidence10aLipids10aMale10aMortality10aMyocardial Infarction10aPopulation Surveillance10aProspective Studies10aRisk Factors10aStroke10aUnited States1 aPsaty, Bruce, M1 aAnderson, Melissa1 aKronmal, Richard, A1 aTracy, Russell, P1 aOrchard, Trevor1 aFried, Linda, P1 aLumley, Thomas1 aRobbins, John1 aBurke, Greg1 aNewman, Anne, B1 aFurberg, Curt, D uhttps://chs-nhlbi.org/node/80301905nas a2200349 4500008004100000022001400041245007700055210006900132260001300201300001200214490000700226520094000233653000901173653002201182653002801204653001101232653002001243653003401263653001101297653002001308653000901328653001301337653001301350653003101363653001801394100002801412700001801440700002201458700001901480700002101499856003501520 2004 eng d a0090-003600aBarriers to health care access among the elderly and who perceives them.0 aBarriers to health care access among the elderly and who perceiv c2004 Oct a1788-940 v943 aOBJECTIVES: We evaluated self-perceived access to health care in a cohort of Medicare beneficiaries.
METHODS: We identified patterns of use and barriers to health care from self-administered questionnaires collected during the 1993-1994 annual examination of the Cardiovascular Health Study.
RESULTS: The questionnaires were completed by 4889 (91.1%) participants, with a mean age of 76.0 years. The most common barriers to seeing a physician were the doctor's lack of responsiveness to patient concerns, medical bills, transportation, and street safety. Low income, no supplemental insurance, older age, and female gender were independently related to perceptions of barriers. Race was not significant after adjustment for other factors.
CONCLUSIONS: Psychological and physical barriers affect access to care among the elderly; these may be influenced by poverty more than by race.
10aAged10aAged, 80 and over10aChi-Square Distribution10aFemale10aHealth Behavior10aHealth Services Accessibility10aHumans10aLogistic Models10aMale10aMedicare10aPatients10aSurveys and Questionnaires10aUnited States1 aFitzpatrick, Annette, L1 aPowe, Neil, R1 aCooper, Lawton, S1 aIves, Diane, G1 aRobbins, John, A uhttps://chs-nhlbi.org/node/80502931nas a2200469 4500008004100000022001400041245005800055210005700113260001600170300001100186490000800197520172200205653000901927653001201936653002401948653002301972653001901995653001202014653000902026653001702035653002502052653001402077653001102091653002202102653001102124653001402135653001802149653003202167653002402199653000902223653001202232653000902244100002502253700002002278700001802298700002402316700002202340700001902362700002102381700002402402856003502426 2004 eng d a1524-453900aFish intake and risk of incident atrial fibrillation.0 aFish intake and risk of incident atrial fibrillation c2004 Jul 27 a368-730 v1103 aBACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is particularly common in the elderly. Although effects of fish intake, including potential antiarrhythmic effects, may favorably influence risk of AF, relationships between fish intake and AF incidence have not been evaluated.
METHODS AND RESULTS: In a prospective, population-based cohort of 4815 adults > or =age 65 years, usual dietary intake was assessed at baseline in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. AF incidence was prospectively ascertained on the basis of hospital discharge records and annual electrocardiograms. During 12 years' follow-up, 980 cases of incident AF were diagnosed. In multivariate analyses, consumption of tuna or other broiled or baked fish was inversely associated with incidence of AF, with 28% lower risk with intake 1 to 4 times per week (HR=0.72, 95% CI=0.58 to 0.91, P=0.005), and 31% lower risk with intake > or =5 times per week (HR=0.69, 95% CI=0.52 to 0.91, P=0.008), compared with <1 time per month (P trend=0.004). Results were not materially different after adjustment for preceding myocardial infarction or congestive heart failure. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of AF.
CONCLUSIONS: Among elderly adults, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower incidence of AF. Fish intake may influence risk of this common cardiac arrhythmia.
10aAged10aAnimals10aAtrial Fibrillation10aCardiotonic Agents10aCohort Studies10aCooking10aDiet10aDietary Fats10aFatty Acids, Omega-310aFish Oils10aFishes10aFollow-Up Studies10aHumans10aIncidence10aMassachusetts10aProportional Hazards Models10aProspective Studies10aRisk10aSeafood10aTuna1 aMozaffarian, Dariush1 aPsaty, Bruce, M1 aRimm, Eric, B1 aLemaitre, Rozenn, N1 aBurke, Gregory, L1 aLyles, Mary, F1 aLefkowitz, David1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/79700961nas a2200313 4500008004100000022001400041245010900055210006900164260001700233300001000250490000700260653000900267653002800276653002400304653002800328653002200356653004200378653001800420653001100438653002000449653001700469653002500486653001700511100002400528700002000552700001900572700002100591856003500612 2004 eng d a1076-746000aMedications and cardiovascular health in older adults: room for improvement in prevention and treatment.0 aMedications and cardiovascular health in older adults room for i c2004 May-Jun a161-70 v1310aAged10aAntihypertensive Agents10aAtrial Fibrillation10aCardiovascular Diseases10aDiabetes Mellitus10aHealth Knowledge, Attitudes, Practice10aHeart Failure10aHumans10aHyperlipidemias10aHypertension10aHypolipidemic Agents10aRisk Factors1 aRhoads, Caroline, S1 aPsaty, Bruce, M1 aOlson, Jean, L1 aFurberg, Curt, D uhttps://chs-nhlbi.org/node/78003920nas a2200409 4500008004100000022001400041245004600055210004500101260001300146300001000159490000700169520282600176653001603002653000903018653002203027653002103049653001803070653001903088653001103107653001103118653000903129653002403138653003203162653003403194653001503228653003703243653001603280100002503296700002103321700002303342700002303365700002403388700002403412700001703436700002203453856003503475 2004 eng d a0741-521400aMesenteric artery disease in the elderly.0 aMesenteric artery disease in the elderly c2004 Jul a45-520 v403 aPURPOSE: The purpose of this study was to estimate the population-based prevalence of mesenteric artery stenosis (MAS) and occlusion among independent elderly Americans.
METHOD: As part of an ancillary investigation to the Cardiovascular Health Study (CHS), participants in the Forsyth County, NC cohort had visceral duplex sonography of the celiac arteries and superior mesenteric arteries (SMAs). Critical MAS was defined by celiac peak systolic velocity >or=2.0 m/s and/or SMA peak systolic velocity >or=2.7 m/s. Occlusion of either vessel was defined by lack of a Doppler-shifted signal within the imaged artery. Demographic data, blood pressures, and blood lipid levels were collected as part of the baseline CHS examination. Participants' weights were measured at baseline and before the duplex exam. Univariate tests of association were performed with two-way contingency tables, Student t tests, and Fisher exact tests. Multivariate associations were examined with logistic regression analysis.
RESULTS: A total of 553 CHS participants had visceral duplex sonography technically adequate to define the presence or absence of MAS. The study group had a mean age of 77.2 +/- 4.9 years and comprised 63% women and 37% men. Participant race was 76% white and 23% African-American. Ninety-seven participants (17.5%) had MAS. There was no significant difference in age, race, gender, body mass index, blood pressure, cholesterol, or low-density lipoproteins for participants with or without MAS. Forward stepwise variable selection found renal artery stenosis (P =.008; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.31, 6.21) and high-density lipoprotein >40 (P =.02; OR, 3.03; 95% CI, 1.17, 7.81) significantly associated with MAS in a multivariate logistic regression model. Eighty-three of the 97 participants with MAS (15.0% of the cohort) had isolated celiac stenosis. Seven participants (1.3% of the cohort) had combined celiac and SMA stenosis. Five participants (0.9% of the cohort) had isolated SMA stenosis. Two participants (0.4% of the cohort) had celiac occlusion. Considering all participants with MAS, there was no association with weight change. However, SMA stenosis and celiac occlusion demonstrated an independent association with annualized weight loss (P =.028; OR, 1.54; 95% CI, 1.05, 2.26) and with renal artery stenosis (P =.001; OR, 9.48; 95% CI, 2.62, 34.47).
CONCLUSION: This investigation provides the first population-based estimate of the prevalence of MAS among independent elderly Americans. MAS existed in 17.5% of the study cohort. The majority had isolated celiac disease. SMA stenosis and celiac artery occlusion demonstrated a significant and independent association with weight loss and concurrent renal artery disease.
10aAge Factors10aAged10aAged, 80 and over10aArteriosclerosis10aCeliac Artery10aCohort Studies10aFemale10aHumans10aMale10aMesenteric Arteries10aMesenteric Artery, Superior10aMesenteric Vascular Occlusion10aPrevalence10aUltrasonography, Doppler, Duplex10aWeight Loss1 aHansen, Kimberley, J1 aWilson, David, B1 aCraven, Timothy, E1 aPearce, Jeffrey, D1 aEnglish, William, P1 aEdwards, Matthew, S1 aAyerdi, Juan1 aBurke, Gregory, L uhttps://chs-nhlbi.org/node/79602816nas a2200337 4500008004100000022001400041245008100055210006900136260001300205300001000218490000700228520187600235653003102111653000902142653002802151653001102179653001802190653001102208653002802219653000902247653001802256100002402274700002902298700002002327700001502347700002102362700002002383700002002403700002002423856003502443 2004 eng d a1523-683800aThe presence of frailty in elderly persons with chronic renal insufficiency.0 apresence of frailty in elderly persons with chronic renal insuff c2004 May a861-70 v433 aBACKGROUND: Frailty has been defined as a tool to define individuals who lack functional reserve and are at risk for functional decline. We hypothesized that chronic renal insufficiency (CRI) would be associated with a greater prevalence of frailty and disability in the elderly.
METHODS: This cross-sectional analysis used baseline data collected from the Cardiovascular Health Study, which enrolled 5,888 community-dwelling adults aged 65 years or older from 4 clinical centers in the United States. Renal insufficiency is defined as a serum creatinine level of 1.3 mg/dL or greater (> or =115 micromol/L) in women and 1.5 mg/dL or greater (> or =133 micromol/L) in men. Frailty is defined by the presence of 3 of the following abnormalities: unintentional weight loss, self-reported exhaustion, measured weakness, slow walking speed, and low physical activity. Disability is defined as any self-reported difficulty with activities of daily living.
RESULTS: Among 5,808 participants with creatinine levels measured at entry, 15.9% of men (n = 394) and 7.6% of women (n = 254) had CRI. Prevalences of frailty (15% versus 6%; P < 0.001) and disability (12% versus 7%; P = 0.001) were greater in participants with CRI compared with those with normal renal function. After multivariate adjustment for comorbidity, CRI remained significantly associated with frailty (odds ratio, 1.76; 95% confidence interval, 1.28 to 2.41), but not disability (odds ratio, 1.26; 95% confidence interval, 0.94 to 1.69).
CONCLUSION: Elderly persons with CRI have a high prevalence of frailty, which may signal their risk for progression to adverse health outcomes. If confirmed in other studies, identification of frailty in patients with CRI may warrant special interventions to preserve their independence, quality of life, and survival.
10aActivities of Daily Living10aAged10aCross-Sectional Studies10aFemale10aFrail Elderly10aHumans10aKidney Failure, Chronic10aMale10aUnited States1 aShlipak, Michael, G1 aStehman-Breen, Catherine1 aFried, Linda, F1 aSong, Xiao1 aSiscovick, David1 aFried, Linda, P1 aPsaty, Bruce, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/77503224nas a2200493 4500008004100000022001400041245017200055210006900227260001300296300001000309490000700319520182100326653002102147653000902168653002202177653001602199653001502215653002002230653001602250653002102266653002802287653002202315653001102337653001102348653001702359653001702376653002002393653000902413653002602422653001502448653001702463653001202480653002002492100002402512700001702536700001802553700002302571700001602594700002002610700002202630700001802652700002502670856003502695 2004 eng d a1523-683800aThe relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study.0 arelationship of cardiovascular risk factors to microalbuminuria c2004 Jul a25-340 v443 aBACKGROUND: Microalbuminuria is a risk factor for coronary heart disease (CHD). It occurs most commonly in the settings of diabetes and hypertension. The mechanisms by which it increases CHD risk are uncertain.
METHODS: We examined the cross-sectional association of microalbuminuria with a broad range of CHD risk factors in 3 groups of adults aged 65 years or older with and without microalbuminuria: those with (1) no diabetes or hypertension (n = 1,098), (2) hypertension only (n = 1,450), and (3) diabetes with or without hypertension (n = 465).
RESULTS: Three factors were related to microalbuminuria in all 3 groups: age, elevated systolic blood pressure, and markers of systemic inflammation. In patients with neither diabetes nor hypertension, increasing C-reactive protein levels were associated with microalbuminuria (odds ratio per 1-mg/L increase, 1.46; 95% confidence interval [CI], 1.15 to 1.84). Among those with diabetes, an increase in white blood cell (WBC) count was associated with microalbuminuria (odds ratio per 1,000-cell/mL increase, 2.57; 95% CI, 1.12 to 5.89). Among those with hypertension, an increase in WBC count (odds ratio per 1,000-cell/mL increase, 1.83; 95% CI, 1.04 to 3.23) and fibrinogen level (odds ratio per 10-mg/dL increase, 1.02; 95% CI, 1.00 to 1.05) were significantly associated with microalbuminuria. In all 3 groups, prevalent CHD was related to an elevated WBC count. In none of the 3 groups was brachial artery reactivity to ischemia, an in vivo marker of endothelial function, related to microalbuminuria.
CONCLUSION: Microalbuminuria is associated with age, systolic blood pressure, and markers of inflammation. These associations reflect potential mechanisms by which microalbuminuria is related to CHD risk.
10aAge Distribution10aAged10aAged, 80 and over10aAlbuminuria10aBiomarkers10aBrachial Artery10aComorbidity10aCoronary Disease10aCross-Sectional Studies10aDiabetes Mellitus10aFemale10aHumans10aHypertension10aInflammation10aLogistic Models10aMale10aMultivariate Analysis10aOdds Ratio10aRisk Factors10aSmoking10aUltrasonography1 aBarzilay, Joshua, I1 aPeterson, Do1 aCushman, Mary1 aHeckbert, Susan, R1 aCao, Jie, J1 aBlaum, Caroline1 aTracy, Russell, P1 aKlein, Ronald1 aHerrington, David, M uhttps://chs-nhlbi.org/node/79402390nas a2200361 4500008004100000022001400041245008000055210006900135260001300204300001100217490000700228520139900235653002801634653001101662653002201673653002901695653001101724653000901735653003401744653002401778653002401802653001701826653001901843100002101862700001401883700001701897700001401914700001701928700001501945700001801960700001501978856003501993 2004 eng d a0040-637600aRespiratory muscle strength and the risk of incident cardiovascular events.0 aRespiratory muscle strength and the risk of incident cardiovascu c2004 Dec a1063-70 v593 aBACKGROUND: Maximal inspiratory pressure (MIP) is a measure of inspiratory muscle strength. The prognostic importance of MIP for cardiovascular events among elderly community dwelling individuals is unknown. Diminished forced vital capacity (FVC) is a risk factor for cardiovascular events which remains largely unexplained.
METHODS: MIP was measured at the baseline examination of the Cardiovascular Health Study. Participants had to be free of prevalent congestive heart failure (CHF), myocardial infarction (MI), and stroke.
RESULTS: Subjects in the lowest quintile of MIP had a 1.5-fold increased risk of MI (HR 1.48, 95% CI 1.07 to 2.06) and cardiovascular disease (CVD) death (HR 1.54, 95% CI 1.09 to 2.15) after adjustment for non-pulmonary function covariates. There was a potential inverse relationship with stroke (HR 1.36, 95% CI 0.97 to 1.90), but there was little evidence of an association between MIP and CHF (HR 1.22, 95% CI 0.93 to 1.60). The addition of FVC to models attenuated the HR associated with MIP only modestly; similarly, addition of MIP attenuated the HR associated with FVC only modestly.
CONCLUSIONS: A reduced MIP is an independent risk factor for MI and CVD death, and a suggestion of an increased risk for stroke. This association with MIP appeared to be mediated through mechanisms other than inflammation.
10aCardiovascular Diseases10aFemale10aFollow-Up Studies10aForced Expiratory Volume10aHumans10aMale10aMaximal Voluntary Ventilation10aProspective Studies10aRespiratory Muscles10aRisk Factors10aVital Capacity1 avan der Palen, J1 aRea, T, D1 aManolio, T A1 aLumley, T1 aNewman, A, B1 aTracy, R P1 aEnright, P, L1 aPsaty, B M uhttps://chs-nhlbi.org/node/81102896nas a2200421 4500008004100000022001400041245010700055210006900162260001300231300001200244490000700256520170000263653003301963653000901996653002802005653002202033653001902055653001902074653001402093653001102107653001802118653001102136653001702147653000902164653001702173653004102190653001802231100002102249700002302270700002102293700002302314700002102337700001902358700002102377700002102398700002002419856003502439 2004 eng d a0002-861400aRisk of congestive heart failure in an elderly population treated with peripheral alpha-1 antagonists.0 aRisk of congestive heart failure in an elderly population treate c2004 Oct a1648-540 v523 aOBJECTIVES: To compare the risk of congestive heart failure (CHF) in elderly individuals treated with any peripheral alpha-1 antagonist for hypertension with any thiazide, test whether the risk persists in subjects without cardiovascular disease (CVD) at baseline, and examine CHF risk in normotensive men with prostatism treated with alpha antagonists.
DESIGN: Prospective cohort study.
SETTING: Four U.S. sites: Washington County, Maryland; Allegheny County, Pennsylvania; Sacramento County, California; and Forsyth County, North Carolina.
PARTICIPANTS: A total of 5,888 community-dwelling subjects aged 65 and older.
MEASUREMENTS: Adjudicated incident CHF.
RESULTS: The 3,105 participants with treated hypertension were at risk for CHF; 22% of men and 8% of women took alpha antagonists during follow-up. The age-adjusted risk of CHF in those receiving monotherapy treated with alpha antagonists was 1.90 (95% confidence interval=1.03-3.50) compared with thiazides. In subjects without CVD at baseline receiving monotherapy, women taking an alpha antagonist had a 3.6 times greater age-adjusted risk of CHF, whereas men had no difference in risk. Adjustment for systolic blood pressure attenuated statistical differences in risk. There were 930 men without hypertension at risk for CHF; 5% used alpha antagonists during follow-up, with no observed increase in CHF risk.
CONCLUSION: Subjects receiving alpha antagonist monotherapy for hypertension had a two to three times greater risk of incident CHF, also seen in lower-risk subjects, but differences in blood pressure control partly explained this.
10aAdrenergic alpha-Antagonists10aAged10aAntihypertensive Agents10aBenzothiadiazines10aBlood Pressure10aCohort Studies10aDiuretics10aFemale10aHeart Failure10aHumans10aHypertension10aMale10aRisk Factors10aSodium Chloride Symporter Inhibitors10aUnited States1 aBryson, Chris, L1 aSmith, Nicholas, L1 aKuller, Lewis, H1 aChaves, Paulo, H M1 aManolio, Teri, A1 aLewis, William1 aBoyko, Edward, J1 aFurberg, Curt, D1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/80402954nas a2200505 4500008004100000022001400041245010700055210006900162260001600231300001100247490000800258520147700266653000901743653002301752653002201775653002001797653001901817653003901836653002801875653003001903653001201933653001101945653002401956653002701980653001102007653002302018653001802041653000902059653001602068653002602084653001902110653002002129653002002149653001702169653003002186653002602216100002302242700001702265700001902282700002402301700002102325700002402346710004302370856003502413 2004 eng d a0002-926200aSleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study.0 aSleepdisordered breathing glucose intolerance and insulin resist c2004 Sep 15 a521-300 v1603 aClinic-based studies suggest that sleep-disordered breathing (SDB) is associated with glucose intolerance and insulin resistance. However, in the available studies, researchers have not rigorously controlled for confounding variables to assess the independent relation between SDB and impaired glucose metabolism. The objective of this study was to determine whether SDB was associated with glucose intolerance and insulin resistance among community-dwelling subjects (n=2,656) participating in the Sleep Heart Health Study (1994-1999). SDB was characterized with the respiratory disturbance index and measurements of oxygen saturation during sleep. Fasting and 2-hour glucose levels measured during an oral glucose tolerance test were used to assess glycemic status. Relative to subjects with a respiratory disturbance index of less than 5.0 events/hour (the reference category), subjects with mild SDB (5.0-14.9 events/hour) and moderate to severe SDB (> or =15 events/hour) had adjusted odds ratios of 1.27 (95% confidence interval: 0.98, 1.64) and 1.46 (95% confidence interval: 1.09, 1.97), respectively, for fasting glucose intolerance (p for trend < 0.01). Sleep-related hypoxemia was also associated with glucose intolerance independently of age, gender, body mass index, and waist circumference. The results of this study suggest that SDB is independently associated with glucose intolerance and insulin resistance and may lead to type 2 diabetes mellitus.
10aAged10aBlood Gas Analysis10aBody Constitution10aBody Mass Index10aCohort Studies10aConfounding Factors, Epidemiologic10aCross-Sectional Studies10aDiabetes Mellitus, Type 210aFasting10aFemale10aGlucose Intolerance10aGlucose Tolerance Test10aHumans10aInsulin Resistance10aLinear Models10aMale10aMiddle Aged10aMultivariate Analysis10aOxyhemoglobins10aPolysomnography10aResearch Design10aRisk Factors10aSeverity of Illness Index10aSleep Apnea Syndromes1 aPunjabi, Naresh, M1 aShahar, Eyal1 aRedline, Susan1 aGottlieb, Daniel, J1 aGivelber, Rachel1 aResnick, Helaine, E1 aSleep Heart Health Study Investigators uhttps://chs-nhlbi.org/node/80003262nas a2200385 4500008004100000022001400041245013700055210006900192260001600261300001100277490000700288520215100295653000902446653002202455653002002477653002102497653002802518653001102546653001102557653001202568653001602580653002002596653003402616653001102650653002002661653002602681100002002707700001702727700001802744700001802762700002002780700002102800700002002821856003502841 2004 eng d a0161-810500aSleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the Sleep Heart Health Study.0 aSleepdisordered breathing is not associated with the presence of c2004 May 01 a467-730 v273 aSTUDY OBJECTIVE: Sleep apnea and milder forms of sleep-disordered breathing (SDB) have been associated with overt clinical cardiovascular disease, but it is unknown whether SDB is associated with arterial microvascular pathology. We examined the relation between SDB and retinal microvascular abnormalities.
DESIGN: Cross-sectional study.
PARTICIPANTS: Subjects were 2,927 men and women, aged 51 to 97 years, who participated in the Sleep Heart Health Study and had retinal photographs taken within approximately 3 years of overnight, unattended, at-home polysomnography.
MEASUREMENTS AND RESULTS: A respiratory disturbance index (RDI), calculated as the average number of apneas and hypopneas per hour of sleep, was used as an indicator of SDB in analysis. The overall prevalence of retinopathy was slightly higher in people with higher RDI values (5.4%, 4.9%, 8.6%, and 7.6%, respectively, in increasing quartiles of RDI), but after adjustment for age, body-mass index, hypertension, diabetes, and other factors, the presence of retinopathy was not associated with SDB. With the possible exceptions of microaneurysms and generalized arteriolar narrowing, as measured by lower arteriole-to-venule ratio, specific retinal abnormalities were not associated consistently with the RDI. Relative to the first quartile of RDI, the adjusted odds ratios (95% confidence interval) for the presence of microaneurysm in the second, third, and fourth quartiles of RDI were 1.05 (0.44-2.55), 1.97 (0.89-4.37), and 1.79 (0.78-4.10), respectively. An increase of RDI from 0 to 10 was associated with a predicted decrease in arteriole-to-venule ratio of 0.01. Results were similar when analyses were conducted in normotensive and nondiabetic persons separately.
CONCLUSIONS: These data do not demonstrate a notable relation between SDB and retinal abnormalities. However, since this is the first investigation of a link between retinopathy and SDB, similar studies should be conducted in other population samples to demonstrate either consistency or inconsistency of our findings across studies.
10aAged10aAged, 80 and over10aBody Mass Index10aCoronary Disease10aCross-Sectional Studies10aFemale10aHumans10aHypoxia10aMiddle Aged10aPolysomnography10aPositive-Pressure Respiration10aRetina10aRetinal Vessels10aSleep Apnea Syndromes1 aBoland, Lori, L1 aShahar, Eyal1 aWong, Tien, Y1 aKlein, Ronald1 aPunjabi, Naresh1 aRobbins, John, A1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/78202681nas a2200409 4500008004100000022001400041245009100055210006900146260001600215300001100231490000800242520154100250653000901791653002201800653001901822653002801841653001101869653002201880653001801902653001101920653001401931653000901945653001401954653003001968653002201998100002602020700001902046700002302065700002302088700001902111700002402130700002302154700002202177700001702199700002002216856003502236 2004 eng d a0002-926200aSurvival associated with two sets of diagnostic criteria for congestive heart failure.0 aSurvival associated with two sets of diagnostic criteria for con c2004 Oct 01 a628-350 v1603 aCongestive heart failure (CHF) definitions vary across epidemiologic studies. The Framingham Heart Study criteria include CHF signs and symptoms assessed by a physician panel. In the Cardiovascular Health Study, a committee of physicians adjudicated CHF diagnoses, confirmed by signs, symptoms, clinical tests, and/or medical therapy. The authors used data from the Cardiovascular Health Study, a population-based cohort study of 5,888 elderly US adults, to compare CHF incidence and survival patterns following onset of CHF as defined by Framingham and/or Cardiovascular Health Study criteria. They constructed an inception cohort of nonfatal, hospitalized CHF patients. Of 875 participants who had qualifying CHF hospitalizations between 1989 and 2000, 54% experienced a first CHF event that fulfilled both sets of diagnostic criteria (concordant), 31% fulfilled only the Framingham criteria (Framingham only), and 15% fulfilled only the Cardiovascular Health Study criteria (Cardiovascular Health Study only). No significant survival difference was found between the Framingham-only group (hazard ratio = 0.87, 95% confidence interval: 0.71, 1.07) or the Cardiovascular Health Study-only group (hazard ratio = 0.89, 95% confidence interval: 0.68, 1.15) and the concordant group (referent). Compared with Cardiovascular Health Study central adjudication, Framingham criteria for CHF identified a larger group of participants with incident CHF, but all-cause mortality rates were similar across these diagnostic classifications.
10aAged10aAged, 80 and over10aCohort Studies10aDiagnosis, Differential10aFemale10aFollow-Up Studies10aHeart Failure10aHumans10aIncidence10aMale10aPrognosis10aSeverity of Illness Index10aSurvival Analysis1 aSchellenbaum, Gina, D1 aRea, Thomas, D1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aLumley, Thomas1 aRoger, Veronique, L1 aKitzman, Dalane, W1 aTaylor, Herman, A1 aLevy, Daniel1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/80202971nas a2200373 4500008004100000022001400041245011900055210006900174260001300243300001000256490000800266520185400274653003202128653000902160653004402169653004502213653001902258653001702277653003002294653001102324653001802335653001102353653000902364653002602373653001502399100002302414700002102437700001902458700002202477700002402499700001902523700002002542856003502562 2004 eng d a1097-674400aTime trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure.0 aTime trends in the use of betablockers and other pharmacotherapi c2004 Oct a710-70 v1483 aBACKGROUND: Evidence supporting pharmacotherapy of congestive heart failure (CHF) has grown substantially over the past decade and includes large, placebo-controlled trials with mortality end points. We describe beta-blocker and other medication temporal treatment trends of CHF in the Cardiovascular Health Study, a community-based cohort study of 5888 adults > or =65 years of age.
METHODS: Prescription medication data were collected from hospital discharge summaries for incident CHF events and at in-study annual clinic visits for prevalent CHF cases from 1989 to 2000. Change in use of agents over time was estimated by using generalized estimating equations while adjusting for potential confounding factors of age, sex, race, and cardiovascular and pulmonary comorbidities.
RESULTS: Among 1033 incident CHF events, beta-blocker use after diagnosis increased an average of 2.4 percentage points annually (95% CI, 1.5 to 3.4 points) from 1989 to 2000. The increasing trend was consistent throughout follow-up. Among participants with coronary disease and/or hypertension and among those with low ejection fractions (<45%), beta-blocker use remained flat from 1989 to 1994 and increased 4.7 points annually (2.5 to 6.9) and 10.0 points annually (6.1 to 13.8), respectively, from 1995 to 2000. Among participants without coronary disease or hypertension, there was no overall increase in use. Use of renin-angiotensin system inhibitors increased 2.3 points annually (1.0 to 3.5), digoxin use decreased 2.4 points annually (-3.6 to -1.1), and loop diuretic use remained flat between 1989 and 2000. In general, treatment trends were similar for prevalent CHF.
CONCLUSIONS: Treatment of CHF has changed gradually in the 1990s and may in part reflect the influence of CHF clinical trial evidence.
10aAdrenergic beta-Antagonists10aAged10aAngiotensin II Type 1 Receptor Blockers10aAngiotensin-Converting Enzyme Inhibitors10aCohort Studies10aDrug Therapy10aDrug Therapy, Combination10aFemale10aHeart Failure10aHumans10aMale10aMultivariate Analysis10aPrevalence1 aSmith, Nicholas, L1 aChan, Jeannie, D1 aRea, Thomas, D1 aWiggins, Kerri, L1 aGottdiener, John, S1 aLumley, Thomas1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/80703206nas a2200409 4500008004100000022001400041245022100055210006900276260001600345300001100361490000800372520196600380653001002346653001602356653000902372653002802381653002802409653001302437653001102450653001102461653001702472653000902489653001602498653001702514653002602531653002502557653001202582100002002594700002302614700001802637700001902655700002402674700002102698700001702719700002502736856003502761 2005 eng d a1524-453900aAge-dependent associations between sleep-disordered breathing and hypertension: importance of discriminating between systolic/diastolic hypertension and isolated systolic hypertension in the Sleep Heart Health Study.0 aAgedependent associations between sleepdisordered breathing and c2005 Feb 08 a614-210 v1113 aBACKGROUND: Sleep-disordered breathing (SDB) is associated with hypertension in the middle-aged. The association is less clear in older persons. Most middle-aged hypertensives have systolic/diastolic hypertension, whereas isolated systolic hypertension (ISH) is common among persons over 60 years. Mechanistically, only systolic/diastolic hypertension is expected to be associated with SDB, but few studies of SDB and hypertension distinguish systolic/diastolic hypertension from ISH. Prior investigations may have underestimated an association between SDB and systolic/diastolic hypertension in the elderly by categorizing individuals with ISH as simply hypertensive.
METHODS AND RESULTS: We conducted cross-sectional analyses of 6120 participants in the Sleep Heart Health Study, stratified by age: 40 to 59 (n=2477) and > or =60 years. Outcome measures included apnea-hypopnea index (AHI; average number of apneas plus hypopneas per hour of sleep), systolic/diastolic hypertension (> or =140 and > or =90 mm Hg), and ISH (> or =140 and <90 mm Hg). With adjustment for covariates, ISH was not associated with SDB in either age category. In those aged<60 years, AHI was significantly associated with higher odds of systolic/diastolic hypertension (AHI 15 to 29.9, OR=2.38 [95% CI 1.30 to 4.38]; AHI > or =30, OR=2.24 [95% CI 1.10 to 4.54]). Among those aged > or =60 years, no adjusted association between AHI and systolic/diastolic hypertension was found.
CONCLUSIONS: SDB is associated with systolic/diastolic hypertension in those aged <60 years. No association was found between SDB and systolic/diastolic hypertension in those aged > or =60 years or between SDB and ISH in either age category. These findings have implications for SDB screening and treatment. Distinguishing between hypertensive subtypes reveals a stronger association between SDB and hypertension for those aged <60 years than previously reported.
10aAdult10aAge Factors10aAged10aAntihypertensive Agents10aCross-Sectional Studies10aDiastole10aFemale10aHumans10aHypertension10aMale10aMiddle Aged10aRisk Factors10aSleep Apnea Syndromes10aSleep Apnea, Central10aSystole1 aHaas, Donald, C1 aFoster, Gregory, L1 aNieto, Javier1 aRedline, Susan1 aResnick, Helaine, E1 aRobbins, John, A1 aYoung, Terry1 aPickering, Thomas, G uhttps://chs-nhlbi.org/node/82202976nas a2200373 4500008004100000022001400041245008600055210006900141260001600210300001100226490000800237520195000245653002702195653000902222653002202231653001902253653001102272653001802283653001102301653001402312653000902326653001902335653001702354653001702371653003202388100001802420700001802438700002302456700002802479700002202507700001802529700002002547856003502567 2005 eng d a1539-370400aAssociation between screening for osteoporosis and the incidence of hip fracture.0 aAssociation between screening for osteoporosis and the incidence c2005 Feb 01 a173-810 v1423 aBACKGROUND: Because direct evidence for the effectiveness of screening is lacking, guidelines disagree on whether people should be screened for osteoporosis.
OBJECTIVE: To determine whether population-based screening for osteoporosis in older adults is associated with fewer incident hip fractures than usual medical care.
DESIGN: Nonconcurrent cohort study.
SETTING: Population-based cohort enrolled in the Cardiovascular Health Study (CHS) from 4 states (California, Pennsylvania, Maryland, and North Carolina).
PATIENTS: 3107 adults 65 years of age and older who attended their CHS study visits in 1994-1995.
MEASUREMENTS: 31 participant characteristics (including demographic characteristics, medical histories, medications, and physical examination findings) and incident hip fractures over 6 years of follow-up.
INTERVENTION: Bone density scans (dual-energy x-ray absorptiometry [DEXA] at the hip) for participants in California and Pennsylvania (n = 1422) and usual care for participants in Maryland and North Carolina (n = 1685).
RESULTS: The incidence of hip fractures per 1000 person-years was 4.8 in the screened group and 8.2 in the usual care group. Screening was associated with a statistically significant lower hazard of hip fracture than usual care after adjustment for sex and propensity to be screened (Cox proportional hazard ratio, 0.64 [95% CI, 0.41 to 0.99]).
LIMITATIONS: The mechanism of the association was unclear. A small unmeasured confounder that decreased the hazard of hip fracture could diminish or erase the observed association.
CONCLUSIONS: Use of hip DEXA scans to screen for osteoporosis in older adults was associated with 36% fewer incident hip fractures over 6 years compared with usual medical care. Further research is needed to explore the mechanism of this association.
10aAbsorptiometry, Photon10aAged10aAged, 80 and over10aCohort Studies10aFemale10aHip Fractures10aHumans10aIncidence10aMale10aMass Screening10aOsteoporosis10aRisk Factors10aSensitivity and Specificity1 aKern, Lisa, M1 aPowe, Neil, R1 aLevine, Michael, A1 aFitzpatrick, Annette, L1 aHarris, Tamara, B1 aRobbins, John1 aFried, Linda, P uhttps://chs-nhlbi.org/node/82102860nas a2200361 4500008004100000022001400041245013800055210006900193260001300262300001100275490000800286520181600294653003202110653001602142653000902158653002202167653001102189653002202200653001802222653001102240653000902251100002102260700001902281700002302300700002102323700002302344700001902367700001802386700002102404700001802425700002002443856003502463 2005 eng d a1097-674400aAssociation of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS).0 aAssociation of betablocker use with mortality among patients wit c2005 Sep a464-700 v1503 aBACKGROUND: In clinical trials, beta-blocker therapy reduces all-cause mortality among people with congestive heart failure (CHF) characterized by depressed systolic function, but few trials included large numbers of elderly participants. This study assessed the association between beta-blocker therapy and mortality among community-dwelling older adults with CHF.
METHODS: The Cardiovascular Health Study (CHS) is a longitudinal, population-based study of adults aged > or = 65 years. Recruitment began in 1989 with follow-up extending through June 2000 or death. Cox proportional hazard regression models were used to assess the association between beta-blocker therapy and all-cause mortality among 950 participants who developed new-onset CHF.
RESULTS: beta-Blocker users (n = 157) were more likely than nonusers (n = 793) to have treated hypertension, clinical coronary artery disease, and valvular disease at the time of CHF diagnosis. Death occurred in 67 users and 446 nonusers during a median follow-up of 2.3 years. Compared with nonuse, use of beta-blockers was associated with a multivariable adjusted hazard ratio (HR) of 0.74 (95% CI 0.56-0.98) for all-cause mortality. Among the 520 participants who had left ventricular ejection fraction assessed within 90 days after CHF diagnosis, the risk for all cause mortality associated with beta-blocker use did not differ significantly between those with ejection fraction of < 40% and those with ejection fraction of > or = 40% (HR 0.56, 95% CI 0.27-1.13; HR 0.82, 95% CI 0.56-1.22, respectively; interaction P = .34).
CONCLUSIONS: This observational study suggests that beta-blocker treatment is associated with a reduced risk of all-cause mortality among community-dwelling older adults with CHF.
10aAdrenergic beta-Antagonists10aAge Factors10aAged10aAged, 80 and over10aFemale10aFollow-Up Studies10aHeart Failure10aHumans10aMale1 aChan, Jeannie, D1 aRea, Thomas, D1 aSmith, Nicholas, L1 aSiscovick, David1 aHeckbert, Susan, R1 aLumley, Thomas1 aChaves, Paulo1 aFurberg, Curt, D1 aKuller, Lewis1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/85603249nas a2200433 4500008004100000022001400041245008500055210006900140260001600209300001000225490000800235520207600243653001602319653000902335653002202344653001802366653002202384653002402406653001102430653002402441653001102465653000902476653001602485653001502501653001502516653002402531653001002555653003102565653001702596653001802613100002402631700002302655700001902678700002402697700001902721700002202740700001802762856003502780 2005 eng d a0003-992600aAssociation of sleep time with diabetes mellitus and impaired glucose tolerance.0 aAssociation of sleep time with diabetes mellitus and impaired gl c2005 Apr 25 a863-70 v1653 aBACKGROUND: Experimental sleep restriction causes impaired glucose tolerance (IGT); however, little is known about the metabolic effects of habitual sleep restriction. We assessed the cross-sectional relation of usual sleep time to diabetes mellitus (DM) and IGT among participants in the Sleep Heart Health Study, a community-based prospective study of the cardiovascular consequences of sleep-disordered breathing.
METHODS: Participants were 722 men and 764 women, aged 53 to 93 years. Usual sleep time was obtained by standardized questionnaire. Diabetes mellitus was defined as a serum glucose level of 126 mg/dL or more (> or =7.0 mmol/L) fasting or 200 mg/dL or more (> or =11.1 mmol/L) 2 hours following standard oral glucose challenge or medication use for DM. Impaired glucose tolerance was defined as a 2-hour postchallenge glucose level of 140 mg/dL or more (> or =7.8 mmol/L) and less than 200 mg/dL. The relation of sleep time to DM and IGT was examined using categorical logistic regression with adjustment for age, sex, race, body habitus, and apnea-hypopnea index.
RESULTS: The median sleep time was 7 hours per night, with 27.1% of subjects sleeping 6 hours or less per night. Compared with those sleeping 7 to 8 hours per night, subjects sleeping 5 hours or less and 6 hours per night had adjusted odds ratios for DM of 2.51 (95% confidence interval, 1.57-4.02) and 1.66 (95% confidence interval, 1.15-2.39), respectively. Adjusted odds ratios for IGT were 1.33 (95% confidence interval, 0.83-2.15) and 1.58 (95% confidence interval, 1.15-2.18), respectively. Subjects sleeping 9 hours or more per night also had increased odds ratios for DM and IGT. These associations persisted when subjects with insomnia symptoms were excluded.
CONCLUSIONS: A sleep duration of 6 hours or less or 9 hours or more is associated with increased prevalence of DM and IGT. Because this effect was present in subjects without insomnia, voluntary sleep restriction may contribute to the large public health burden of DM.
10aAge Factors10aAged10aAged, 80 and over10aBlood Glucose10aDiabetes Mellitus10aDisease Progression10aFemale10aGlucose Intolerance10aHumans10aMale10aMiddle Aged10aOdds Ratio10aPrevalence10aProspective Studies10aSleep10aSurveys and Questionnaires10aTime Factors10aUnited States1 aGottlieb, Daniel, J1 aPunjabi, Naresh, M1 aNewman, Ann, B1 aResnick, Helaine, E1 aRedline, Susan1 aBaldwin, Carol, M1 aNieto, Javier uhttps://chs-nhlbi.org/node/83403325nas a2200421 4500008004100000022001400041245012000055210006900175260001300244300001000257490000700267520209400274653002202368653002802390653002102418653002802439653004002467653001102507653001302518653001502531653001102546653001702557653001402574653000902588653001602597653002602613653003402639653001702673100002302690700002302713700002002736700001902756700002402775700002502799700002202824700002202846856003502868 2005 eng d a0895-706100abeta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study.0 abeta2Adrenergic receptor polymorphisms and determinants of cardi c2005 Mar a392-70 v183 aBACKGROUND: Common Arg16Gly and Gln27Glu polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) have been associated with hypertension and coronary disease. This analysis of older adults in the Cardiovascular Health Study examined whether these polymorphisms were associated with blood pressure (BP), subclinical atherosclerosis, and, among treated hypertensive individuals, differences in coronary disease risk according to antihypertensive drug class.
METHODS: Altogether, 5249 participants (4441 white and 808 African American, median follow-up time 10.2 years) were genotyped for both polymorphisms. Ankle-arm index (AAI), carotid intima-media thickness (IMT), and brachial flow-mediated dilation were measured cross-sectionally. All estimates were adjusted for ethnicity.
RESULTS: Relative to Gln27 homozygotes, carrying the Glu27 allele was not associated with new-onset hypertension (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 0.87 to 1.16), BP control (odds ratio [OR] = 0.97, 95% CI = 0.89 to 1.06), AAI (mean difference 0.0042 +/- 0.0052), carotid IMT (mean difference 0.0044 +/- 0.02 mm), or brachial flow-mediated dilation (mean difference in baseline diameter -0.028 +/- 0.036 mm; the most marked of three measures). Among treated hypertensive individuals, coronary disease risk was similar in Glu27 carriers relative to Gln27 homozygotes in subgroups defined by use of beta-blockers (HR = 1.09, 95% CI = 0.64 to 1.87) or other antihypertensive medications (HR = 1.00, 95% CI = 0.78 to 1.28). Results were similar for the Arg16Gly polymorphism.
CONCLUSIONS: The association of beta(2)AR genotype with coronary disease previously reported in this older adult population is not likely to be explained by BP levels, subclinical atherosclerosis, or antihypertensive treatment. Other measures of vascular response, gene-gene or gene-environment interactions, or characteristics developing earlier in life may mediate the association between beta(2)AR genotype and coronary disease and merit further research.
10aAfrican Americans10aAntihypertensive Agents10aArteriosclerosis10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aGenotype10aHomozygote10aHumans10aHypertension10aIncidence10aMale10aMiddle Aged10aPolymorphism, Genetic10aReceptors, Adrenergic, beta-210aRisk Factors1 aHindorff, Lucia, A1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aLumley, Thomas1 aSiscovick, David, S1 aHerrington, David, M1 aEdwards, Karen, L1 aTracy, Russell, P uhttps://chs-nhlbi.org/node/82503889nas a2200337 4500008004100000022001400041245011100055210006900166260001600235300001200251490000800263520291100271653000903182653002803191653002003219653001103239653002003250653002503270653001703295100002403312700002003336700001803356700002103374700001703395700002903412700002003441700001703461700002103478700001703499856003503516 2005 eng d a1538-359800aCardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors.0 aCardiovascular mortality risk in chronic kidney disease comparis c2005 Apr 13 a1737-450 v2933 aCONTEXT: Elderly persons with chronic kidney disease have substantial risk for cardiovascular mortality, but the relative importance of traditional and novel risk factors is unknown.
OBJECTIVE: To compare traditional and novel risk factors as predictors of cardiovascular mortality.
DESIGN, SETTING, AND PATIENTS: A total of 5808 community-dwelling persons aged 65 years or older living in 4 communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to June 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up in this longitudinal study was 8.6 years.
MAIN OUTCOME MEASURES: Cardiovascular mortality among those with and without chronic kidney disease. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2.
RESULTS: Among the participants, 1249 (22%) had chronic kidney disease at baseline. The cardiovascular mortality risk rate was 32 deaths/1000 person-years among those with chronic kidney disease vs 16/1000 person-years among those without it. In multivariate analyses, diabetes, systolic hypertension, smoking, low physical activity, nonuse of alcohol, and left ventricular hypertrophy were predictors of cardiovascular mortality in persons with chronic kidney disease (all P values <.05). Among the novel risk factors, only log C-reactive protein (P = .05) and log interleukin 6 (P<.001) were associated with the outcome as linear predictors. Traditional risk factors were associated with the largest absolute increases in risks for cardiovascular deaths among persons with chronic kidney disease: for left ventricular hypertrophy, there were 25 deaths per 1000 person-years; current smoking, 20 per 1000 person-years; physical inactivity, 15 per 1000 person-years; systolic hypertension, 14 per 1000 person-years; diabetes, 14 per 1000 person-years; and nonuse of alcohol, 11 per 1000 person-years vs 5 deaths per 1000 person-years for those with increased C-reactive protein and 5 per 1000 person-years for those with increased interleukin 6 levels. A receiver operating characteristic analysis found that traditional risk factors had an area under the curve of 0.73 (95% confidence interval, 0.70-0.77) among those with chronic kidney disease. Adding novel risk factors only increased the area under the curve to 0.74 (95% confidence interval, 0.71-0.78; P for difference = .15).
CONCLUSIONS: Traditional cardiovascular risk factors had larger associations with cardiovascular mortality than novel risk factors in elderly persons with chronic kidney disease. Future research should investigate whether aggressive lifestyle intervention in patients with chronic kidney disease can reduce their substantial cardiovascular risk.
10aAged10aCardiovascular Diseases10aChronic Disease10aHumans10aKidney Diseases10aLongitudinal Studies10aRisk Factors1 aShlipak, Michael, G1 aFried, Linda, F1 aCushman, Mary1 aManolio, Teri, A1 aPeterson, Do1 aStehman-Breen, Catherine1 aBleyer, Anthony1 aNewman, Anne1 aSiscovick, David1 aPsaty, Bruce uhttps://chs-nhlbi.org/node/83102760nas a2200505 4500008004100000022001400041245013500055210006900190260001300259300001100272490000800283520133700291653000901628653001001637653002401647653001901671653001901690653001101709653001301720653001801733653001101751653001701762653001401779653000901793653001601802653003801818653002601856653003001882653002401912653001701936653001501953100002501968700001701993700002302010700002602033700002002059700001802079700002202097700002002119700001902139700002002158700002102178700002002199856003502219 2005 eng d a0021-915000aCommon promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study.0 aCommon promoter polymorphisms of inflammation and thrombosis gen c2005 Jul a175-830 v1813 aInflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 -174 G/C, beta-fibrinogen -455 G/A, plasminogen activator inhibitor (PAI)-1 -675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) -438 G/A in 2224 men and women > or = 65 years old at baseline. During 10 years of follow-up, men with the TAFI -438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the -438 G allele. The effects of TAFI -438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 -174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.
10aAged10aAging10aCarboxypeptidase B210aCause of Death10aCohort Studies10aFemale10aGenotype10aHealth Status10aHumans10aInflammation10aLongevity10aMale10aMiddle Aged10aPlasminogen Activator Inhibitor 110aPolymorphism, Genetic10aPromoter Regions, Genetic10aProspective Studies10aRisk Factors10aThrombosis1 aReiner, Alexander, P1 aDiehr, Paula1 aBrowner, Warren, S1 aHumphries, Stephen, E1 aJenny, Nancy, S1 aCushman, Mary1 aTracy, Russell, P1 aWalston, Jeremy1 aLumley, Thomas1 aNewman, Anne, B1 aKuller, Lewis, H1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/84202779nas a2200397 4500008004100000022001400041245013200055210006900187260001600256300001000272490000800282520164900290653001601939653000901955653002201964653001501986653002302001653002102024653001102045653001102056653001402067653001702081653000902098653002602107653003002133653001702163100001802180700002102198700002002219700002102239700002102260700002202281700002102303700002202324856003502346 2005 eng d a1524-453900aC-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study.0 aCreactive protein and the 10year incidence of coronary heart dis c2005 Jul 05 a25-310 v1123 aBACKGROUND: High C-reactive protein (CRP) is associated with increased coronary heart disease risk. Few long-term data in the elderly are available.
METHODS AND RESULTS: Baseline CRP was measured in 3971 men and women > or =65 years of age without prior vascular diseases; 26% had elevated concentrations (>3 mg/L). With 10 years of follow-up, 547 participants developed coronary heart disease (CHD; defined as myocardial infarction or coronary death). With elevated CRP, the 10-year cumulative CHD incidences were 33% in men and 17% in women. The age-, ethnicity-, and sex-adjusted relative risk of CHD for CRP >3 mg/L compared with <1 mg/L was 1.82 (95% CI, 1.46 to 2.28). Adjusting for conventional risk factors reduced the relative risk to 1.45 (95% CI, 1.14 to 1.86). The population-attributable risk of CHD for elevated CRP was 11%. Risk relationships did not differ in subgroups defined by baseline risk factors. We assessed whether CRP improved prediction by the Framingham Risk Score. Among men with a 10-year Framingham-predicted risk of 10% to 20%, the observed CHD incidence was 32% for elevated CRP. Among women, CRP discriminated best among those with a 10-year predicted risk >20%; the incidences were 31% and 10% for elevated and normal CRP levels, respectively.
CONCLUSIONS: In older men and women, elevated CRP was associated with increased 10-year risk of CHD, regardless of the presence or absence of cardiac risk factors. A single CRP measurement provided information beyond conventional risk assessment, especially in intermediate-Framingham-risk men and high-Framingham-risk women.
10aAge Factors10aAged10aAged, 80 and over10aBiomarkers10aC-Reactive Protein10aCoronary Disease10aFemale10aHumans10aIncidence10aInflammation10aMale10aMyocardial Infarction10aPredictive Value of Tests10aRisk Factors1 aCushman, Mary1 aArnold, Alice, M1 aPsaty, Bruce, M1 aManolio, Teri, A1 aKuller, Lewis, H1 aBurke, Gregory, L1 aPolak, Joseph, F1 aTracy, Russell, P uhttps://chs-nhlbi.org/node/84503555nas a2200445 4500008004100000022001400041245008100055210006900136260001600205300001200221490000800233520234700241653000902588653001502597653001502612653001502627653001402642653001102656653002202667653003102689653001802720653001102738653001402749653001102763653002602774653000902800653001702809653001802826100002002844700001602864700003202880700002002912700002502932700002002957700002002977700002102997700002403018710003203042856003503074 2005 eng d a1539-370400aCystatin C concentration as a risk factor for heart failure in older adults.0 aCystatin C concentration as a risk factor for heart failure in o c2005 Apr 05 a497-5050 v1423 aBACKGROUND: Previous studies that evaluated the association of kidney function with incident heart failure may be limited by the insensitivity of serum creatinine concentration for detecting abnormal kidney function.
OBJECTIVE: To compare serum concentrations of cystatin C (a novel marker of kidney function) and creatinine as predictors of incident heart failure.
DESIGN: Observational study based on measurement of serum cystatin C from frozen sera obtained at the 1992-1993 visit of the Cardiovascular Health Study. Follow-up occurred every 6 months.
SETTING: Adults 65 years of age or older from 4 communities in the United States.
PARTICIPANTS: 4384 persons without previous heart failure who had measurements of serum cystatin C and serum creatinine.
MEASUREMENTS: Incident heart failure.
RESULTS: The mean (+/-SD) serum concentrations of cystatin C and creatinine were 82 +/- 25 nmol/L (1.10 +/- 0.33 mg/L) and 89 +/- 34 micromol/L (1.01 +/- 0.39 mg/dL), respectively. During a median follow-up of 8.3 years (maximum, 9.1 years), 763 (17%) participants developed heart failure. After adjustment for demographic factors, traditional and novel cardiovascular risk factors, cardiovascular disease status, and medication use, sequential quintiles of cystatin C concentration were associated with a stepwise increased risk for heart failure in Cox proportional hazards models (hazard ratios, 1.0 [reference], 1.30 [95% CI, 0.96 to 1.75], 1.44 [CI, 1.07 to 1.94], 1.58 [CI, 1.18 to 2.12], and 2.16 [CI, 1.61 to 2.91]). In contrast, quintiles of serum creatinine concentration were not associated with risk for heart failure in adjusted analysis (hazard ratios, 1.0 [reference], 0.77 [CI, 0.59 to 1.01], 0.85 [CI, 0.64 to 1.13], 0.97 [CI, 0.72 to 1.29], and 1.14 [CI, 0.87 to 1.49]).
LIMITATIONS: The mechanism by which cystatin C concentration predicts risk for heart failure remains unclear.
CONCLUSIONS: The cystatin C concentration is an independent risk factor for heart failure in older adults and appears to provide a better measure of risk assessment than the serum creatinine concentration. *For a full list of participating Cardiovascular Health Study investigators and institutions, see http://www.chs-nhlbi.org.
10aAged10aBiomarkers10aCreatinine10aCystatin C10aCystatins10aFemale10aFollow-Up Studies10aGlomerular Filtration Rate10aHeart Failure10aHumans10aIncidence10aKidney10aKidney Function Tests10aMale10aRisk Factors10aUnited States1 aSarnak, Mark, J1 aKatz, Ronit1 aStehman-Breen, Catherine, O1 aFried, Linda, F1 aJenny, Nancy, Swords1 aPsaty, Bruce, M1 aNewman, Anne, B1 aSiscovick, David1 aShlipak, Michael, G1 aCardiovascular Health Study uhttps://chs-nhlbi.org/node/82702928nas a2200433 4500008004100000022001400041245006700055210006500122260001300187300000900200490000800209520175900217653001601976653000901992653001502001653002302016653002802039653001502067653001402082653001102096653001502107653003102122653001102153653002002164653000902184653003002193653003202223100002402255700001602279700001802295700002002313700002902333700002002362700002102382700002202403700001702425700001702442856003502459 2005 eng d a1555-716200aCystatin-C and inflammatory markers in the ambulatory elderly.0 aCystatinC and inflammatory markers in the ambulatory elderly c2005 Dec a14160 v1183 aPURPOSE: Inflammatory factors are elevated in persons with severe renal dysfunction, but their association across all levels of renal function is unclear. We compared cystatin-C, a novel marker of renal function, with creatinine and estimated glomerular filtration rate (eGFR) as predictors of C-reactive protein and fibrinogen levels.
METHODS: This study is a cross-sectional analysis to evaluate cystatin-C, creatinine, and eGFR as predictors of the inflammatory markers C-reactive protein and fibrinogen. Participants included 4637 ambulatory elderly patients from the Cardiovascular Health Study. Multivariate linear regression was used to determine the independent associations of each renal function measurement with the inflammatory marker outcomes.
RESULTS: After adjustment for confounding factors, cystatin-C was correlated with both C-reactive protein (coefficient = 0.13; 95% confidence interval: 0.10-1.16, P <.0001) and fibrinogen levels (0.15; 0.13-0.18, P <.0001). Associations were larger than those for creatinine and C-reactive protein (0.05; 0.02-0.07, P = .003) or fibrinogen (0.07; 0.04-0.10, P <.0001). Adjusted levels of C-reactive protein increased incrementally across quintiles of cystatin-C, from a median of 2.2 mg/L in quintile 1 to 3.7 mg/L in quintile 5. In contrast, both C-reactive protein and fibrinogen had U-shaped associations with quintiles of creatinine and eGFR, because the inflammatory markers were equivalently elevated in quintiles 1 and 5.
CONCLUSIONS: The finding of a significant linear association of cystatin-C and inflammation markers suggests that even small reductions in renal function may be associated with adverse pathophysiologic consequences.
10aAge Factors10aAged10aBiomarkers10aC-Reactive Protein10aCross-Sectional Studies10aCystatin C10aCystatins10aFemale10aFibrinogen10aGlomerular Filtration Rate10aHumans10aKidney Diseases10aMale10aPredictive Value of Tests10aSensitivity and Specificity1 aShlipak, Michael, G1 aKatz, Ronit1 aCushman, Mary1 aSarnak, Mark, J1 aStehman-Breen, Catherine1 aPsaty, Bruce, M1 aSiscovick, David1 aTracy, Russell, P1 aNewman, Anne1 aFried, Linda uhttps://chs-nhlbi.org/node/87602720nas a2200433 4500008004100000022001400041245006800055210006600123260001600189300001100205490000700216520154600223653001601769653000901785653002201794653001501816653001501831653001401846653001101860653002201871653003101893653001801924653001101942653000901953653001901962653003001981653002002011653002202031100002402053700001602077700002002093700002502113700003202138700002002170700002102190700002002211700002002231856003502251 2005 eng d a0735-109700aCystatin-C and mortality in elderly persons with heart failure.0 aCystatinC and mortality in elderly persons with heart failure c2005 Jan 18 a268-710 v453 aOBJECTIVES: We sought to evaluate cystatin-C, a novel measure of renal function, as a predictor of mortality in elderly persons with heart failure (HF) and to compare it with creatinine.
BACKGROUND: Renal function is an important prognostic factor in patients with HF, but creatinine levels, which partly reflect muscle mass, may be insensitive for detecting renal insufficiency.
METHODS: A total of 279 Cardiovascular Health Study participants with prevalent HF and measures of serum cystatin-C and creatinine were followed for mortality outcomes over a median of 6.5 years.
RESULTS: Median creatinine and cystatin-C levels were 1.05 mg/dl and 1.26 mg/l. Each standard deviation increase in cystatin-C (0.35 mg/l) was associated with a 31% greater adjusted mortality risk (95% confidence interval [CI] 20% to 43%, p < 0.001), whereas each standard deviation increase in creatinine (0.39 mg/dl) was associated with a 17% greater adjusted mortality risk (95% CI 1% to 36%, p = 0.04). When both measures were combined in a single adjusted model, cystatin-C remained associated with elevated mortality risk (hazard ratio 1.60, 95% CI 1.32 to 1.94), whereas creatinine levels appeared associated with lower risk (hazard ratio 0.73, 95% CI 0.57 to 0.95).
CONCLUSIONS: Cystatin-C is a stronger predictor of mortality than creatinine in elderly persons with HF. If confirmed in future studies, this new marker of renal function could improve risk stratification in patients with HF.
10aAge Factors10aAged10aAged, 80 and over10aCreatinine10aCystatin C10aCystatins10aFemale10aFollow-Up Studies10aGlomerular Filtration Rate10aHeart Failure10aHumans10aMale10aPilot Projects10aPredictive Value of Tests10aRisk Assessment10aSurvival Analysis1 aShlipak, Michael, G1 aKatz, Ronit1 aFried, Linda, F1 aJenny, Nancy, Swords1 aStehman-Breen, Catherine, O1 aNewman, Anne, B1 aSiscovick, David1 aPsaty, Bruce, M1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/81602904nas a2200409 4500008004100000022001400041245009300055210006900148260001300217300001000230490000700240520174800247653002201995653002102017653000902038653002202047653002802069653004002097653001102137653002502148653001102173653001402184653002502198653000902223653002102232653001802253653001802271100002102289700002002310700002102330700002202351700002102373700002002394700002102414700002402435856003502459 2005 eng d a0002-861400aIncidence of cardiovascular disease in older Americans: the cardiovascular health study.0 aIncidence of cardiovascular disease in older Americans the cardi c2005 Feb a211-80 v533 aOBJECTIVES: To estimate incidence rates of major cardiovascular disease (CVD) in older Americans.
DESIGN: Longitudinal cohort study using prospectively collected data on cardiovascular events.
SETTING: Four U.S. communities in the Cardiovascular Health Study (CHS).
PARTICIPANTS: Five thousand eight hundred eighty-eight participants in CHS, aged 65 or older at enrollment, including 3,393 women (581 African American) and 2,495 men (343 African American).
MEASUREMENTS: At semiannual contacts, participants reported any occurrence of clinical CVD. Medical records were obtained and adjudicated to confirm diagnosis of CVD.
RESULTS: During 10 years of follow-up, incidence of coronary heart disease (CHD) per 1,000 person-years was 39.6 (95% confidence interval (CI)=36.4-43.1) in men and 22.3 (95% CI=20.4-24.2) in women. Cumulative event rates for CHD and myocardial infarction for women aged 75 and older at baseline were similar to those for men aged 65 to 74. The overall incidence of stroke was similar for men and women (14.7 (95% CI=13.0-16.6) and 13.7 (95% CI=12.4-15.1) per 1,000 person-years, respectively), but the risk of stroke increased with age more rapidly in women, resulting in a greater cumulative event rate for stroke in women than in men aged 75 and older. The incidence of congestive heart failure increased 9% with each year of age over 65 and was greater than 6% per year in Caucasian men and women aged 85 and older at baseline. Rates were similar in African Americans and Caucasians.
CONCLUSION: The occurrence of new CVD in older Americans is high, indicating that preventive efforts need to be maintained into older ages.
10aAfrican Americans10aAge Distribution10aAged10aAged, 80 and over10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aGeriatric Assessment10aHumans10aIncidence10aLongitudinal Studies10aMale10aSex Distribution10aSurvival Rate10aUnited States1 aArnold, Alice, M1 aPsaty, Bruce, M1 aKuller, Lewis, H1 aBurke, Gregory, L1 aManolio, Teri, A1 aFried, Linda, P1 aRobbins, John, A1 aKronmal, Richard, A uhttps://chs-nhlbi.org/node/82002144nas a2200253 4500008004100000022001400041245009100055210006900146260001300215300001200228490000700240520138900247653003101636653001001667653002901677653001101706653002501717653003201742100001701774700002401791700002301815700001701838856003501855 2005 eng d a0895-435600aMethods for incorporating death into health-related variables in longitudinal studies.0 aMethods for incorporating death into healthrelated variables in c2005 Nov a1115-240 v583 aBACKGROUND AND OBJECTIVES: Longitudinal studies of health over time may be misleading if some people die. Self-rated health (excellent to poor) and the SF-36 profile scores have been transformed to incorporate death. We applied the same approaches to incorporate death into activities of daily living difficulties (ADLs), IADLs, mini-mental state examination, depressive symptoms, blocks walked per week, bed days, the timed walk, body mass index and blood pressure.
STUDY DESIGN AND SETTING: The Cardiovascular Health Study of 5,888 older adults, was followed up to 9 years. Mean age was 73 at baseline, and 658 had an incident stroke during follow-up.
METHODS: We recoded each variable as the probability of being healthy 1 year in the future (PHF), conditional on the current value of the variable. This was done for 11 health variables, using three definitions of healthy, and two estimation models. Deaths were set to zero, and mean PHF was plotted in the 3 years before and after an incident stroke.
RESULTS: Analyses without the deaths were too optimistic. The effect of stroke was greatest on hospitalization, self-rated health, and IADLs. Alternative transformation approaches had slightly different results.
CONCLUSION: These methods provide an additional approach for handling death in longitudinal studies.
10aActivities of Daily Living10aDeath10aHealth Status Indicators10aHumans10aLongitudinal Studies10aProportional Hazards Models1 aDiehr, Paula1 aJohnson, Laura, Lee1 aPatrick, Donald, L1 aPsaty, Bruce uhttps://chs-nhlbi.org/node/86102544nas a2200397 4500008004100000022001400041245011400055210006900169260001600238300001100254490000800265520141500273653000901688653002201697653002201719653002201741653001301763653002301776653001101799653001301810653001101823653000901834653001901843653003201862653002401894653001701918653001801935100002601953700002001979700002101999700002002020700002002040700002202060700002902082856003502111 2005 eng d a0002-926200aPhysical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study.0 aPhysical activity APOE genotype and dementia risk findings from c2005 Apr 01 a639-510 v1613 aPhysical activity may help preserve cognitive function and decrease dementia risk, but epidemiologic findings are inconsistent. The authors conducted a prospective study to determine the association between physical activity and risk of dementia, Alzheimer's disease, and vascular dementia. The US study population comprised 3,375 men and women aged 65 years or older, free of dementia at baseline, who participated in the Cardiovascular Health Cognition Study in 1992-2000. Leisure-time energy expenditure and an activity index reflecting number of different physical activities were calculated. Analyses were based on Cox proportional hazards models. There were 480 incident cases of dementia over an average of 5.4 years of follow-up. After multivariate adjustment, participants in the highest quartile of physical energy expenditure had a relative risk of dementia of 0.85 (95% confidence interval: 0.61, 1.19) compared with those in the lowest quartile, and participants engaging in >or=4 activities had a relative risk of dementia of 0.51 (95% confidence interval: 0.33, 0.79) compared with those engaging in 0-1 activity. These associations were more marked in apolipoprotein E genotype (APOE) epsilon4 allele noncarriers but were absent in carriers. A similar pattern was observed for Alzheimer's disease and vascular dementia. Mechanisms to explain the observed relations deserve further study.
10aAged10aAged, 80 and over10aAlzheimer Disease10aApolipoproteins E10aDementia10aDementia, Vascular10aFemale10aGenotype10aHumans10aMale10aMotor Activity10aProportional Hazards Models10aProspective Studies10aRisk Factors10aUnited States1 aPodewils, Laura, Jean1 aGuallar, Eliseo1 aKuller, Lewis, H1 aFried, Linda, P1 aLopez, Oscar, L1 aCarlson, Michelle1 aLyketsos, Constantine, G uhttps://chs-nhlbi.org/node/82403543nas a2200469 4500008004100000022001400041245012700055210006900182260001300251300001100264490000700275520219900282653002202481653000902503653001002512653001502522653002802537653001902565653001102584653002502595653001302620653001102633653000902644653002002653653001402673653003602687653002802723653001702751653002602768100002502794700001402819700002002833700002802853700002402881700002402905700001702929700003202946700002202978700002003000700001803020856003503038 2005 eng d a0002-929700aPopulation structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study.0 aPopulation structure admixture and agingrelated phenotypes in Af c2005 Mar a463-770 v763 aU.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.
10aAfrican Americans10aAged10aAging10aAlgorithms10aCardiovascular Diseases10aCohort Studies10aFemale10aGenetics, Population10aGenotype10aHumans10aMale10aModels, Genetic10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors10aSocioeconomic Factors1 aReiner, Alexander, P1 aZiv, Elad1 aLind, Denise, L1 aNievergelt, Caroline, M1 aSchork, Nicholas, J1 aCummings, Steven, R1 aPhong, Angie1 aBurchard, Esteban González1 aHarris, Tamara, B1 aPsaty, Bruce, M1 aKwok, Pui-Yan uhttps://chs-nhlbi.org/node/81703046nas a2200361 4500008004100000022001400041245017300055210006900228260001600297300001000313490000800323520194100331653000902272653002202281653001402303653002502317653001102342653002402353653001402377653001202391653004902403653003302452653000902485653002402494653001702518100001402535700001502549700001702564700002502581700002402606700001902630856003502649 2005 eng d a0008-543X00aProstate carcinoma incidence in relation to prediagnostic circulating levels of insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin.0 aProstate carcinoma incidence in relation to prediagnostic circul c2005 Jan 01 a76-840 v1033 aBACKGROUND: There have been several epidemiologic studies investigating the association between circulating levels of insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and insulin in relation to the risk of prostate carcinoma, with conflicting results. To examine this issue further, the authors conducted a nested case-control study within the Cardiovascular Health Study cohort.
METHODS: In men who were diagnosed with prostate carcinoma (cases) between 1990 and 1999 (n=174), the levels of IGF-I, IGFBP-3, and insulin were measured on blood samples that were obtained 1-9 years prior to diagnosis (mean, 3.4 years). Similar measurements were made on 174 male participants without prostate carcinoma (controls) who were matched to cases based on the year blood was drawn, survival until the date of diagnosis, race, and age.
RESULTS: Relative to the men with IGF-I levels in the first (lowest) quartile of the distribution, the risk of prostate carcinoma for men in the second, third, and fourth (upper) quartiles were 0.77 (95% confidence interval [95% CI], 0.43-1.38), 0.73 (95% CI, 0.41-1.30), and 0.67 (95% CI, 0.37-1.25), respectively. The results were influenced little by adjustment for levels of IGFBP-3 or, instead, by evaluating the molar IGF-I/IGFBP-3 ratio. An analysis that was restricted to men who had plasma prostate-specific antigen levels <4 ng/mL at the time of the blood draw yielded similar results. The corresponding relative risks for IGFBP-3 were 0.91 (95% CI, 0.49-1.68), 0.47 (95% CI, 0.25-0.94), and 0.65 (95% CI, 0.35-1.20), respectively. The distribution of serum insulin levels in cases and controls were nearly identical.
CONCLUSIONS: The IGF-I level was not associated positively with the risk of prostate carcinoma; however, an increase in the IGFBP-3 level was associated with a modest decrease in risk.
10aAged10aAged, 80 and over10aCarcinoma10aCase-Control Studies10aHumans10aHypoglycemic Agents10aIncidence10aInsulin10aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aProstatic Neoplasms10aRisk Factors1 aChen, Chu1 aLewis, Kay1 aVoigt, Lynda1 aFitzpatrick, Annette1 aPlymate, Stephen, R1 aWeiss, Noel, S uhttps://chs-nhlbi.org/node/81003279nas a2200541 4500008004100000022001400041245008300055210006900138260001300207300001100220490000700231520176200238653002202000653000902022653001002031653002102041653001902062653002802081653001902109653001502128653002802143653001302171653002402184653004002208653001102248653001102259653003102270653001102301653002002312653002602332653000902358653001702367653002902384653002202413653001702435653002102452653001202473653003702485653001802522100002302540700002402563700002302587700002402610700002202634700002102656700002502677856003502702 2005 eng d a1523-683800aRenal duplex parameters, blood pressure, and renal function in elderly people.0 aRenal duplex parameters blood pressure and renal function in eld c2005 May a842-500 v453 aBACKGROUND: Changes in renal artery and renal parenchyma perfusion are believed to correlate with severity of hypertension and worsened renal function, but population-based studies of these associations are not available. This study examines relationships between parameters derived from renal duplex sonography (RDS), blood pressure (BP), and excretory renal function in a population-based cohort of elderly Americans.
METHODS: Through an ancillary study to the Cardiovascular Health Study, 758 participants (37% men; mean age, 77 years) underwent RDS in which flow velocities and frequency shifts were determined from spectral analysis of Doppler-shifted signals obtained from the renal artery and parenchyma. Associations of these duplex parameters with BP and inverse serum creatinine were examined by using multivariate regression techniques.
RESULTS: Main renal artery peak systolic flow velocity (PSV) showed independent associations with BP, with an SD increase in PSV (0.53 m/s) associated with a 3.3-mm Hg increase in systolic BP (SBP) and a 2.4-mm Hg decrease in diastolic BP (DBP). An SD decrease in end-diastolic frequency shift (EDF; 131 kHz) was associated with a 6.0-mm Hg increase in SBP, a 4.2-mm Hg decrease in DBP, and a significant 3.7% decrease in inverse serum creatinine.
CONCLUSION: Increases in renal artery PSV and decreases in parenchymal EDF are associated with increased SBP and decreased DBP. Moreover, decreased parenchymal EDF showed significant associations with impaired excretory renal function. These results suggest that renal duplex parameters are associated with renal parenchymal changes caused by hypertension and progressive renal dysfunction in elderly people.
10aAfrican Americans10aAged10aAging10aArteriosclerosis10aBlood Pressure10aCardiovascular Diseases10aCohort Studies10aCreatinine10aCross-Sectional Studies10aDiastole10aDisease Progression10aEuropean Continental Ancestry Group10aFemale10aHumans10aHypertension, Renovascular10aKidney10aKidney Diseases10aKidney Function Tests10aMale10aRenal Artery10aRenal Artery Obstruction10aRenal Circulation10aRisk Factors10aSampling Studies10aSystole10aUltrasonography, Doppler, Duplex10aUnited States1 aPearce, Jeffrey, D1 aEdwards, Matthew, S1 aCraven, Timothy, E1 aEnglish, William, P1 aMondi, Matthew, M1 aReavis, Scott, W1 aHansen, Kimberley, J uhttps://chs-nhlbi.org/node/83602852nas a2200373 4500008004100000022001400041245012100055210006900176260001600245300001300261490000800274520178900282653000902071653002202080653001002102653002002112653002802132653001102160653001102171653000902182653003302191653002002224653001702244100002202261700001702283700002102300700002302321700002002344700002102364700002202385700001802407700001802425856003502443 2005 eng d a0003-992600aRisk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study.0 aRisk factors for declining anklebrachial index in men and women c2005 Sep 12 a1896-9020 v1653 aBACKGROUND: An ankle-brachial index (ABI) of less than 0.9 is a noninvasive measure of lower extremity arterial disease and a predictor of cardiovascular events. Little information is available on longitudinal change in ABI or on risk factors for declining ABI in a community-based population.
METHODS: To assess risk factors for ABI decline, we studied 5888 participants in the Cardiovascular Health Study cohort (men and women 65 years or older). We measured ABI in 1992-1993 and again in 1998-1999. At baseline, we excluded individuals with an ABI less than 0.9, ABI greater than 1.4, or confirmed symptomatic lower extremity arterial disease (n = 823). The group with ABI decline included 218 participants with decline greater than 0.15 and to 0.9 or less. The comparison group comprised the remaining 2071 participants with follow-up ABI.
RESULTS: The percentage of participants with ABI decline was 9.5% over 6 years of follow-up. The mean +/- SD decline was 0.33 +/- 0.12 in cases of ABI decline and 0.02 +/- 0.13 in non-cases. Independent predictors of ABI decline, reported as odds ratios, were age, 1.96 (95% confidence interval [CI], 1.42-2.71) for 75 to 84 years and 3.79 (95% CI, 1.36-10.5) for those older than 85 years compared with those younger than 75 years; current cigarette use, 1.74 (95% CI, 1.02-2.96); hypertension, 1.64 (95% CI, 1.18-2.28); diabetes, 1.77 (95% CI, 1.14-2.76); higher low-density lipoprotein cholesterol level, 1.60 (95% CI, 1.03-2.51), and lipid-lowering drug use 1.74 (95% CI, 1.05-2.89).
CONCLUSION: Worsening lower extremity arterial disease, assessed as ABI decline, occurred in 9.5% of this elderly cohort over 6 years and was associated with modifiable vascular disease risk factors.
10aAged10aAged, 80 and over10aAnkle10aBrachial Artery10aCardiovascular Diseases10aFemale10aHumans10aMale10aPeripheral Vascular Diseases10aRisk Assessment10aRisk Factors1 aKennedy, Margaret1 aSolomon, Cam1 aManolio, Teri, A1 aCriqui, Michael, H1 aNewman, Anne, B1 aPolak, Joseph, F1 aBurke, Gregory, L1 aEnright, Paul1 aCushman, Mary uhttps://chs-nhlbi.org/node/85503069nas a2200397 4500008004100000022001400041245008300055210006900138260001300207300001200220490000700232520193800239653000902177653002202186653002802208653001902236653001302255653001102268653001102279653005102290653002002341653000902361100001902370700002202389700002002411700002802431700002002459700002002479700002402499700002002523700002202543700002902565700002102594700002102615856003502636 2005 eng d a0003-994200aStatin use and the risk of incident dementia: the Cardiovascular Health Study.0 aStatin use and the risk of incident dementia the Cardiovascular c2005 Jul a1047-510 v623 aBACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk through mechanisms that might affect the development of dementia.
OBJECTIVE: To evaluate whether statin use is associated with a lower risk of dementia compared with never use of lipid-lowering agents (LLAs).
DESIGN: Cohort study of community-dwelling adults 65 years and older. The analysis included 2798 participants free of dementia at baseline.
MAIN OUTCOME MEASURES: Using Cox proportional hazards regression analysis, we estimated the risk of incident all-cause and type-specific dementia associated with time-dependent statin therapy compared with never use of LLAs. The primary analyses incorporated a 1-year lag between exposure and outcome. Secondary analyses included the final year of exposure and modeled statin use as current use vs nonuse to simulate a case-control approach.
RESULTS: Compared with never use of LLAs, ever use of statins was not associated with the risk of all-cause dementia (multivariable-adjusted hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.77-1.52), Alzheimer disease alone (HR, 1.21; 95% CI, 0.76-1.91), mixed Alzheimer disease and vascular dementia (HR, 0.87; 95% CI, 0.44-1.72), or vascular dementia alone (HR, 1.36; 95% CI, 0.61-3.06). In contrast, in secondary analyses, current use of statins compared with nonuse of LLAs was associated with HRs of 0.69 (95% CI, 0.46-1.02) for all-cause dementia and 0.56 (95% CI, 0.35-0.92) for any Alzheimer disease.
CONCLUSIONS: In this cohort study, statin therapy was not associated with a decreased risk of dementia. Methodological differences may explain why results of this cohort investigation differ from those of prior case-control studies. Additional investigation is needed to determine whether and for whom statin use may affect dementia risk.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aCohort Studies10aDementia10aFemale10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aHyperlipidemias10aMale1 aRea, Thomas, D1 aBreitner, John, C1 aPsaty, Bruce, M1 aFitzpatrick, Annette, L1 aLopez, Oscar, L1 aNewman, Anne, B1 aHazzard, William, R1 aZandi, Peter, P1 aBurke, Gregory, L1 aLyketsos, Constantine, G1 aBernick, Charles1 aKuller, Lewis, H uhttps://chs-nhlbi.org/node/84603211nas a2200505 4500008004100000022001400041245009700055210006900152260001600221300001100237490000700248520187300255653001602128653000902144653002202153653001002175653001902185653002802204653001902232653001902251653001602270653002802286653002102314653001102335653001102346653002002357653001702377653002502394653000902419653001402428653002402442653001502466653001602481653001102497653002202508100001702530700002102547700002002568700001702588700001802605700001702623700001502640700001502655856003502670 2005 eng d a1526-632X00aVascular events, mortality, and preventive therapy following ischemic stroke in the elderly.0 aVascular events mortality and preventive therapy following ische c2005 Sep 27 a835-420 v653 aBACKGROUND: The authors studied mortality, vascular events, and preventive therapies following ischemic stroke among adults aged > or =65 years.
METHODS: The authors identified 546 subjects with first ischemic stroke during 1989 to 2001 among Cardiovascular Health Study participants. Deaths, recurrent strokes, and coronary heart disease (CHD) events were identified over 3.2 years (median) follow-up.
RESULTS: During the first year of follow-up, rates were 105.4/1,000 for recurrent stroke and 59.3/1,000 for CHD. After the first year, the stroke rate was 52.0/1,000 and the CHD rate was 46.5/1,000. Cardioembolic strokes had the highest mortality (185.4/1,000) and recurrence rates (86.6/1,000). Lacunar strokes had the lowest mortality (119.3/1,000) and recurrence rates (43.0/1,000). Age and male sex predicted death and CHD, but not recurrence. Outcomes did not differ by race. Following stroke, 47.8% used aspirin and 13.5% used other antiplatelet agents; 52.6% of patients with atrial fibrillation used warfarin; 31.3% of hyperlipidemic subjects, 57.0% of diabetic patients, and 81.5% of hypertensive patients were drug-treated; and 40.0% of hypertensive patients had blood pressure (BP) <140/90 mm Hg. Older subjects were less likely to use lipid-lowering therapy, women were less likely to have BP <140/90 mm Hg, and low-income subjects were less likely to use diabetes medications.
CONCLUSIONS: Recurrent strokes were nearly twice as frequent as coronary heart disease (CHD) events during the first year after initial stroke, but stroke and CHD rates were similar after the first year. Preventive drug therapies were underused, which may reflect clinical uncertainty due to the lack of clinical trials among the elderly. Utilization was lower among the oldest patients, women, and low-income individuals.
10aAge Factors10aAged10aAged, 80 and over10aAging10aAnticoagulants10aAntihypertensive Agents10aBrain Ischemia10aCohort Studies10aComorbidity10aCoronary Artery Disease10aDrug Utilization10aFemale10aHumans10aHyperlipidemias10aHypertension10aHypolipidemic Agents10aMale10aMortality10aProspective Studies10aRecurrence10aSex Factors10aStroke10aTreatment Outcome1 aKaplan, R, C1 aTirschwell, D, L1 aLongstreth, W T1 aManolio, T A1 aHeckbert, S R1 aLefkowitz, D1 aEl-Saed, A1 aPsaty, B M uhttps://chs-nhlbi.org/node/86002874nas a2200409 4500008004100000022001400041245014200055210006900197260001300266300001400279490000700293520165500300653000901955653002201964653004501986653001102031653001802042653001802060653001102078653001702089653000902106653002602115653003602141653002402177653002402201653001802225653001602243100002602259700002302285700002302308700001902331700001902350700002102369700001902390700002002409856003502429 2005 eng d a0002-861400aWeight loss, muscle strength, and angiotensin-converting enzyme inhibitors in older adults with congestive heart failure or hypertension.0 aWeight loss muscle strength and angiotensinconverting enzyme inh c2005 Nov a1996-20000 v533 aOBJECTIVES: To determine whether angiotensin-converting enzyme (ACE) inhibitor use may be associated with weight maintenance and sustained muscle strength (measured by grip strength) in older adults.
DESIGN: Data from the Cardiovascular Health Study (CHS), a community-based prospective cohort study of 5,888 older adults, were used.
SETTING: Subjects were recruited from four U.S. sites beginning in 1989; this analysis included data through 2001.
PARTICIPANTS: CHS participants with congestive heart failure (CHF) or treated hypertension.
MEASUREMENTS: The exposure, current ACE inhibitor use, was ascertained by medication inventory at annual clinic visits; the outcomes were weight change and grip-strength change during the following year. Multivariate linear regression was used, accounting for correlations between observations on the same participant over time.
RESULTS: The average annual weight change was -0.38 kg in 2,834 participants (14,443 person-years) with treated hypertension and -0.62 kg in 342 participants (980 person-years) with CHF. ACE inhibitor use was associated with less annual weight loss after adjustment for potential confounders: a difference of 0.17 kg (95% confidence interval (CI)=0.05-0.29) in those with treated hypertension and 0.29 kg (95% CI=-0.25-0.83) in those with CHF. There was no evidence of association between ACE inhibitor use and grip-strength change.
CONCLUSION: ACE inhibitor use may be associated with weight maintenance, but not maintenance of muscle strength, in older adults with treated hypertension.
10aAged10aAged, 80 and over10aAngiotensin-Converting Enzyme Inhibitors10aFemale10aHand Strength10aHeart Failure10aHumans10aHypertension10aMale10aMultivariate Analysis10aOutcome Assessment, Health Care10aProspective Studies10aStatistics as Topic10aUnited States10aWeight Loss1 aSchellenbaum, Gina, D1 aSmith, Nicholas, L1 aHeckbert, Susan, R1 aLumley, Thomas1 aRea, Thomas, D1 aFurberg, Curt, D1 aLyles, Mary, F1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/86803299nas a2200481 4500008004100000022001400041245013100055210006900186260001600255300000900271490000800280520187800288653003902166653000902205653002802214653002802242653001602270653002102286653002102307653004002328653001102368653002202379653001102401653001402412653000902426653002602435653001502461653003202476653002402508653001702532653002102549653001802570100002102588700002102609700002002630700002102650700002302671700002202694700002202716700002102738700002302759856003502782 2006 eng d a0003-992600a10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study.0 a10year followup of subclinical cardiovascular disease and risk o c2006 Jan 09 a71-80 v1663 aBACKGROUND: The incidence of coronary heart disease (CHD) is very high among individuals 65 years or older.
METHODS: We evaluated the relationships between measurements of subclinical disease at baseline (1989-1990) and at the third-year follow-up examination (1992-1993) and subsequent incidence of cardiovascular disease and total mortality as of June 2001. Approximately 61% of the participants without clinical cardiovascular disease at baseline had subclinical disease based on our previously described criteria from the Cardiovascular Health Study.
RESULTS: The incidence of CHD was substantially increased for participants with subclinical disease compared with those who had no subclinical disease: 30.5 per 1000 person-years with and 16.3 per 1000 person-years without for white individuals, and 31.2 per 1000 person-years with and 12.5 per 1000 person-years without for black individuals. The risk persisted over the entire follow-up period. Incidence rates were higher for men than for women with or without subclinical disease, but there was little difference in rates for black individuals and white individuals.
CONCLUSIONS: In multivariable models, subclinical disease at baseline remained a significant predictor of CHD in both men and women; the hazard ratios (95% confidence intervals) of their relative risks were 1.64 (1.30-2.06) and 1.49 (1.21-1.84), respectively. The presence of subclinical disease substantially increased the risk of subsequent CHD for participants with hypertension, diabetes mellitus, or elevated C-reactive protein. In summary, subclinical disease is very prevalent among older individuals, is independently associated with risk of CHD even over a 10-year follow-up period, and substantially increases the risk of CHD among participants with hypertension or diabetes mellitus.
10aAfrican Continental Ancestry Group10aAged10aBlood Chemical Analysis10aCardiovascular Diseases10aComorbidity10aCoronary Disease10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aMultivariate Analysis10aPrevalence10aProportional Hazards Models10aRegression Analysis10aRisk Factors10aSex Distribution10aUnited States1 aKuller, Lewis, H1 aArnold, Alice, M1 aPsaty, Bruce, M1 aRobbins, John, A1 aO'Leary, Daniel, H1 aTracy, Russell, P1 aBurke, Gregory, L1 aManolio, Teri, A1 aChaves, Paolo, H M uhttps://chs-nhlbi.org/node/87803443nas a2200421 4500008004100000022001400041245012400055210006900179260001300248300001100261490000700272520226300279653002202542653000902564653001502573653002802588653001502616653001402631653002402645653001102669653003102680653001102711653002002722653001802742653002502760653000902785653001702794100002302811700001402834700001602848700001702864700003202881700001702913700001802930700001702948700002102965856003502986 2006 eng d a1046-667300aAfrican ancestry, socioeconomic status, and kidney function in elderly African Americans: a genetic admixture analysis.0 aAfrican ancestry socioeconomic status and kidney function in eld c2006 Dec a3491-60 v173 aKidney disease is a major public health problem in the United States that affects African Americans disproportionately. The relative contribution of environmental and genetic factors to the increased burden of kidney disease among African Americans is unknown. The associations of genetic African ancestry and socioeconomic status with kidney function were studied cross-sectionally and longitudinally among 736 community-dwelling African Americans who were aged >65 yr and participating in the Cardiovascular Health Study. Genetic African ancestry was determined by genotyping 24 biallelic ancestry-informative markers and combining this information statistically to generate an estimate of ancestry for each individual. Kidney function was evaluated by cystatin C and estimated GFR (eGFR) using the Modification of Diet in Renal Disease equation. Longitudinal changes in serum creatinine and eGFR were estimated using baseline and follow-up values. In cross-sectional analyses, there was no association between genetic African ancestry and either measure of kidney function (P = 0.36 for cystatin C and 0.68 for eGFR). African ancestry was not associated with change in serum creatinine > or =0.05 mg/dl per yr (odds ratio [OR] 0.94; 95% confidence interval [CI] 0.83 to 1.06) or with change in eGFR > or =3 ml/min per 1.73 m(2) per yr (OR 1.02; 95% CI 0.92 to 1.13). In contrast, self reported African-American race was strongly associated with increased risk for kidney disease progression compared with white individuals for change in creatinine (OR 1.77; 95% CI 1.33 to 2.36) and for change in eGFR (OR 3.21; 95% CI 2.54 to 4.06). Among self-identified African Americans, low income (< US dollars 8000/yr) was strongly associated with prevalent kidney dysfunction by cystatin C >1.29 g/dl (adjusted OR 2.7; 95% CI 1.0 to 7.5) or by eGFR <60 ml/min per 1.73 m(2) (adjusted OR 3.2; 95% CI 1.1 to 9.4) compared with those with incomes >US dollars 35,000/yr. Alleles that are known to be present more frequently in the African ancestral group were not associated with kidney dysfunction or kidney disease progression. Rather, kidney dysfunction in elderly African Americans seems more attributable to differences in environmental and social factors.
10aAfrican Americans10aAged10aCreatinine10aCross-Sectional Studies10aCystatin C10aCystatins10aDisease Progression10aFemale10aGlomerular Filtration Rate10aHumans10aKidney Diseases10aLinear Models10aLongitudinal Studies10aMale10aSocial Class1 aPeralta, Carmen, A1 aZiv, Elad1 aKatz, Ronit1 aReiner, Alex1 aBurchard, Esteban González1 aFried, Linda1 aKwok, Pui-Yan1 aPsaty, Bruce1 aShlipak, Michael uhttps://chs-nhlbi.org/node/92703137nas a2200457 4500008004100000022001400041245010900055210006900164260001300233300000900246490000700255520188900262653000902151653002102160653002202181653000902203653001902212653002102231653001102252653001302263653002002276653001102296653001402307653000902321653003002330653002002360653002602380653001802406653000902424100002402433700001702457700002002474700002102494700002002515700002502535700002202560700001802582700002002600700002402620856003502644 2006 eng d a0002-861400aAlcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study.0 aAlcohol consumption and risk of coronary heart disease in older c2006 Jan a30-70 v543 aOBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome.
DESIGN: Prospective cohort study.
SETTING: Four U.S. communities.
PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline.
MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly.
RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95% confidence interval (CI)=0.71-1.14), 0.93 (95% CI=0.73-1.20), 0.76 (95% CI=0.53-1.10), and 0.58 (95% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9% to 10% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele.
CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.
10aAged10aAlcohol Drinking10aApolipoproteins E10aBeer10aCohort Studies10aCoronary Disease10aFemale10aGenotype10aHealth Behavior10aHumans10aIncidence10aMale10aResidence Characteristics10aRisk Assessment10aSocioeconomic Factors10aUnited States10aWine1 aMukamal, Kenneth, J1 aChung, Hyoju1 aJenny, Nancy, S1 aKuller, Lewis, H1 aLongstreth, W T1 aMittleman, Murray, A1 aBurke, Gregory, L1 aCushman, Mary1 aPsaty, Bruce, M1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/88103064nas a2200433 4500008004100000022001400041245015800055210006900213260001300282300001000295490000800305520182700313653000902140653002202149653001602171653002002187653002802207653002102235653002202256653001102278653001102289653001702300653000902317653003302326653001502359653001702374653001102391653001802402100001602420700002402436700001702460700002102477700002002498700001802518700001802536700002302554700001802577856003502595 2006 eng d a0021-915000aThe association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: the Cardiovascular Health Study.0 aassociation of microalbuminuria with clinical cardiovascular dis c2006 Aug a372-70 v1873 aPURPOSE: Microalbuminuria (MA) is a risk factor for cardiovascular disease (CVD). It is not known whether this association is due to the effect of MA on the development of subclinical atherosclerosis or whether MA destabilizes subclinical atherosclerosis, leading to clinical events.
METHODS: In a cross-sectional analysis we evaluated 3312 Cardiovascular Health Study participants, age >or=65 years, who had MA testing. Participants were divided into three groups: those without diabetes or hypertension (33%), those with hypertension (52%) and those with diabetes, with or without hypertension (15%). Clinical CVD was defined as presence of coronary heart disease (angina, MI, CABG, PTCA), cerebrovascular disease (stroke, TIA) and peripheral arterial disease (requiring intervention). Among those without clinical disease, subclinical atherosclerosis was defined as increased carotid artery intima-media thickness, decreased ankle arm index or increased left ventricular mass.
RESULTS: In each of the three groups of participants, the adjusted odds of prevalent clinical CVD in the presence of MA was 1.70-1.80-fold increased, independent of other risk factors. MA was not associated with risk of subclinical atherosclerosis in those without hypertension or diabetes (OR 1.14 [95% CI 0.59, 2.23]), whereas it was associated with subclinical atherosclerosis in those with hypertension (OR 1.58 [95% CI 1.08, 2.30]) or diabetes (OR 2.51 [95% CI 1.27, 4.94]).
CONCLUSION: In the absence of hypertension or diabetes, MA was associated with clinical CVD but not with subclinical atherosclerosis. Thus, a hypothesis may be made that the mechanism of association of MA with clinical vascular disease involves destabilization of the vasculature, leading to clinical disease.
10aAged10aAged, 80 and over10aAlbuminuria10aAtherosclerosis10aCardiovascular Diseases10aCoronary Disease10aDiabetes Mellitus10aFemale10aHumans10aHypertension10aMale10aPeripheral Vascular Diseases10aPrevalence10aRisk Factors10aStroke10aUnited States1 aCao, Jie, J1 aBarzilay, Joshua, I1 aPeterson, Do1 aManolio, Teri, A1 aPsaty, Bruce, M1 aKuller, Lewis1 aWexler, Jason1 aBleyer, Anthony, J1 aCushman, Mary uhttps://chs-nhlbi.org/node/86303674nas a2200505 4500008004100000022001400041245011900055210006900174260001600243300001200259490000800271520220500279653003902484653000902523653002302532653002802555653002102583653004002604653001102644653001302655653001102668653000902679653002602688653003602714653003202750653000902782653001102791653001802802100002102820700002802841700002302869700002002892700002002912700001702932700001802949700001902967700001802986700001503004700002103019700002603040700002003066700002203086700002503108856003503133 2006 eng d a1538-359800aAssociation of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events.0 aAssociation of polymorphisms in the CRP gene with circulating Cr c2006 Dec 13 a2703-110 v2963 aCONTEXT: C-reactive protein (CRP) is an inflammation protein that may play a role in the pathogenesis of cardiovascular disease (CVD).
OBJECTIVE: To assess whether polymorphisms in the CRP gene are associated with plasma CRP, carotid intima-media thickness (CIMT), and CVD events.
DESIGN, SETTING, AND PARTICIPANTS: In the prospective, population-based Cardiovascular Health Study, 4 tag single-nucleotide polymorphisms (SNPs) (1919A/T, 2667G/C, 3872G/A, 5237A/G) were genotyped in 3941 white (European American) participants and 5 tag SNPs (addition of 790A/T) were genotyped in 700 black (African American) participants, aged 65 years or older, all of whom were without myocardial infarction (MI) or stroke before study entry. Median follow-up was 13 years (1989-2003).
MAIN OUTCOME MEASURES: Baseline CIMT; occurrence of MI, stroke, and CVD mortality during follow-up.
RESULTS: In white participants, 461 incident MIs, 491 incident strokes, and 490 CVD-related deaths occurred; in black participants, 67 incident MIs, 78 incident strokes, and 75 CVD-related deaths occurred. The 1919T and 790T alleles were associated with higher CRP levels in white and black participants, respectively. The 3872A allele was associated with lower CRP levels in both populations, and the 2667C allele was associated with lower CRP levels in white participants only. There was no association between CIMT and any CRP gene polymorphism in either population. In white participants, the 1919T allele was associated with increased risk of stroke for TT vs AA (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.06-1.87) and for CVD mortality (HR, 1.40; 95% CI, 1.10-1.90). In black participants, homozygosity for the 790T allele was associated with a 4-fold increased risk of MI compared with homozygosity for the 790A allele (95% CI, 1.58-10.53). The minor alleles of the 2 SNPs associated with lower plasma CRP concentration in white participants (2667C and 3872A) were associated with decreased risk of CVD mortality.
CONCLUSIONS: Genetic variation in the CRP gene is associated with plasma CRP levels and CVD risk in older adults.
10aAfrican Continental Ancestry Group10aAged10aC-Reactive Protein10aCardiovascular Diseases10aCarotid Arteries10aEuropean Continental Ancestry Group10aFemale10aGenotype10aHumans10aMale10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aRisk10aStroke10aTunica Intima1 aLange, Leslie, A1 aCarlson, Christopher, S1 aHindorff, Lucia, A1 aLange, Ethan, M1 aWalston, Jeremy1 aDurda, Peter1 aCushman, Mary1 aBis, Joshua, C1 aZeng, Donglin1 aLin, Danyu1 aKuller, Lewis, H1 aNickerson, Deborah, A1 aPsaty, Bruce, M1 aTracy, Russell, P1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/93203456nas a2200445 4500008004100000022001400041245008900055210006900144260001300213300001200226490000700238520224900245653001002494653000902504653002202513653002002535653001902555653001602574653002802590653001102618653001902629653001102648653001702659653000902676653001602685653001502701653002402716653001002740653002902750653002202779653002402801100002402825700001902849700001802868700002202886700002002908700002402928700002302952856003502975 2006 eng d a0161-810500aAssociation of usual sleep duration with hypertension: the Sleep Heart Health Study.0 aAssociation of usual sleep duration with hypertension the Sleep c2006 Aug a1009-140 v293 aSTUDY OBJECTIVES: Limited experimental data suggest that sleep restriction acutely elevates blood pressure; however, little is known about the relationship between usual sleep duration and hypertension. This study assesses the relationship between usual sleep duration and hypertension in a community-based cohort.
DESIGN: Cross-sectional observational study.
SETTING: The Sleep Heart Health Study, a community-based prospective study of the cardiovascular consequences of sleep-disordered breathing.
PARTICIPANTS: Two thousand eight hundred thirteen men and 3097 women, aged 40 to 100 years.
INTERVENTIONS: None.
MEASUREMENTS AND RESULTS: Usual weekday and weekend sleep durations were obtained by questionnaire, and their weighted average were categorized as less than 6, 6 to less than 7, 7 to less than 8, 8 to less than 9, and 9 or more hours per night. Hypertension was defined as a systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or use of medication to treat hypertension. The relationship between sleep duration and hypertension was examined using categorical logistic regression with adjustment for age, sex, race, apnea-hypopnea index, and body mass index. Compared to subjects sleeping 7 to less than 8 hours per night, those sleeping less than 6 and between 6 and 7 hours per night had adjusted odds ratios for hypertension of 1.66 (95% confidence interval 1.35-2.04) and 1.19 (1.02-1.39), respectively, whereas those sleeping between 8 and 9 and 9 or more hours per night had adjusted odds ratios for hypertension of 1.19 (1.04-1.37) and 1.30 (1.04-1.62), respectively (p < .0001 for association of sleep duration with hypertension). These associations persisted when analyses were further adjusted for caffeine and alcohol consumption, current smoking, insomnia symptoms, depression symptoms, sleep efficiency, and prevalent diabetes mellitus or cardiovascular disease.
CONCLUSIONS: Usual sleep duration above or below the median of 7 to less than 8 hours per night is associated with an increased prevalence of hypertension, particularly at the extreme of less than 6 hours per night.
10aAdult10aAged10aAged, 80 and over10aBody Mass Index10aCohort Studies10aComorbidity10aCross-Sectional Studies10aFemale10aHealth Surveys10aHumans10aHypertension10aMale10aMiddle Aged10aOdds Ratio10aProspective Studies10aSleep10aSleep Apnea, Obstructive10aSleep Deprivation10aStatistics as Topic1 aGottlieb, Daniel, J1 aRedline, Susan1 aNieto, Javier1 aBaldwin, Carol, M1 aNewman, Anne, B1 aResnick, Helaine, E1 aPunjabi, Naresh, M uhttps://chs-nhlbi.org/node/91503303nas a2200505 4500008004100000022001400041245008100055210006900136260001600205300001100221490000800232520183100240653003902071653000902110653002502119653002702144653004002171653001102211653001902222653003802241653002202279653001402301653001502315653001502330653001102345653000902356653003602365653003402401653003102435100002202466700002402488700001802512700002002530700002202550700002302572700002402595700001902619700001702638700001902655700002202674700002102696700002202717700002302739856003502762 2006 eng d a1524-453900aBeta2-adrenergic receptor genetic variants and risk of sudden cardiac death.0 aBeta2adrenergic receptor genetic variants and risk of sudden car c2006 Apr 18 a1842-80 v1133 aBACKGROUND: Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk.
METHODS AND RESULTS: In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study.
CONCLUSIONS: Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.
10aAfrican Continental Ancestry Group10aAged10aCase-Control Studies10aDeath, Sudden, Cardiac10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenetic Variation10aGlutamine10aHaplotypes10aHomozygote10aHumans10aMale10aPolymorphism, Single Nucleotide10aReceptors, Adrenergic, beta-210aReproducibility of Results1 aSotoodehnia, Nona1 aSiscovick, David, S1 aVatta, Matteo1 aPsaty, Bruce, M1 aTracy, Russell, P1 aTowbin, Jeffrey, A1 aLemaitre, Rozenn, N1 aRea, Thomas, D1 aDurda, Peter1 aChang, Joel, M1 aLumley, Thomas, S1 aKuller, Lewis, H1 aBurke, Gregory, L1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/89302904nas a2200397 4500008004100000022001400041245009400055210006900149260001300218300001200231490000700243520180100250653000902051653002202060653001902082653001902101653001102120653002202131653001102153653000902164653003602173653002402209653001502233653001102248653001802259100002202277700002502299700002002324700002102344700002302365700002302388700002102411700001902432700002002451856003502471 2006 eng d a0002-861400aBlood pressure level and outcomes in adults aged 65 and older with prior ischemic stroke.0 aBlood pressure level and outcomes in adults aged 65 and older wi c2006 Sep a1309-160 v543 aOBJECTIVES: To examine the association between blood pressure (BP) levels and long-term stroke outcomes in elderly stroke survivors.
DESIGN: Observational study.
SETTING: The Cardiovascular Health Study (CHS) of 5,888 community-dwelling adults.
PARTICIPANTS: Two hundred fifty-four adults aged 65 and older (mean age 78.6) who sustained a nonfatal first ischemic stroke.
MEASUREMENTS: BP levels assessed at prestroke and poststroke CHS visits were examined as predictors of stroke recurrence, coronary heart disease (CHD), combined vascular events (CVEs), and mortality.
RESULTS: Higher poststroke BP level, assessed 261.6 days (mean) after stroke, was associated with higher risk of stroke recurrence over 5.4 years (mean) of follow-up. The multivariate-adjusted hazard ratio for stroke recurrence was 1.42 (95% confidence interval (CI) = 1.03-1.99) per standard deviation (SD) of systolic BP (P = .04) and 1.39 (95% CI = 1.01-1.91) per SD of diastolic BP (P = .04). Mortality was significantly greater in patients with low or high poststroke BP than in those with intermediate BP. Poststroke BP was not associated with risk of CHD or CVE, although further analyses suggested that high systolic BP predicted CHD and CVE in younger but not older subjects. Prestroke BP did not predict poststroke outcomes.
CONCLUSION: In this observational study of adults aged 65 and older assessed approximately 8 months after stroke, low BP was associated with favorable risk of recurrent stroke, although high and low poststroke BP levels were associated with greater mortality. Long-term antihypertensive trials in older stroke survivors would increase knowledge about the benefits of lowering BP in this population.
10aAged10aAged, 80 and over10aBlood Pressure10aBrain Ischemia10aFemale10aFollow-Up Studies10aHumans10aMale10aOutcome Assessment, Health Care10aProspective Studies10aRecurrence10aStroke10aSurvival Rate1 aKaplan, Robert, C1 aTirschwell, David, L1 aLongstreth, W T1 aManolio, Teri, A1 aHeckbert, Susan, R1 aLeValley, Aaron, J1 aLefkowitz, David1 aEl-Saed, Aiman1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/91704109nas a2200553 4500008004100000022001400041245016500055210006900220260001600289300001200305490000800317520252600325653001602851653000902867653002202876653002702898653001902925653001602944653002102960653002202981653002403003653001103027653002203038653001603060653001803076653002103094653002003115653001103135653002003146653001703166653000903183653002603192653002603218653001503244653003003259653001703289653002103306653001803327653001703345653001803362100002303380700002103403700002203424700002003446700001803466700001803484700001803502856003503520 2006 eng d a1524-453900aCharacteristics and baseline clinical predictors of future fatal versus nonfatal coronary heart disease events in older adults: the Cardiovascular Health Study.0 aCharacteristics and baseline clinical predictors of future fatal c2006 May 09 a2177-850 v1133 aBACKGROUND: Although >80% of annual coronary heart disease (CHD) deaths occur in adults aged >65 years and the population is aging rapidly, CHD event fatality and its predictors in the elderly have not been well described.
METHODS AND RESULTS: The first myocardial infarction (MI) or CHD death among the 5888 adults aged > or =65 years occurring during enrollment in the Cardiovascular Health Study during 1989-2001 was identified and adjudicated. Characteristics measured at examinations before the event were examined for associations with case fatality (death before hospitalization or hospital discharge) and for differences in predictors by demographics or clinical history. During a median follow-up of 8.2 years, 985 CHD events occurred, of which 30% were fatal. Case fatality decreased slightly over time, ranging from 28% to 30% per year in the early 1990s versus 23% by 2000-2001; with adjustment for age at MI and gender, there was a 6% lower odds of fatality with each successive year (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.90 to 0.98). Case fatality was similar by race and gender but higher with age and prior CHD (MI, angina, or revascularization). When considered alone, many subclinical disease measures, such as common carotid intima-media thickness, ankle-arm index, left ventricular mass by ECG, and a major ECG abnormality, and traditional risk factors, such as diabetes and hypertension, were associated with fatality. In multivariable analysis, independent predictors of fatality were prior congestive heart failure (OR, 3.20; 95% CI, 2.32 to 4.41), prior CHD rather than only history of MI (OR, 2.51; 95% CI, 1.84 to 3.43), diabetes (OR, 1.66; 95% CI, 1.10 to 2.31), and age (OR, 1.21 per 5 years; 95% CI, 1.07 to 1.37), adjusted for gender and each other. Prior congestive heart failure, regardless of left ventricular systolic function, age, gender, or prior CHD, conferred a > or =3-fold increased risk of fatality in almost all subgroups.
CONCLUSIONS: Among community-dwelling older adults, CHD case fatality remains substantial, with easily identifiable risk factors that may be different from those that predict incident disease. In the elderly in whom the risk/benefit of therapies may be influenced by multiple competing comorbidities and care needs, risk stratification possibly may be improved further by focusing more aggressive care on specific patients, especially those with a history of congestive heart failure or prior CHD.
10aAge Factors10aAged10aAged, 80 and over10aCarotid Artery, Common10aCohort Studies10aComorbidity10aCoronary Disease10aDiabetes Mellitus10aElectrocardiography10aFemale10aFollow-Up Studies10aForecasting10aHeart Failure10aHeart Ventricles10aHospitalization10aHumans10aHyperlipidemias10aHypertension10aMale10aMultivariate Analysis10aMyocardial Infarction10aOrgan Size10aPredictive Value of Tests10aRisk Factors10aSampling Studies10aTunica Intima10aTunica Media10aUnited States1 aPearte, Camille, A1 aFurberg, Curt, D1 aO'Meara, Ellen, S1 aPsaty, Bruce, M1 aKuller, Lewis1 aPowe, Neil, R1 aManolio, Teri uhttps://chs-nhlbi.org/node/89602391nas a2200361 4500008004100000022001400041245005600055210005500111260001600166300001100182490000800193520147400201653000901675653001201684653002801696653001101724653001101735653000901746653001601755653002001771653001501791653002401806653001701830653001701847653002501864653001201889653001801901100001501919700002001934700001701954700002301971856003501994 2006 eng d a0002-926200aCigarette smoking and nocturnal sleep architecture.0 aCigarette smoking and nocturnal sleep architecture c2006 Sep 15 a529-370 v1643 aCigarette smoking has been associated with a high prevalence of sleep-related complaints. However, its effects on sleep architecture have not been fully examined. The primary objective of this investigation was to assess the impact of cigarette smoking on sleep architecture. Polysomnography was used to characterize sleep architecture among 6,400 participants of the Sleep Heart Health Study (United States, 1994-1999). Sleep parameters included total sleep time, latency to sleep onset, sleep efficiency, and percentage of time in each sleep stage. The study sample consisted of 2,916 never smokers, 2,705 former smokers, and 779 current smokers. Compared with never smokers, current smokers had a longer initial sleep latency (5.4 minutes, 95% confidence interval (CI): 2.9, 7.9) and less total sleep time (14.0 minutes, 95% CI: 6.4, 21.7). Furthermore, relative to never smokers, current smokers also had more stage 1 sleep (relative proportion = 1.24, 95% CI: 1.14, 1.33) and less slow wave sleep (relative proportion = 0.86, 95% CI: 0.78, 0.95). Finally, no differences in sleep architecture were noted between former and never smokers. The results of this study show that cigarette smoking is independently associated with disturbances in sleep architecture, including a longer latency to sleep onset and a shift toward lighter stages of sleep. Nicotine in cigarette smoke and acute withdrawal from it may contribute to disturbances in sleep architecture.
10aAged10aArousal10aChi-Square Distribution10aFemale10aHumans10aMale10aMiddle Aged10aPolysomnography10aPrevalence10aRegression Analysis10aRisk Factors10aSleep Stages10aSleep Wake Disorders10aSmoking10aUnited States1 aZhang, Lin1 aSamet, Jonathan1 aCaffo, Brian1 aPunjabi, Naresh, M uhttps://chs-nhlbi.org/node/90402705nas a2200337 4500008004100000022001400041245016900055210006900224260001600293300001100309490000700320520169200327653000902019653002102028653002402049653001102073653001102084653000902095653000902104100002602113700001502139700002402154700002802178700002002206700002102226700002002247700001802267700002402285700002302309856003502332 2006 eng d a0002-914900aComparison of mortality risk for electrocardiographic abnormalities in men and women with and without coronary heart disease (from the Cardiovascular Health Study).0 aComparison of mortality risk for electrocardiographic abnormalit c2006 Feb 01 a309-150 v973 aMortality risk associated with electrocardiographic (ECG) abnormalities has been commonly reported to be lower in women than in men. We compared coronary heart disease (CHD) and all-cause mortality risk for ECG variables during a mean 9.1-year follow-up in 4,912 participants in the Cardiovascular Health Study who were > or = 65 years of age. The hypothesis was that mortality risk for ECG abnormalities is not lower in women than in men. Five ECG variables were significant mortality predictors in Cox regression models that were adjusted for demographic, clinical, and medication variables. Gender differences were significant and mortality risk was higher in women for ECG estimates of left ventricular mass for both end points and for nondipolar QRS voltage for all-cause mortality. When evaluated simultaneously in multiple ECG variable risk models in subgroups that were stratified by baseline CHD status, no gender difference was significant. In the latter models, ST depression was a strong predictor of CHD mortality in groups with and without previous CHD. Other significant ECG predictors were previous myocardial infarction in the previous CHD group and nondipolar QRS voltage in the CHD-free group. Four ECG abnormalities were significant predictors of all-cause mortality in the CHD-free group, with risk increases of 18% to 50%. The risk of all-cause mortality in the previous CHD group was significantly increased for ST depression (by 64%), the ECG estimate of left ventricular mass (by 48%), and previous myocardial infarction (by 34%). In conclusion, we found no evidence that the relative risk of mortality for ECG abnormalities is lower in women than in men.
10aAged10aCoronary Disease10aElectrocardiography10aFemale10aHumans10aMale10aRisk1 aRautaharju, Pentti, M1 aGe, Sijian1 aNelson, Jennifer, C1 aLarsen, Emily, K Marino1 aPsaty, Bruce, M1 aFurberg, Curt, D1 aZhang, Zhu-Ming1 aRobbins, John1 aGottdiener, John, S1 aChaves, Paulo, H M uhttps://chs-nhlbi.org/node/88702489nas a2200361 4500008004100000022001400041245013800055210006900193260001300262300001100275490000700286520145100293653000901744653002201753653001901775653001101794653001801805653001101823653001401834653000901848653002201857653001401879100002601893700002301919700002301942700001901965700001901984700002302003700002402026700002202050700002002072856003502092 2006 eng d a1047-279700aCongestive heart failure incidence and prognosis: case identification using central adjudication versus hospital discharge diagnoses.0 aCongestive heart failure incidence and prognosis case identifica c2006 Feb a115-220 v163 aPURPOSE: We compared hospitalized congestive heart failure (CHF) incidence and prognosis estimates using hospital discharge diagnoses or central adjudication.
METHODS: We used the Cardiovascular Health Study (CHS), a population-based cohort study of 5888 elderly adults. A physician committee adjudicated potential CHF events, confirmed by signs, symptoms, clinical tests, and/or medical therapy. A CHF discharge diagnosis included any of these ICD-9 codes in any position: 428, 425, 398.91, 402.01, 402.11, 402.91, and 997.1. We constructed an inception cohort of 1209 hospitalized, nonfatal, incident CHF cases, identified by discharge diagnosis, adjudication, or both.
RESULTS: Incidence rates for hospitalized CHF were 24.6 per 1000 person-years using discharge diagnoses and 17.1 per 1000 person-years using central adjudication. Compared to the group identified as having CHF by both methods, the group with only a discharge diagnosis (hazard ratio=0.77, 95% confidence interval=0.65-0.91) and the group with central adjudication only (hazard ratio=0.72, 95% confidence interval=0.55-0.94) had lower mortality rates.
CONCLUSIONS: In the elderly, studies using only discharge diagnoses, as compared to central adjudication, may estimate higher rates of incident hospitalized CHF. Mortality following CHF onset may be similar for these methods and higher if both methods are used together.
10aAged10aAged, 80 and over10aCohort Studies10aFemale10aHeart Failure10aHumans10aIncidence10aMale10aPatient Discharge10aPrognosis1 aSchellenbaum, Gina, D1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aRea, Thomas, D1 aLumley, Thomas1 aKitzman, Dalane, W1 aRoger, Veronique, L1 aTaylor, Herman, A1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/84404065nas a2200433 4500008004100000022001400041245011900055210006900174260001600243300001100259490000800270520281000278653000903088653001503097653002803112653001503140653001503155653001403170653003103184653001103215653001103226653002503237653001403262653003203276653003303308653001703341100002403358700001603382700002003398700002003418700002003438700002903458700002403487700002203511700001703533700002203550700002403572856003503596 2006 eng d a1539-370400aCystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease.0 aCystatin C and prognosis for cardiovascular and kidney outcomes c2006 Aug 15 a237-460 v1453 aBACKGROUND: Cystatin C is an alternative measure of kidney function that may have prognostic importance among elderly persons who do not meet standard criteria for chronic kidney disease (estimated glomerular filtration rate [GFR] > or =60 mL/min per 1.73 m2).
OBJECTIVE: To evaluate cystatin C as a prognostic biomarker for death, cardiovascular disease, and incident chronic kidney disease among elderly persons without chronic kidney disease.
DESIGN: Cohort study.
SETTING: The Cardiovascular Health Study, a population-based cohort recruited from 4 communities in the United States.
PARTICIPANTS: 4663 elderly persons.
MEASUREMENTS: Measures of kidney function were creatinine-based estimated GFR by using the Modification of Diet in Renal Disease equation and cystatin C concentration. Outcomes were death, cardiovascular death, noncardiovascular death, heart failure, stroke, myocardial infarction, and incident chronic kidney disease during follow-up (median, 9.3 years).
RESULTS: At baseline, 78% of participants did not have chronic kidney disease (estimated GFR > or =60 mL/min per 1.73 m2) and mean cystatin C concentration, creatinine concentration, and estimated GFR were 1.0 mg/L, 79.6 micromol/L (0.9 mg/dL), and 83 mL/min per 1.73 m2, respectively. Cystatin C concentrations (per SD, 0.18 mg/L) had strong associations with death (hazard ratio, 1.33 [95% CI, 1.25 to 1.40]), cardiovascular death (hazard ratio, 1.42 [CI, 1.30 to 1.54]), noncardiovascular death (hazard ratio, 1.26 [CI, 1.17 to 1.36]), incident heart failure (hazard ratio, 1.28 [CI, 1.17 to 1.40]), stroke (hazard ratio, 1.22 [CI, 1.08 to 1.38]), and myocardial infarction (hazard ratio, 1.20 [CI, 1.06 to 1.36]) among these participants. Serum creatinine concentrations had much weaker associations with each outcome and only predicted cardiovascular death. Participants without chronic kidney disease who had elevated cystatin C concentrations (> or =1.0 mg/L) had a 4-fold risk for progressing to chronic kidney disease after 4 years of follow-up compared with those with cystatin C concentrations less than 1.0 mg/L.
LIMITATIONS: Because this study did not directly measure GFR or albuminuria, the extent to which cystatin C may be influenced by nonrenal factors was not determined and participants with albuminuria might have been misclassified as having no kidney disease.
CONCLUSIONS: Among elderly persons without chronic kidney disease, cystatin C is a prognostic biomarker of risk for death, cardiovascular disease, and chronic kidney disease. In this setting, cystatin C seems to identify a "preclinical" state of kidney dysfunction that is not detected with serum creatinine or estimated GFR.
10aAged10aBiomarkers10aCardiovascular Diseases10aCreatinine10aCystatin C10aCystatins10aGlomerular Filtration Rate10aHumans10aKidney10aLongitudinal Studies10aPrognosis10aProportional Hazards Models10aRenal Insufficiency, Chronic10aRisk Factors1 aShlipak, Michael, G1 aKatz, Ronit1 aSarnak, Mark, J1 aFried, Linda, F1 aNewman, Anne, B1 aStehman-Breen, Catherine1 aSeliger, Stephen, L1 aKestenbaum, Brian1 aPsaty, Bruce1 aTracy, Russell, P1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/91202997nas a2200349 4500008004100000022001400041245009800055210006900153260001600222300001100238490000700249520203700256653000902293653001202302653002602314653002802340653000902368653002402377653002502401653001102426653001102437653001002448653001502458653001102473653000902484653002502493100002502518700002302543700002202566700002402588856003502612 2006 eng d a1558-359700aDietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans.0 aDietary fish and n3 fatty acid intake and cardiac electrocardiog c2006 Aug 01 a478-840 v483 aOBJECTIVES: We evaluated the association between dietary fish intake and several cardiac electrocardiographic parameters in humans relevant to arrhythmic risk.
BACKGROUND: Fish consumption may reduce the incidence of sudden death and atrial fibrillation, possibly related to anti-arrhythmic effects.
METHODS: In a population-based study of 5,096 men and women, we evaluated cross-sectional associations between usual dietary fish intake and electrocardiographic measures of heart rate, atrioventricular conduction (PR interval), ventricular repolarization (QT interval), and ventricular conduction (QRS interval). Multivariate models were adjusted for age, gender, race, education, smoking, body mass index, diabetes, coronary heart disease, physical activity, and intakes of beef or pork, fried fish, fruits, vegetables, alcohol, and total calories.
RESULTS: Consumption of tuna or other broiled or baked fish (comparing the highest to the lowest category of intake) was associated with lower heart rate (-3.2 beats/min, 95% confidence interval [CI] = 1.3 to 5.1; p trend <0.001), slower atrioventricular conduction (PR interval +7.2 ms, 95% CI = 1.4 to 12.9; p trend = 0.03), and substantially lower likelihood of prolonged QT (relative risk = 0.50, 95% CI = 0.27 to 0.95; p trend = 0.03). Tuna/other fish intake was not associated with ventricular conduction (p = 0.60). Findings were similar for estimated intake of marine n-3 fatty acids: a 1 g/day higher intake was associated with 2.3 beats/min lower heart rate (95% CI = 0.9 to 3.7), 7.6 ms longer PR interval (95% CI = 3.3 to 11.9), and 46% lower likelihood of prolonged QT (relative risk = 0.54, 95% CI = 0.33 to 0.88).
CONCLUSIONS: These findings in this large, population-based study suggest that dietary fish intake is associated with cardiac electrophysiology in humans, including heart rate, atrioventricular conduction, and ventricular repolarization, with potential implications for arrhythmic risk.
10aAged10aAnimals10aAtrioventricular Node10aCross-Sectional Studies10aDiet10aElectrocardiography10aFatty Acids, Omega-310aFemale10aFishes10aHeart10aHeart Rate10aHumans10aMale10aVentricular Function1 aMozaffarian, Dariush1 aPrineas, Ronald, J1 aStein, Phyllis, K1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/91003633nas a2200517 4500008004100000022001400041245016400055210006900219260001300288300001100301490000700312520215100319653001002470653002202480653001602502653000902518653001202527653002002539653002802559653002102587653001902608653000802627653004002635653001902675653002202694653001102716653001102727653001702738653002202755653002202777653001002799653002502809653000902834653001602843653001802859653002402877653001802901100002502919700002402944700002302968700002502991700002203016700002103038700002103059856003503080 2006 eng d a0026-049500aLipoprotein subclass and particle size differences in Afro-Caribbeans, African Americans, and white Americans: associations with hepatic lipase gene variation.0 aLipoprotein subclass and particle size differences in AfroCaribb c2006 Jan a96-1020 v553 aDespite a higher prevalence of coronary heart disease risk factors, men of African origin have less coronary atherosclerosis, as measured by coronary calcification, than whites. In part, this is thought to be because of the less atherogenic lipoprotein profile observed in men of African origin, characterized by lower triglycerides and higher high-density lipoprotein (HDL) cholesterol. We hypothesized that the -514C>T polymorphism in the hepatic lipase gene (LIPC) plays a significant role in determining a less atherogenic lipoprotein profile observed in men of African origin. Previously conducted studies of the LIPC -514C>T polymorphism in African Americans may have been confounded by a higher level of European admixture; in addition, the results from these studies do not necessarily apply to other African populations because gene-environment interactions may differ. Thus, we compared nuclear magnetic resonance spectroscopy-measured lipoprotein subclass patterns and LIPC -514C>T genotypes in population-based samples of older white American (n = 532) and African American (n = 97) men from the Cardiovascular Health Study to those among older, less admixed, Afro-Caribbean men (n = 205) from the Tobago Health Study. Men of African origin had a more favorable lipoprotein profile than whites. In addition, levels of low-density lipoprotein cholesterol, total cholesterol, and triglyceride, and large and small very low-density lipoprotein, small low-density lipoprotein, as well as very low-density lipoprotein particle size, were remarkably lower in Afro-Caribbean men than in either African American or white men. The frequency of the LIPC -514T allele was much higher in Afro-Caribbeans (0.57) and in African Americans (0.49) than in whites (0.20). The -514T allele in both populations of African origin, but not in whites, was associated with elevated large HDL and greater HDL size. Our findings indicate that the higher frequency of the LIPC -514T allele found in men of African origin living in different environments significantly contributes to the more favorable distribution of HDL subclasses compared with whites.
10aAdult10aAfrican Americans10aAge Factors10aAged10aAlleles10aBody Mass Index10aCardiovascular Diseases10aCaribbean Region10aCohort Studies10aDNA10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Variation10aHumans10aLipase10aLipoproteins10aLipoproteins, HDL10aLipoproteins, LDL10aLiver10aLongitudinal Studies10aMale10aMiddle Aged10aParticle Size10aTrinidad and Tobago10aUnited States1 aMiljkovic-Gacic, Iva1 aBunker, Clareann, H1 aFerrell, Robert, E1 aKammerer, Candace, M1 aEvans, Rhobert, W1 aPatrick, Alan, L1 aKuller, Lewis, H uhttps://chs-nhlbi.org/node/87202947nas a2200385 4500008004100000022001400041245011500055210006900170260001300239300000900252490000600261520183800267653002502105653000902130653002802139653002102167653002202188653001102210653001102221653002402232653001202256653000902268653003202277653002402309653002002333653002102353100002402374700002402398700002302422700002002445700002102465700002202486700001802508856003502526 2006 eng d a1549-167600aMortality in pharmacologically treated older adults with diabetes: the Cardiovascular Health Study, 1989-2001.0 aMortality in pharmacologically treated older adults with diabete c2006 Oct ae4000 v33 aBACKGROUND: Diabetes mellitus (DM) confers an increased risk of mortality in young and middle-aged individuals and in women. It is uncertain, however, whether excess DM mortality continues beyond age 75 years, is related to type of hypoglycemic therapy, and whether women continue to be disproportionately affected by DM into older age.
METHODS AND FINDINGS: From the Cardiovascular Health Study, a prospective study of 5,888 adults, we examined 5,372 participants aged 65 y or above without DM (91.2%), 322 with DM treated with oral hypoglycemic agents (OHGAs) (5.5%), and 194 with DM treated with insulin (3.3%). Participants were followed (1989-2001) for total, cardiovascular disease (CVD), coronary heart disease (CHD), and non-CVD/noncancer mortality. Compared with non-DM participants, those treated with OHGAs or insulin had adjusted hazard ratios (HRs) for total mortality of 1.33 (95% confidence interval [CI], 1.10 to 1.62) and 2.04 (95% CI, 1.62 to 2.57); CVD mortality, 1.99 (95% CI, 1.54 to 2.57) and 2.16 (95% CI, 1.54 to 3.03); CHD mortality, 2.47 (95% CI, 1.89 to 3.24) and 2.75 (95% CI, 1.95 to 3.87); and infectious and renal mortality, 1.35 (95% CI, 0.70 to 2.59) and 6.55 (95% CI, 4.18 to 10.26), respectively. The interaction of age (65-74 y versus > or =75 y) with DM was not significant. Women treated with OHGAs had a similar HR for total mortality to men, but a higher HR when treated with insulin.
CONCLUSIONS: DM mortality risk remains high among older adults in the current era of medical care. Mortality risk and type of mortality differ between OHGA and insulin treatment. Women treated with insulin therapy have an especially high mortality risk. Given the high absolute CVD mortality in older people, those with DM warrant aggressive CVD risk factor reduction.
10aAdministration, Oral10aAged10aCardiovascular Diseases10aCoronary Disease10aDiabetes Mellitus10aFemale10aHumans10aHypoglycemic Agents10aInsulin10aMale10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aSex Distribution1 aKronmal, Richard, A1 aBarzilay, Joshua, I1 aSmith, Nicholas, L1 aPsaty, Bruce, M1 aKuller, Lewis, H1 aBurke, Gregory, L1 aFurberg, Curt uhttps://chs-nhlbi.org/node/92302785nas a2200361 4500008004100000022001400041245010800055210006900163260001300232300001100245490000700256520173700263653000902000653002202009653002002031653001802051653002802069653002702097653002202124653002202146653001102168653002602179653001702205653001802222653001702240100002302257700002402280700002102304700001902325700002402344700002002368856003502388 2006 eng d a0149-599200aNew-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study.0 aNewonset diabetes and risk of allcause and cardiovascular mortal c2006 Sep a2012-70 v293 aOBJECTIVE: Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes.
RESEARCH DESIGN AND METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality.
RESULTS: During a median of 5.9 years of follow-up, there were 352 deaths, of which 41% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95% CI 1.7-10.8]), and did not increase over time.
CONCLUSIONS: Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.
10aAged10aAged, 80 and over10aAtherosclerosis10aBlood Glucose10aCardiovascular Diseases10aDiabetes Complications10aDiabetes Mellitus10aFollow-Up Studies10aHumans10aKaplan-Meier Estimate10aRisk Factors10aSurvival Rate10aTime Factors1 aSmith, Nicholas, L1 aBarzilay, Joshua, I1 aKronmal, Richard1 aLumley, Thomas1 aEnquobahrie, Daniel1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/91403146nas a2200433 4500008004100000022001400041245009500055210006900150260001300219300001100232490000700243520191200250653002402162653002002186653001902206653001102225653001102236653001702247653000902264653001602273653002602289653002502315653001202340653002002352653001502372653003002387653003002417653002902447100002602476700002202502700001702524700002402541700001802565700002302583700002002606700002402626700002702650856003502677 2006 eng d a0161-810500aObstructive sleep apnea and plasma natriuretic peptide levels in a community-based sample.0 aObstructive sleep apnea and plasma natriuretic peptide levels in c2006 Oct a1301-60 v293 aSTUDY OBJECTIVES: We hypothesized that alterations in cardiac hemodynamics associated with obstructive sleep apnea-hypopnea (OSAH) would be reflected in higher natriuretic peptide levels. We examined the association of OSAH with natriuretic peptides in a community-based sample.
DESIGN: Cross-sectional, retrospective, observational study.
SETTING: Framingham Heart Study Offspring Cohort and Sleep Heart Health Study.
PARTICIPANTS: Community-based sample of 623 individuals.
MEASUREMENTS: Full-montage home polysomnography was used to determine apnea-hypopnea index (AHI) and percentage of time with an oxyhemoglobin saturation < 90% (PctLt90). Sensitive immunoradiometric assays were used to measure plasma B-type (BNP) and N-terminal pro-atrial natriuretic peptide (NT-ANP). Multivariable regression was used to examine the relations between natriuretic peptides and indicators of OSAH, adjusting for age, sex, body mass index, and clinical covariates.
RESULTS: No statistically significant relations between OSAH indices and BNP were observed in the multivariable model. Compared with an AHI < 5, relative levels of 1.20, 0.88, and 0.91 were observed forAHI categories 5-15, 15-30, >30 events per hour, respectively. For NT-ANP, no significant relations were seen with AHI in the multivariable model (relative levels of 0.98, 0.91, and 0.90). An inverse association was observed between NT-ANP and PctLt90 in age- and sex-adjusted models (relative levels of 0.93, 0.87, and 0.80), although this association became statistically nonsignificant after adjusting for body mass index.
CONCLUSION: Lack of association of natriuretic peptides with OSAH indices suggests that undiagnosed OSAH may not be associated with major alterations in left ventricular function, as reflected in morning natriuretic peptide levels.
10aAtrial Fibrillation10aBody Mass Index10aCohort Studies10aFemale10aHumans10aHypertension10aMale10aMiddle Aged10aMyocardial Infarction10aNatriuretic Peptides10aObesity10aPolysomnography10aPrevalence10aResidence Characteristics10aSeverity of Illness Index10aSleep Apnea, Obstructive1 aPatwardhan, Anjali, A1 aLarson, Martin, G1 aLevy, Daniel1 aBenjamin, Emelia, J1 aLeip, Eric, P1 aKeyes, Michelle, J1 aWang, Thomas, J1 aGottlieb, Daniel, J1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/92503255nas a2200433 4500008004100000022001400041245018000055210006900235260001300304300001100317490000700328520198600335653000902321653001002330653001902340653001802359653001902377653002802396653001902424653003002443653001202473653001102485653002402496653002802520653001102548653001202559653001502571653001102586653002002597653000902617653002202626100002702648700002102675700002302696700002102719700002102740700002502761856003502786 2006 eng d a0021-972X00aThe prevalence of the 65-kilodalton isoform of glutamic acid decarboxylase autoantibodies by glucose tolerance status in elderly patients from the cardiovascular health study.0 aprevalence of the 65kilodalton isoform of glutamic acid decarbox c2006 Aug a2871-70 v913 aCONTEXT: Autoantibodies (AA) to glutamic acid decarboxylase (GAD65), a determinant of risk for autoimmune diabetes, have been found in up to 10% of patients with type 2 diabetes. In older adults, this marker may also serve as a determinant of risk for autoimmune diabetes and enhance diabetes classification.
OBJECTIVE: The objective of this study was to evaluate the relationship between GAD65AA and glucose tolerance status, current diabetes treatment, and clinical measures in older adults.
DESIGN: GAD65AA were measured at baseline in 3318 participants from the Cardiovascular Health Study, a cohort study of 5888 individuals 65 or older.
SETTING: The population-based cohort was recruited from four U.S. sites.
PATIENTS: Patients included all Cardiovascular Health Study participants with known diabetes, newly diagnosed diabetes, impaired fasting glucose, impaired glucose tolerance, and a sample of normal glucose-tolerant participants.
MAIN OUTCOME MEASURES: GAD65AA, body mass index, fasting glucose and insulin levels, blood pressure, lipid levels, and diabetes treatment at baseline were measured.
RESULTS: The prevalence of GAD65AA increased with decreasing glucose tolerance in both Blacks (n = 560) and Whites (n = 2730), being more pronounced in known diabetic individuals. GAD65AA were found in 2.3, 5.8, 7.8, and 8.3% of diabetic participants, reporting use of no diabetes medication, oral hypoglycemic agents, insulin only, and both oral hypoglycemic agents and insulin, respectively (P = 0.02, linear trend). Among diabetic participants, GAD65AA positivity was associated with diabetes treatment, higher fasting glucose, and lower body mass index.
CONCLUSIONS: Even among older individuals with diabetes, GAD65AA may be a useful marker in identifying a subgroup of autoimmune diabetes, serve as a marker of insulin requirement, and remain stable over years.
10aAged10aAging10aAutoantibodies10aBlood Glucose10aBlood Pressure10aCardiovascular Diseases10aCohort Studies10aDiabetes Mellitus, Type 210aFasting10aFemale10aGlucose Intolerance10aGlutamate Decarboxylase10aHumans10aInsulin10aIsoenzymes10aLipids10aLogistic Models10aMale10aNutrition Surveys1 aBarinas-Mitchell, Emma1 aKuller, Lewis, H1 aPietropaolo, Susan1 aZhang, Ying-Jian1 aHenderson, Tyona1 aPietropaolo, Massimo uhttps://chs-nhlbi.org/node/89804012nas a2200445 4500008004100000022001400041245009500055210006900150260001300219300002900232490000700261520271900268653000902987653002202996653002003018653002403038653001903062653002403081653001103105653002203116653001103138653001403149653000903163653001903172653002803191653001403219653002403233653002903257653003003286653001703316653003703333100002303370700002303393700002303416700001703439700002603456700002403482700002503506856003503531 2006 eng d a0741-521400aProgression of atherosclerotic renovascular disease: A prospective population-based study.0 aProgression of atherosclerotic renovascular disease A prospectiv c2006 Nov a955-62; discussion 962-30 v443 aOBJECTIVE: Previous reports from select hypertensive patients suggest that atherosclerotic renovascular disease (RVD) is rapidly progressive and associated with a decline in kidney size and kidney function. This prospective, population-based study estimates the incidence of new RVD and progression of established RVD among elderly, free-living participants in the Cardiovascular Health Study (CHS).
METHOD: The CHS is a multicenter, longitudinal cohort study of cardiovascular risk factors, morbidity, and mortality among men and women aged >65 years old. From 1995 through 1996, 834 participants underwent renal duplex sonography (RDS) to define the presence or absence of significant RVD. Between 2002 and 2005, a second RDS study was performed in 119 participants (mean study interval, 8.0 +/- 0.8 years). Significant RVD was defined as hemodynamically significant stenosis (renal artery peak systolic velocity [RA-PSV] exceeding 1.8 m/s) or renal artery occlusion. Prevalent RVD was significant RVD at the first RDS, and incident disease was defined as new significant RVD at the second RDS. Significant change of RVD was defined as a change in RA-PSV of greater than two times the standard deviation of expected change over time, regardless of hemodynamic significance or progression to renal artery occlusion.
RESULTS: The second RDS study cohort included 119 CHS participants with 235 kidneys (35% men; mean age, 82.8 +/- 3.4). On follow-up, no prevalent RVD (n = 13 kidneys; 6.0%) progressed to occlusion. Twenty-nine kidneys without RVD at the first RDS demonstrated significant change in PSV at the second RDS; including nine kidneys with new significant RVD (8 new stenoses; 1 new occlusion). Controlling for within-subject correlation, the overall estimated change in RVD among all 235 kidneys was 14.0% (95% confidence interval [CI], 9.2% to 21.4%), with progression to significant RVD in 4.0% (95% CI, 1.9% to 8.2%). Longitudinal increase in diastolic blood pressure and decrease in renal length were significantly associated with progression to new (ie, incident) significant RVD but not prevalent RVD.
CONCLUSIONS: This is the first prospective, population-based estimate of incident RVD and progression of prevalent RVD among free-living elderly Americans. In contrast to previous reports among select hypertensive patients, CHS participants with a low rate of clinical hypertension demonstrated a significant change of RVD in only 14.0% of kidneys on follow-up of 8 years (annualized rate, 1.3% per year). Progression to significant RVD was observed in only 4.0% (annualized rate, 0.5% per year), and no prevalent RVD progressed to occlusion.
10aAged10aAged, 80 and over10aAtherosclerosis10aBlood Flow Velocity10aBlood Pressure10aDisease Progression10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aNorth Carolina10aPopulation Surveillance10aPrognosis10aProspective Studies10aRenal Artery Obstruction10aSeverity of Illness Index10aTime Factors10aUltrasonography, Doppler, Duplex1 aPearce, Jeffrey, D1 aCraven, Brandon, L1 aCraven, Timothy, E1 aPiercy, Todd1 aStafford, Jeanette, M1 aEdwards, Matthew, S1 aHansen, Kimberley, J uhttps://chs-nhlbi.org/node/91902509nas a2200349 4500008004100000022001400041245006400055210005900119260001300178300001100191490000600202520158700208653000901795653002201804653001501826653001301841653002801854653001101882653001101893653000901904653002401913653001701937653001401954653003201968653001702000100001602017700002902033700001802062700001902080700002502099856003502124 2006 eng d a1465-464400aThe sensitivity and specificity of markers for event times.0 asensitivity and specificity of markers for event times c2006 Apr a182-970 v73 aThe statistical literature on assessing the accuracy of risk factors or disease markers as diagnostic tests deals almost exclusively with settings where the test, Y, is measured concurrently with disease status D. In practice, however, disease status may vary over time and there is often a time lag between when the marker is measured and the occurrence of disease. One example concerns the Framingham risk score (FR-score) as a marker for the future risk of cardiovascular events, events that occur after the score is ascertained. To evaluate such a marker, one needs to take the time lag into account since the predictive accuracy may be higher when the marker is measured closer to the time of disease occurrence. We therefore consider inference for sensitivity and specificity functions that are defined as functions of time. Semiparametric regression models are proposed. Data from a cohort study are used to estimate model parameters. One issue that arises in practice is that event times may be censored. In this research, we extend in several respects the work by Leisenring et al. (1997) that dealt only with parametric models for binary tests and uncensored data. We propose semiparametric models that accommodate continuous tests and censoring. Asymptotic distribution theory for parameter estimates is developed and procedures for making statistical inference are evaluated with simulation studies. We illustrate our methods with data from the Cardiovascular Health Study, relating the FR-score measured at enrollment to subsequent risk of cardiovascular events.
10aAged10aAged, 80 and over10aBiomarkers10aBiometry10aCardiovascular Diseases10aFemale10aHumans10aMale10aModels, Statistical10aRisk Factors10aROC Curve10aSensitivity and Specificity10aTime Factors1 aCai, Tianxi1 aPepe, Margaret, Sullivan1 aZheng, Yingye1 aLumley, Thomas1 aJenny, Nancy, Swords uhttps://chs-nhlbi.org/node/84902915nas a2200421 4500008004100000022001400041245014000055210006900195260001300264300001100277490000700288520167100295653001901966653002001985653002802005653002502033653002802058653002202086653001102108653001102119653002802130653000902158653001602167653001502183653001902198653003002217653002602247100001902273700002102292700001902313700002102332700002002353700002302373700001902396700002302415700002002438856003502458 2006 eng d a1046-667300aSleep apnea in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the Sleep Heart Health Study.0 aSleep apnea in patients on conventional thriceweekly hemodialysi c2006 Dec a3503-90 v173 aSleep-disordered breathing (SDB) has been noted commonly in hemodialysis (HD) patients, but it is not known whether this is related directly to the treatment of kidney failure with HD or to the higher prevalence of obesity and older age. Forty-six HD patients were compared with 137 participants from the Sleep Heart Health Study (SHHS) who were matched for age, gender, body mass index (BMI), and race. Home unattended polysomnography was performed and scored using similar protocols. The study sample was 62.7 +/- 10.1 yr, was predominantly male (72%) and white (63%), and had an average BMI of 28 +/- 5.3 kg/m(2). The HD sample had a higher systolic BP (137 versus 121 mmHg; P < 0.01) and a higher prevalence of diabetes (33 versus 9%; P < 0.01) and cardiovascular disease (33 versus 13%; P < 0.01) compared with the SHHS sample. The HD group had significantly less sleep time (320 versus 379 min; P < 0.0001) but similar sleep efficiency. HD patients had a higher frequency of arousals per hour (25.1 versus 17.1; P < 0.0001) and apnea-hypopneas per hour (27.2 versus 15.2; P < 0.0001) and greater percentage of the total sleep time below an oxygen saturation of 90% (7.2 versus 1.8; P < 0.0001). HD patients were more likely to have severe SDB (>30 respiratory events per hour) compared with the SHHS sample (odds ratio 4.07; 95% confidence interval 1.83 to 9.07). There was a strong association of HD with severe SDB and nocturnal hypoxemia independent of age, BMI, and the higher prevalence of chronic disease. The potential mechanisms for the higher likelihood of SDB in the HD population must be identified to provide specific prevention and therapy.
10aBlood Pressure10aBody Mass Index10aCardiovascular Diseases10aCase-Control Studies10aCross-Sectional Studies10aDiabetes Mellitus10aFemale10aHumans10aKidney Failure, Chronic10aMale10aMiddle Aged10aPrevalence10aRenal Dialysis10aSeverity of Illness Index10aSleep Apnea Syndromes1 aUnruh, Mark, L1 aSanders, Mark, H1 aRedline, Susan1 aPiraino, Beth, M1 aUmans, Jason, G1 aHammond, Terese, C1 aSharief, Imran1 aPunjabi, Naresh, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/92602758nas a2200421 4500008004100000022001400041245012400055210006900179260001300248300001100261490000600272520161000278653000901888653002201897653002001919653001501939653002801954653001101982653001101993653001402004653003802018653000902056653001402065653002602079653002402105653001702129653001602146653001502162653001102177100001602188700001702204700001602221700001902237700001502256700001502271700001502286856003502301 2006 eng d a1538-793300aSoluble intracellular adhesion molecule-1 is associated with cardiovascular disease risk and mortality in older adults.0 aSoluble intracellular adhesion molecule1 is associated with card c2006 Jan a107-130 v43 aBACKGROUND: Intracellular adhesion molecule-1 (ICAM-1) regulates leukocyte-endothelial attachment, a process crucial to atherosclerosis. Circulating soluble ICAM-1 (sICAM-1) may serve as a marker of cardiovascular disease (CVD) progression.
OBJECTIVES: We examined the association of sICAM-1 with measures of subclinical CVD and risk of incident CVD events and death in older men and women (age > or = 65 years) from the Cardiovascular Health Study.
METHODS: Selected participants were free of clinical CVD at baseline. Non-exclusive incident case groups were angina (n = 534), myocardial infarction (n = 304), stroke (n = 327), and death (n = 842; CVD death = 310). A total 643 subjects were free of events during follow-up.
RESULTS: sICAM-1 was positively associated with C-reactive protein, interleukin-6 and fibrinogen and measures of subclinical CVD in these older men and women. In Cox regression models adjusted for age, gender, and race, increasing levels of sICAM-1 were associated with increased risk of all cause mortality in men and women. Hazard ratios (95% confidence intervals) for a one standard deviation increase in sICAM-1 (89.7 ng mL(-1)) were 1.3 (1.1-1.4) in men and 1.2 (1.1-1.3) in women. sICAM-1 was associated with increased risk of CVD death in women (1.2; 1.0-1.5), but not men (1.1; 0.9-1.3). There were no associations of sICAM-1 with non-fatal CVD events.
CONCLUSIONS: While sICAM-1 was associated with death in older men and women, there was a more marked association between sICAM-1 and CVD death in women.
10aAged10aAged, 80 and over10aAngina Pectoris10aBiomarkers10aCardiovascular Diseases10aFemale10aHumans10aIncidence10aIntercellular Adhesion Molecule-110aMale10aMortality10aMyocardial Infarction10aRegression Analysis10aRisk Factors10aSex Factors10aSolubility10aStroke1 aJenny, N, S1 aArnold, A, M1 aKuller, L H1 aSharrett, A, R1 aFried, L P1 aPsaty, B M1 aTracy, R P uhttps://chs-nhlbi.org/node/88003370nas a2200409 4500008004100000022001400041245022900055210006900284260001600353300001000369490000700379520208600386653001602472653000902488653002202497653001002519653002802529653003002557653001102587653001802598653001102616653003402627653000902661653003302670653002602703653003002729653001702759653001602776653001102792100002202803700002102825700001802846700002002864700002002884700002102904856003502925 2006 eng d a0002-914900aUsefulness of aortic root dimension in persons > or = 65 years of age in predicting heart failure, stroke, cardiovascular mortality, all-cause mortality and acute myocardial infarction (from the Cardiovascular Health Study).0 aUsefulness of aortic root dimension in persons or 65 years of ag c2006 Jan 15 a270-50 v973 aEchocardiographic measures of left ventricular (LV) function and structure as well as left atrial size have been reported to predict adverse cardiovascular disease (CVD) outcomes. Although anatomic changes of the aortic root are likely to reflect effects of hypertension and atherosclerosis, few data are available on the predictive value of aortic root dimension (ARD) for outcome in free-living populations. The purpose of this investigation was to determine whether in a cohort of patients aged > or = 65 years ARD was associated with traditional coronary heart disease (CHD) risk factors and with 10-year incident CVD outcomes. In the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Health Study, 3,933 free-living black and white men and women > or = 65 years of age without prevalent CVD had 2-dimensional directed M-mode echocardiographic measurements of ARD as part of a comprehensive evaluation. ARD was associated with age and gender (greater in men) but not race. ARD was also positively associated with diastolic blood pressure, LV hypertrophy, major electrocardiographic abnormalities, and other echocardiographic measures, including LV mass, ventricular septal and posterior wall thickness, and LV dimension. After adjustment for other known risk factors, high ARD was associated with an increased risk for incident congestive heart failure (CHF) in men (hazard ratio for upper compared with all other quintiles 1.47, p = 0.014), stroke in men and women (hazard ratio 1.39 per cm, p = 0.015), CVD mortality in men and women (hazard ratio 1.48 per cm, p = 0.007), and total mortality in men and women taking antihypertensive medications (hazard ratio 1.46 per cm, p = 0.007), but not with incident myocardial infarction (MI) (hazard ratio 0.89, p = 0.39). In conclusion, in a cohort of patients aged > or = 65 years without clinical CVD at baseline, ARD was associated with several CHD risk factors and measures of subclinical disease and was predictive of incident CHF, stroke, CVD mortality, and all-cause mortality, but not of incident MI.
10aAge Factors10aAged10aAged, 80 and over10aAorta10aCardiovascular Diseases10aEchocardiography, Doppler10aFemale10aHeart Failure10aHumans10aHypertrophy, Left Ventricular10aMale10aMulticenter Studies as Topic10aMyocardial Infarction10aPredictive Value of Tests10aRisk Factors10aSex Factors10aStroke1 aGardin, Julius, M1 aArnold, Alice, M1 aPolak, Joseph1 aJackson, Sharon1 aSmith, Vivienne1 aGottdiener, John uhttps://chs-nhlbi.org/node/88602744nas a2200361 4500008004100000022001400041245012300055210006900178260001300247300001000260490000800270520170700278653000901985653002101994653002402015653001102039653002202050653001102072653001402083653002502097653000902122653001402131653001702145100002402162700002002186700002602206700002102232700002102253700002502274700002402299700002402323856003502347 2007 eng d a1097-674400aAlcohol consumption and risk and prognosis of atrial fibrillation among older adults: the Cardiovascular Health Study.0 aAlcohol consumption and risk and prognosis of atrial fibrillatio c2007 Feb a260-60 v1533 aBACKGROUND: The relationship of alcohol consumption with risk of atrial fibrillation (AF) is inconsistent in previous studies, and its relationship with prognosis of AF is undetermined.
METHODS: As part of the Cardiovascular Health Study, a population-based cohort of adults 65 years and older from 4 US communities, 5609 participants reported their use of beer, wine, and spirits yearly. We identified cases of AF with routine study electrocardiograms and validated discharge diagnoses from hospitalizations.
RESULTS: A total of 1232 cases of AF were documented during a mean of 9.1 years of follow-up. Compared with long-term abstainers, the multivariable-adjusted hazard ratios were 1.25 (95% CI, 1.02-1.54) among former drinkers, 1.09 (95% CI, 0.94-1.28) among consumers of less than 1 drink per week, 1.00 (95% CI, 0.84-1.19) among consumers of 1 to 6 drinks per week, 1.06 (95% CI, 0.82-1.37) among consumers of 7 to 13 drinks per week, and 1.09 (95% CI, 0.88-1.37) among consumers of 14 or more drinks per week (P trend = 0.64). In analyses of mortality among participants with AF, the hazard ratios were 1.27 (95% CI, 1.06-1.52) among former drinkers, 0.94 (95% CI, 0.76-1.18) among consumers of less than 1 drink per week, 0.98 (95% CI, 0.78-1.23) among consumers of 1 to 6 drinks per week, 0.73 (95% CI, 0.51-1.03) among consumers of 7 to 13 drinks per week, and 0.81 (95% CI, 0.59-1.11) among consumers of 14 or more drinks per week (P trend = 0.12).
CONCLUSIONS: Current moderate alcohol consumption is not associated with risk of AF or with risk of death after diagnosis of AF, but former drinking identifies individuals at higher risk.
10aAged10aAlcohol Drinking10aAtrial Fibrillation10aFemale10aFollow-Up Studies10aHumans10aIncidence10aLongitudinal Studies10aMale10aPrognosis10aRisk Factors1 aMukamal, Kenneth, J1 aPsaty, Bruce, M1 aRautaharju, Pentti, M1 aFurberg, Curt, D1 aKuller, Lewis, H1 aMittleman, Murray, A1 aGottdiener, John, S1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/93903594nas a2200661 4500008004100000022001400041245018300055210006900238260001600307300000900323490000800332520170200340653002202042653000902064653001502073653002302088653002802111653002802139653001902167653001602186653002202202653004002224653001102264653002202275653001102297653002002308653001702328653001402345653001702359653002602376653000902402653001902411653001402430653002602444653001202470653003002482653003202512653002402544653002002568653001702588653001402605653001202619653001102631653002202642653001802664653001702682653002002699653001802719100001602737700002102753700002102774700002102795700002002816700002202836700002102858700001802879856003502897 2007 eng d a1524-453900aAssociation of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study.0 aAssociation of carotid artery intimamedia thickness plaques and c2007 Jul 03 a32-80 v1163 aBACKGROUND: Carotid atherosclerosis, measured as carotid intima-media thickness or as characteristics of plaques, has been linked to cardiovascular disease (CVD) and to C-reactive protein (CRP) levels. We investigated the relationship between carotid atherosclerosis and CRP and their joint roles in CVD prediction.
METHODS AND RESULTS: Of 5888 participants in the Cardiovascular Health Study, an observational study of adults aged > or = 65 years, 5020 without baseline CVD were included in the analysis. They were followed up for as long as 12 years for CVD incidence and all-cause mortality after baseline ultrasound and CRP measurement. When CRP was elevated (> 3 mg/L) among those with detectable atherosclerosis on ultrasound, there was a 72% (95% CI, 1.46 to 2.01) increased risk for CVD death and a 52% (95% CI, 1.37 to 1.68) increased risk for all-cause mortality. Elevated CRP in the absence of atherosclerosis did not increase CVD or all-cause mortality risk. The proportion of excess risk attributable to the interaction of high CRP and atherosclerosis was 54% for CVD death and 79% for all-cause mortality. Addition of CRP or carotid atherosclerosis to conventional risk factors modestly increased in the ability to predict CVD, as measured by the c statistic.
CONCLUSIONS: In older adults, elevated CRP was associated with increased risk for CVD and all-cause mortality only in those with detectable atherosclerosis based on carotid ultrasound. Despite the significant associations of CRP and carotid atherosclerosis with CVD, these measures modestly improve the prediction of CVD outcomes after one accounts for the conventional risk factors.
10aAfrican Americans10aAged10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aCarotid Artery Diseases10aCohort Studies10aComorbidity10aDiabetes Mellitus10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHumans10aHyperlipidemias10aHypertension10aIncidence10aInflammation10aKaplan-Meier Estimate10aMale10aMass Screening10aMortality10aMyocardial Infarction10aObesity10aPredictive Value of Tests10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aROC Curve10aSmoking10aStroke10aSurvival Analysis10aTunica Intima10aTunica Media10aUltrasonography10aUnited States1 aCao, Jie, J1 aArnold, Alice, M1 aManolio, Teri, A1 aPolak, Joseph, F1 aPsaty, Bruce, M1 aHirsch, Calvin, H1 aKuller, Lewis, H1 aCushman, Mary uhttps://chs-nhlbi.org/node/96703188nas a2200409 4500008004100000022001400041245018100055210006900236260001300305300001200318490000700330520189900337653000902236653002802245653002502273653001902298653002102317653001102338653001102349653004902360653004902409653003302458653000902491653002602500653001702526653001102543100002202554700002202576700002302598700002102621700002502642700001802667700002102685700001702706700002002723856003502743 2007 eng d a0021-972X00aAssociation of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke.0 aAssociation of total insulinlike growth factorI insulinlike grow c2007 Apr a1319-250 v923 aCONTEXT: Prior observational studies have demonstrated that the GH/IGF axis is associated with cardiovascular disease. However, this association has not been extensively studied among older adults.
OBJECTIVE: The objective of this study was to assess the association between levels of total IGF-I and IGF binding proteins (IGFBP-1, IGFBP-3) and risk of incident coronary events and ischemic stroke.
DESIGN AND PARTICIPANTS: A case-cohort analysis was conducted among adults 65 yr and older in the Cardiovascular Health Study.
MAIN OUTCOME MEASURES: A total of 534 coronary events [316 nonfatal myocardial infarctions (MIs), 48 fatal MIs, and 170 fatal coronary heart disease events] and 370 ischemic strokes were identified on follow-up. Comparison subjects were 1122 randomly selected participants from the Cardiovascular Health Study.
RESULTS: Mean follow-up time was 6.7 yr for coronary events, 5.6 yr for strokes, and 9.3 yr for comparison subjects. Hazard ratios (95% confidence intervals) associated with baseline levels of total IGF-I and IGFBPs were estimated using multivariate adjusted Cox proportional hazards models. Neither IGF-I nor IGFBP-1 levels predicted risk of incident coronary events or stroke. IGFBP-3 had an inverse association with risk of coronary events [adjusted hazard ratio per sd=0.88 (0.78-1.00), P=0.05] but was not associated with stroke. Exploratory analyses suggested that low IGF-I and low IGFBP-3 levels were significantly associated with higher risk of nonfatal MI (P<0.05) but not with risk of fatal MI or fatal coronary heart disease.
CONCLUSION: Circulating levels of total IGF-I or IGFBP-1 were not associated with risk of total coronary events or ischemic stroke among older adults, whereas low IGFBP-3 level was associated with increased risk of incident coronary events.
10aAged10aCardiovascular Diseases10aCase-Control Studies10aCohort Studies10aCoronary Disease10aFemale10aHumans10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aMultivariate Analysis10aRisk Factors10aStroke1 aKaplan, Robert, C1 aMcGinn, Aileen, P1 aPollak, Michael, N1 aKuller, Lewis, H1 aStrickler, Howard, D1 aRohan, Tom, E1 aCappola, Anne, R1 aXue, XiaoNan1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/94003097nas a2200409 4500008004100000022001400041245013700055210006900192260001600261300001100277490000700288520191300295653000902208653002202217653001702239653002602256653002302282653001502305653002802320653001902348653002402367653001102391653002202402653002502424653001102449653000902460653001702469100002002486700001602506700002302522700002402545700001802569700002002587700002302607700002202630856003502652 2007 eng d a1558-359700aClinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study.0 aClinical factors but not Creactive protein predict progression o c2007 Nov 13 a1992-80 v503 aOBJECTIVES: The purpose of this study was to examine the relationship between C-reactive protein (CRP) and calcific aortic valve disease in a large, randomly selected, population-based cohort.
BACKGROUND: The pathobiology of calcific aortic stenosis involves an active inflammatory, atheromatous, osteogenic process. Elevations in CRP, a measure of systemic inflammation, have been associated with aortic stenosis.
METHODS: Two-dimensional and Doppler echocardiography and CRP measurement were performed at baseline in 5,621 participants in the Cardiovascular Health Study. Multivariable analysis was used to identify CRP as a predictor of baseline and incident aortic stenosis.
RESULTS: At a mean echocardiographic follow-up of 5 years, 9% of subjects with aortic sclerosis progressed to some degree of aortic stenosis. Increasing age (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.16; p < 0.001) and male gender (OR 3.05, 95% CI 1.76 to 5.27; p < 0.001) were related to risk of incident aortic stenosis, whereas increasing height (OR 0.96, 95% CI 0.94 to 0.99; p = 0.013) and African-American ethnicity conveyed a lower risk (OR 0.49, 95% CI 0.25 to 0.95; p = 0.035). C-reactive protein, treated as a continuous variable, was not associated with baseline aortic stenosis, progression to aortic sclerosis (adjusted OR 0.93, 95% CI 0.85 to 1.02; p = 0.107), or progression to aortic stenosis (adjusted OR 0.85, 95% CI 0.70 to 1.03; p = 0.092).
CONCLUSIONS: In this large population-based cohort, approximately 9% of subjects with aortic sclerosis progressed to aortic stenosis over a 5-year follow-up period. There was no association between CRP levels and the presence of calcific aortic-valve disease or incident aortic stenosis. C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease.
10aAged10aAged, 80 and over10aAortic Valve10aAortic Valve Stenosis10aC-Reactive Protein10aCalcinosis10aCardiovascular Diseases10aCohort Studies10aDisease Progression10aFemale10aFollow-Up Studies10aHeart Valve Diseases10aHumans10aMale10aRisk Factors1 aNovaro, Gian, M1 aKatz, Ronit1 aAviles, Ronnier, J1 aGottdiener, John, S1 aCushman, Mary1 aPsaty, Bruce, M1 aOtto, Catherine, M1 aGriffin, Brian, P uhttps://chs-nhlbi.org/node/99704735nas a2200925 4500008004100000022001400041245013000055210006900185260001300254300000900267490000700276520238700283653005102670653002802721653001102749653002202760110003402782700001802816700001502834700001302849700001502862700001502877700001402892700001502906700001602921700001602937700001402953700001502967700001602982700001202998700001503010700001603025700001403041700001503055700002003070700001603090700001503106700001403121700001603135700002003151700001403171700001303185700001403198700001403212700001203226700001703238700001503255700002203270700001403292700001403306700002103320700001403341700001903355700002003374700001503394700001403409700001803423700001503441700001503456700002703471700001403498700001803512700001703530700001503547700001403562700001003576700001403586700001703600700001603617700001603633700001503649700002303664700001503687700001603702700001603718700001403734700001403748700001203762856003503774 2007 eng d a1741-826700aCollaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases.0 aCollaborative metaanalysis of individual participant data from o c2007 Feb a3-110 v143 aBACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors.
OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes.
METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aCardiovascular Diseases10aHumans10aPhospholipases A21 aLp-PLA2 Studies Collaboration1 aBallantyne, C1 aCushman, M1 aPsaty, B1 aFurberg, C1 aKhaw, K, T1 aSandhu, M1 aOldgren, J1 aRossi, G, P1 aMaiolino, G1 aCesari, M1 aLenzini, L1 aJames, S, K1 aRimm, E1 aCollins, R1 aAnderson, J1 aKoenig, W1 aBrenner, H1 aRothenbacher, D1 aBerglund, G1 aPersson, M1 aBerger, P1 aBrilakis, E1 aMcConnell, J, P1 aKoenig, W1 aSacco, R1 aElkind, M1 aTalmud, P1 aRimm, E1 aCannon, C, P1 aPackard, C1 aBarrett-Connor, E1 aHofman, A1 aKardys, I1 aWitteman, J, C M1 aCriqui, M1 aCorsetti, J, P1 aRainwater, D, L1 aMoss, A, J1 aRobins, S1 aBloomfield, H1 aCollins, D1 aPackard, C1 aWassertheil-Smoller, S1 aRidker, P1 aBallantyne, C1 aCannon, C, P1 aCushman, M1 aDanesh, J1 aGu, D1 aHofman, A1 aNelson, J, J1 aThompson, S1 aZalewski, A1 aZariffa, N1 aDi Angelantonio, E1 aKaptoge, S1 aThompson, A1 aThompson, S1 aWalker, M1 aWatson, S1 aWood, A uhttps://chs-nhlbi.org/node/94308392nas a2202725 4500008004100000022001400041245020200055210006900257260000900326300001100335490000700346520180300353653001302156653001502169653002802184653002302212653001302235653001102248653001702259653002002276653001102296653002202307653002402329653001702353653001802370110004002388700001402428700001302442700001402455700001902469700001502488700001202503700001502515700001602530700001502546700001702561700002002578700001502598700001802613700002202631700001702653700001502670700001402685700001402699700001202713700001202725700001502737700001602752700002002768700001702788700001602805700001702821700001802838700002102856700001802877700001502895700001502910700001502925700001502940700002302955700002302978700002203001700001703023700001603040700001403056700001503070700001503085700001403100700001603114700001903130700001903149700001403168700001603182700001403198700001603212700001603228700001503244700001403259700001503273700001803288700002003306700001503326700001403341700001803355700001803373700001603391700002103407700001503428700001503443700001803458700002003476700001703496700001403513700001703527700001503544700001503559700001303574700001703587700001803604700001403622700001603636700001803652700001403670700001303684700001403697700001803711700001703729700001703746700001603763700001703779700001503796700002203811700001203833700001103845700001203856700001103868700001603879700001203895700001703907700001503924700001803939700001803957700001903975700001203994700002104006700001304027700001404040700001504054700001604069700001604085700001504101700001404116700001704130700001204147700001404159700001404173700001504187700001404202700001404216700001704230700001704247700001404264700001804278700001904296700001704315700001604332700002004348700001204368700001304380700001304393700001604406700001304422700001904435700001404454700001404468700002304482700001504505700001604520700001304536700001704549700001504566700001504581700001604596700001504612700001404627700001404641700001604655700001804671700001904689700002204708700001504730700001904745700001604764700001604780700001804796700001604814700001604830700001604846700001404862700001604876700001404892700002204906700001704928700001704945700001804962700001704980700001304997700001205010700001305022700001205035700001605047700001605063700001705079700001705096700001705113700001805130700001605148700001405164700001305178700001205191700001405203700001805217700001505235700001505250700001505265700001405280700001605294700001205310700001705322700001005339700001705349700002005366700001605386700001505402700002305417700001505440700001705455700001305472700001605485700001305501700001105514700001405525700001605539700001605555700001405571700001505585700001605600700001505616856003505631 2007 eng d a0393-299000aThe Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases.0 aEmerging Risk Factors Collaboration analysis of individual data c2007 a839-690 v223 aMany long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
10aAlbumins10aBiomarkers10aCardiovascular Diseases10aDatabases, Factual10aFar East10aHumans10aInflammation10aLeukocyte Count10aLipids10aLipoproteins, HDL10aProspective Studies10aRisk Factors10aTriglycerides1 aEmerging Risk Factors Collaboration1 aDanesh, J1 aErqou, S1 aWalker, M1 aThompson, S, G1 aTipping, R1 aFord, C1 aPressel, S1 aWalldius, G1 aJungner, I1 aFolsom, A, R1 aChambless, L, E1 aKnuiman, M1 aWhincup, P, H1 aWannamethee, S, G1 aMorris, R, W1 aWilleit, J1 aKiechl, S1 aSanter, P1 aMayr, A1 aWald, N1 aEbrahim, S1 aLawlor, D A1 aYarnell, J, W G1 aGallacher, J1 aCasiglia, E1 aTikhonoff, V1 aNietert, P, J1 aSutherland, S, E1 aBachman, D, L1 aKeil, J, E1 aCushman, M1 aPsaty, B M1 aTracy, R P1 aTybjaerg-Hansen, A1 aNordestgaard, B, G1 aFrikke-Schmidt, R1 aGiampaoli, S1 aPalmieri, L1 aPanico, S1 aVanuzzo, D1 aPilotto, L1 aSimons, L1 aMcCallum, J1 aFriedlander, Y1 aFowkes, F, G R1 aLee, A, J1 aSmith, F, B1 aTaylor, J1 aGuralnik, J1 aPhillips, C1 aWallace, R1 aBlazer, D1 aKhaw, K, T1 aJansson, J, H1 aDonfrancesco, C1 aSalomaa, V1 aHarald, K1 aJousilahti, P1 aVartiainen, E1 aWoodward, M1 aD'Agostino, R, B1 aWolf, P, A1 aVasan, R S1 aPencina, M, J1 aBladbjerg, E, M1 aJorgensen, T1 aMoller, L1 aJespersen, J1 aDankner, R1 aChetrit, A1 aLubin, F1 aRosengren, A1 aWilhelmsen, L1 aLappas, G1 aEriksson, H1 aBjorkelund, C1 aCremer, P1 aNagel, D1 aTilvis, R1 aStrandberg, T1 aRodriguez, B1 aBouter, L, M1 aHeine, R, J1 aDekker, J, M1 aNijpels, G1 aStehouwer, C, D A1 aRimm, E1 aPai, J1 aSato, S1 aIso, H1 aKitamura, A1 aNoda, H1 aGoldbourt, U1 aSalomaa, V1 aSalonen, J, T1 aNyyssönen, K1 aTuomainen, T-P1 aDeeg, D1 aPoppelaars, J, L1 aMeade, T1 aCooper, J1 aHedblad, B1 aBerglund, G1 aEngstrom, G1 aDöring, A1 aKoenig, W1 aMeisinger, C1 aMraz, W1 aKuller, L1 aSelmer, R1 aTverdal, A1 aNystad, W1 aGillum, R1 aMussolino, M1 aHankinson, S1 aManson, J1 aDe Stavola, B1 aKnottenbelt, C1 aCooper, J, A1 aBauer, K, A1 aRosenberg, R, D1 aSato, S1 aNaito, Y1 aHolme, I1 aNakagawa, H1 aMiura, H1 aDucimetiere, P1 aJouven, X1 aCrespo, C1 aGarcia-Palmieri, M1 aAmouyel, P1 aArveiler, D1 aEvans, A1 aFerrieres, J1 aSchulte, H1 aAssmann, G1 aShepherd, J1 aPackard, C1 aSattar, N1 aCantin, B1 aLamarche, B1 aDesprés, J-P1 aDagenais, G, R1 aBarrett-Connor, E1 aWingard, D1 aBettencourt, R1 aGudnason, V1 aAspelund, T1 aSigurdsson, G1 aThorsson, B1 aTrevisan, M1 aWitteman, J1 aKardys, I1 aBreteler, M1 aHofman, A1 aTunstall-Pedoe, H1 aTavendale, R1 aLowe, G, D O1 aBen-Shlomo, Y1 aHoward, B, V1 aZhang, Y1 aBest, L1 aUmans, J1 aOnat, A1 aMeade, T, W1 aNjolstad, I1 aMathiesen, E1 aLochen, M, L1 aWilsgaard, T1 aGaziano, J, M1 aStampfer, M1 aRidker, P1 aUlmer, H1 aDiem, G1 aConcin, H1 aRodeghiero, F1 aTosetto, A1 aBrunner, E1 aShipley, M1 aBuring, J1 aCobbe, S, M1 aFord, I1 aRobertson, M1 aHe, Y1 aIbanez, A, M1 aFeskens, E, J M1 aKromhout, D1 aCollins, R1 aDi Angelantonio, E1 aKaptoge, S1 aLewington, S1 aOrfei, L1 aPennells, L1 aPerry, P1 aRay, K1 aSarwar, N1 aScherman, M1 aThompson, A1 aWatson, S1 aWensley, F1 aWhite, I, R1 aWood, A, M uhttps://chs-nhlbi.org/node/98402748nas a2200349 4500008004100000022001400041245010200055210006900157260001300226300001000239490000700249520177800256653000902034653002202043653001002065653001902075653001102094653000902105653003102114653001102145653000902156653002402165653002402189653001702213653001202230100002302242700002802265700002102293700002902314700002002343856003502363 2007 eng d a1079-500600aGait variability and the risk of incident mobility disability in community-dwelling older adults.0 aGait variability and the risk of incident mobility disability in c2007 Sep a983-80 v623 aBACKGROUND: Gait speed is a strong predictor of incident walking disability. The objective was to determine if gait variability adds to the prediction of incident mobility disability independent of gait speed.
METHODS: Participants included 379 older adults (mean age = 79 years; 78% Caucasian, and 40% men) in the Cardiovascular Health Study at the Pittsburgh site. All could ambulate independently and reported no difficulty walking a half mile. Gait characteristics were determined from a 4-meter computerized walkway. For each gait parameter, variability was defined as the standard deviation from the individual steps from two passes. Incident walking disability was obtained by phone interview every 6 months for 54 months and was defined as new difficulty walking a half mile or inability to walk a half mile.
RESULTS: Of the 379 participants, 222 (58.6%) developed incident mobility disability. In unadjusted Cox proportional hazards models gait speed, mean step length, mean stance time, and stance time variability were associated with incident mobility disability. After adjusting for gait speed, demographics, chronic conditions, prescription medications, health status, and physical activity level, only stance time variability remained an important indicator of disability. In the adjusted model, an increase in stance time variability of 0.01 seconds was associated with a 13% higher incidence of mobility disability (hazard ratio 1.13, 95% confidence interval, 1.01-1.27).
CONCLUSIONS: Stance time variability is an independent predictor of future mobility disability. Future efforts are needed to determine whether interventions that decrease stance time variability will also delay mobility disability.
10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGait10aGait Disorders, Neurologic10aHumans10aMale10aMobility Limitation10aProspective Studies10aRisk Factors10aWalking1 aBrach, Jennifer, S1 aStudenski, Stephanie, A1 aPerera, Subashan1 aVanSwearingen, Jessie, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/98702708nas a2200469 4500008004100000022001400041245014600055210006900201260001300270300001100283490000800294520133100302653002201633653000901655653001201664653002301676653002801699653001901727653004001746653001101786653001901797653003801816653002201854653001101876653001801887653001201905653002501917653000901942653003601951653003001987100002302017700002002040700001802060700001802078700001702096700001702113700002002130700001902150700001702169700001702186856003502203 2007 eng d a1432-120300aIL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study.0 aIL6 gene variation is associated with IL6 and Creactive protein c2007 Dec a485-940 v1223 aInterleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.
10aAfrican Americans10aAged10aAlleles10aC-Reactive Protein10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenetic Variation10aHumans10aInterleukin-610aIntrons10aLongitudinal Studies10aMale10aPolymorphism, Single Nucleotide10aPromoter Regions, Genetic1 aWalston, Jeremy, D1 aFallin, Daniele1 aCushman, Mary1 aLange, Leslie1 aPsaty, Bruce1 aJenny, Nancy1 aBrowner, Warren1 aTracy, Russell1 aDurda, Peter1 aReiner, Alex uhttps://chs-nhlbi.org/node/98202561nas a2200373 4500008004100000022001400041245015100055210006900206260001300275300001100288490000700299520147200306653001601778653000901794653001901803653001101822653001101833653001401844653002801858653000901886653003201895653003001927653001701957653001601974653001701990653001802007100002602025700002202051700001802073700002002091700002302111700001802134856003502152 2007 eng d a0277-953600aIndividual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: The Cardiovascular Health Study.0 aIndividual and neighborhood socioeconomic status and progressive c2007 Aug a809-210 v653 aFew studies have focused on the association between socioeconomic status (SES) and progressive chronic kidney disease (pCKD) in an elderly population. We conducted a cohort study of 4735 Cardiovascular Health Study participants, ages 65 and older and living in 4 US communities, to examine the independent risk of pCKD associated with income, education and living in a low SES area. pCKD was defined as creatinine elevation 0.4 mg/dL (35 micromol/L) over a 4-7 year follow-up or CKD hospitalization. Area SES was characterized using measures of income, wealth, education and occupation for 1990 (corresponding to time of enrollment) US Census block groups of residence. Age and study site-adjusted incidence rates (per 1000 person years) of pCKD by quartiles of area-level SES score, income and education showed decreasing rates with increasing SES. Cox proportional hazards models showed that living in the lowest SES area quartile, as opposed to the highest, was associated with 50% greater risk of pCKD, after adjusting for age, gender, study site, baseline creatinine, and individual-level SES. This increased risk and trend persisted after adjusting for lifestyle risk factors, diabetes and hypertension. We found no significant independent associations between pCKD and individual-level income or education (after adjusting for all other SES factors). As such, living in a low SES area is associated with greater risk of pCKD in an elderly US population.
10aAge Factors10aAged10aCohort Studies10aFemale10aHumans10aIncidence10aKidney Failure, Chronic10aMale10aProportional Hazards Models10aResidence Characteristics10aRisk Factors10aSex Factors10aSocial Class10aUnited States1 aMerkin, Sharon, Stein1 aRoux, Ana, V Diez1 aCoresh, Josef1 aFried, Linda, F1 aJackson, Sharon, A1 aPowe, Neil, R uhttps://chs-nhlbi.org/node/96403065nas a2200457 4500008004100000022001400041245011600055210006900171260001300240300001200253490000600265520185200271653000902123653001002132653001502142653002302157653002802180653001602208653001902224653001602243653001102259653001502270653001502285653001702300653001102317653002702328653001802355653002002373653001902393653000902412653002402421653001702445100001602462700001202478700001602490700001502506700001702521700001902538700001502557856003502572 2007 eng d a1538-793300aInflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study.0 aInflammation and hemostasis biomarkers and cardiovascular risk i c2007 Jun a1128-350 v53 aBACKGROUND: There are few studies of inflammation and hemostasis biomarkers and cardiovascular disease risk (CVD) in older adults.
OBJECTIVES: To assess multiple biomarkers simultaneously and in combinations for CVD risk assessment in older individuals.
PATIENTS/METHODS: Thirteen biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, factor VII, factor VIII, leukocyte count (WBC), platelet count, lipoprotein(a), soluble intercellular adhesion molecule-1 (sICAM-1), albumin, homocysteine and uric acid, were correlated with incident CVD in 4510 individuals in the Cardiovascular Health Study. Baseline biomarkers were analyzed as gender-specific SD increments and quintiles in proportional hazards models adjusted for demographics, CVD risk factors and medications.
RESULTS: Over 9 years with 1700 CVD events, seven biomarkers were associated with CVD. Adjusted hazard ratios (HRs, 95% CI) per SD increment were 1.16 (1.09, 1.23) for IL-6, 1.16 (1.09, 1.23) for CRP, 1.13 (1.05, 1.21) for D-dimer, 1.17 (1.09, 1.25) for homocysteine, 1.06 (1.00, 1.12) for WBC, 1.06 (1.00, 1.12) for factor VIII, and 1.07 (1.00, 1.13) for lipoprotein(a). Fibrinogen was associated with CVD in men only (HR 1.12, 95% CI 1.04, 1.22) and sICAM-1 in women only (HR 1.16, 95% CI 1.05, 1.27). IL-6 and CRP remained associated with CVD when modeled with WBC. Participants were classified by all combinations of two biomarkers being high or low (IL-6, CRP, WBC, factor VIII, cholesterol/HDL). All were associated with CVD when cholesterol/HDL was low and none when CRP was low.
CONCLUSIONS: Seven biomarkers were associated with CVD in older adults, with CRP having some advantages compared with others. Even larger studies are needed to better characterize these associations.
10aAged10aAging10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aCholesterol10aCohort Studies10aFactor VIII10aFemale10aFibrinogen10aHemostasis10aHomocysteine10aHumans10aInflammation Mediators10aInterleukin-610aLeukocyte Count10aLipoprotein(a)10aMale10aProspective Studies10aRisk Factors1 aZakai, N, A1 aKatz, R1 aJenny, N, S1 aPsaty, B M1 aReiner, A, P1 aSchwartz, S, M1 aCushman, M uhttps://chs-nhlbi.org/node/95002766nas a2200517 4500008004100000022001400041245006200055210006000117260001600177300001100193490000800204520138100212653002101593653000901614653001501623653002301638653002801661653002701689653002601716653001101742653001501753653002201768653001101790653002501801653001701826653001701843653000901860653001601869653001201885653002801897653003001925653001401955653003201969653001702001653002102018653001202039653001702051653001802068100002502086700001702111700002002128700002102148700002202169700002202191856003502213 2007 eng d a0002-926200aInflammation biomarkers and near-term death in older men.0 aInflammation biomarkers and nearterm death in older men c2007 Mar 15 a684-950 v1653 aAssociations of C-reactive protein (CRP) and fibrinogen with death may weaken over time. Combining both markers may improve prediction of death in older adults. In 5,828 Cardiovascular Health Study participants (United States, 1989-2000), 383 deaths (183 cardiovascular disease (CVD)) in years 1-3 (early) and 914 deaths (396 CVD) in years 4-8 (late) occurred. For men, when comparing highest to lowest quartiles, hazard ratios for early death were 4.1 (95% confidence interval (CI): 2.7, 6.3) for CRP and 4.1 (95% CI: 2.7, 6.4) for fibrinogen in models adjusted for CVD risk. For early CVD death, hazard ratios were 4.3 (95% CI: 2.2, 8.4) and 3.4 (95% CI: 1.8, 6.3), respectively. When comparing men in the highest quartiles of both biomarkers with those in the lowest, hazard ratios were 9.6 (95% CI: 4.3, 21.1) for early death and 13.5 (95% CI: 3.2, 56.5) for early CVD death. Associations were weaker for late deaths. For women, CRP (hazard ratio = 2.3, 95% CI: 1.4, 3.9), but not fibrinogen (hazard ratio = 1.3, 95% CI: 0.8, 2.2), was associated with early death. Results were similar for CVD death. Neither was associated with late deaths. CRP and fibrinogen were more strongly associated with death in older men than women and more strongly associated with early than late death. Combining both markers may identify older men at greatest risk of near-term death.
10aAge Distribution10aAged10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aDiabetes Complications10aEpidemiologic Studies10aFemale10aFibrinogen10aFollow-Up Studies10aHumans10aHypercholesterolemia10aHypertension10aInflammation10aMale10aMiddle Aged10aObesity10aPopulation Surveillance10aPredictive Value of Tests10aPrognosis10aProportional Hazards Models10aRisk Factors10aSex Distribution10aSmoking10aTime Factors10aUnited States1 aJenny, Nancy, Swords1 aYanez, David1 aPsaty, Bruce, M1 aKuller, Lewis, H1 aHirsch, Calvin, H1 aTracy, Russell, P uhttps://chs-nhlbi.org/node/93602852nas a2200421 4500008004100000022001400041245009800055210006900153260001300222300001000235490000600245520167800251653000901929653002201938653002401960653002801984653002002012653002102032653002402053653001102077653001102088653001102099653002002110653000902130653002002139100002202159700002002181700002402201700002002225700002002245700001602265700002002281700002102301700002902322700002002351700002402371856003502395 2007 eng d a1555-905X00aKidney function, electrocardiographic findings, and cardiovascular events among older adults.0 aKidney function electrocardiographic findings and cardiovascular c2007 May a501-80 v23 aChronic kidney disease (CKD) is associated with cardiovascular (CV) disease and mortality. It is not known whether cardiac rhythm disturbances are more prevalent among individuals with CKD or whether resting electrocardiogram findings predict future CV events in the CKD setting. Data were obtained from the Cardiovascular Health Study, a community-based study of adults aged >/=65 yr. After exclusions for prevalent heart disease, atrial fibrillation, implantable pacemaker, or antiarrhythmic medication use, 3238 participants were analyzed. CKD was defined by an estimated GFR <60 ml/min per 1.73 m(2). Outcomes were adjudicated incident heart failure (HF), incident coronary heart disease (CHD), and mortality. Participants with CKD had longer PR and corrected QT intervals compared with those without CKD; however, differences in electrocardiographic markers were explained by traditional CV risk factors and CV medication use. After adjustment for known risk factors, each 10-ms increase in the QRS interval was associated with a 15% greater risk for incident HF (95% confidence interval [CI] 1.04 to 1.27), a 13% greater risk for CHD (95% CI 1.04 to 1.24), and a 17% greater risk for mortality (95% CI 1.09, 1.25) among CKD participants. Each 5% increase in QTI was associated with a 42% (95% CI 1.23 to 1.65), 22% (95% CI 1.07 to 1.40), and 10% (95% CI 0.98 to 1.22) greater risk for HF, CHD, and mortality, respectively. Associations seemed stronger for participants with CKD; however, no significant interactions were detected. Resting electrocardiographic abnormalities are common in CKD and independently predict future clinical CV events in this setting.
10aAged10aAged, 80 and over10aCardiac Output, Low10aCardiovascular Diseases10aChronic Disease10aCoronary Disease10aElectrocardiography10aFemale10aHumans10aKidney10aKidney Diseases10aMale10aRisk Assessment1 aKestenbaum, Bryan1 aRudser, Kyle, D1 aShlipak, Michael, G1 aFried, Linda, F1 aNewman, Anne, B1 aKatz, Ronit1 aSarnak, Mark, J1 aSeliger, Stephen1 aStehman-Breen, Catherine1 aPrineas, Ronald1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/97502795nas a2200433 4500008004100000022001400041245009300055210006900148260001600217300001000233490000800243520160000251653000901851653002801860653000801888653001101896653001101907653001701918653001501935653000901950653002601959653002101985653001902006653004602025653000902071653002002080653001702100653001302117100002802130700002402158700002402182700002002206700002002226700002202246700002002268700002002288700001802308856003502326 2007 eng d a0002-926200aLeukocyte telomere length and cardiovascular disease in the cardiovascular health study.0 aLeukocyte telomere length and cardiovascular disease in the card c2007 Jan 01 a14-210 v1653 aThe telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age = 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio = 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio = 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.
10aAged10aCardiovascular Diseases10aDNA10aFemale10aHumans10aInflammation10aLeukocytes10aMale10aMyocardial Infarction10aOxidative Stress10aPilot Projects10aPolymorphism, Restriction Fragment Length10aRisk10aRisk Assessment10aRisk Factors10aTelomere1 aFitzpatrick, Annette, L1 aKronmal, Richard, A1 aGardner, Jeffrey, P1 aPsaty, Bruce, M1 aJenny, Nancy, S1 aTracy, Russell, P1 aWalston, Jeremy1 aKimura, Masyuki1 aAviv, Abraham uhttps://chs-nhlbi.org/node/92202996nas a2200373 4500008004100000022001400041245012700055210006900182260001300251300001100264490000800275520192400283653000902207653002802216653001102244653002102255653001802276653001102294653000902305653001302314653002402327653001702351100001902368700002202387700002402409700002002433700002202453700002302475700002502498700002002523700002302543700002102566856003502587 2007 eng d a1097-674400aLong-term costs and resource use in elderly participants with congestive heart failure in the Cardiovascular Health Study.0 aLongterm costs and resource use in elderly participants with con c2007 Feb a245-520 v1533 aBACKGROUND: Although heart failure (HF) afflicts nearly 5 million Americans, the long-term cost of HF care has not been described previously. In a prospective, longitudinal cohort of community-dwelling elderly from 4 regions, we examined the long-term costs and resource use of elderly patients with HF.
METHODS: We linked 4860 elderly participants in the National Heart, Lung, and Blood Institute Cardiovascular Health Study to Medicare part A and part B claims from 1992 to 2003. Costs were calculated from Medicare payments and discounted at 3% annually. We applied nonparametric estimators to calculate mean costs and resource use per patient for a 10-year period. To describe the relationship between patient characteristics and long-term costs, we constructed censoring-adjusted regression models.
RESULTS: There were 343 participants (84.8% white; 50.1% men; mean age, 78.2 years) with prevalent HF and 4517 participants without HF at study entry. Mean follow-up was 6.7 years (median, 6.4 years). The 10-year survival rates were 33% and 63% for the prevalent HF and nonprevalent HF groups (P < .001), respectively. The mean 10-year medical costs were significantly higher for the prevalent HF cohort (54,704 dollars vs 41 dollars,780, P < .001). The higher costs associated with HF were also reflected in greater resource use with more hospitalizations (P < .05) and more intensive care unit days (P < .05). Participants with HF had more physician visits (P < .05), with most of these encounters involving noncardiology physicians. However, in multivariate models, prevalent HF was not an independent predictor of higher costs.
CONCLUSION: Patients with HF consume substantially more health care resources than their elderly peers, and these higher costs persist through 10 years of follow-up. Many of these costs may be related to other comorbid conditions.
10aAged10aCosts and Cost Analysis10aFemale10aHealth Resources10aHeart Failure10aHumans10aMale10aMedicare10aProspective Studies10aTime Factors1 aLiao, Lawrence1 aAnstrom, Kevin, J1 aGottdiener, John, S1 aPappas, Paul, A1 aWhellan, David, J1 aKitzman, Dalane, W1 aAurigemma, Gerard, P1 aMark, Daniel, B1 aSchulman, Kevin, A1 aJollis, James, G uhttps://chs-nhlbi.org/node/93801432nas a2200361 4500008004100000022001400041245008100055210006900136260001600205300001100221490000700232520043800239653003100677653000900708653002200717653002400739653001900763653002700782653002400809653001100833653001100844653003100855653000900886653001900895653001800914100001900932700001500951700001700966700001900983700001601002700001701018856003501035 2007 eng d a1526-632X00aPhysical activity and white matter lesion progression: assessment using MRI.0 aPhysical activity and white matter lesion progression assessment c2007 Apr 10 a1223-60 v683 aWe evaluated the association between physical activity and changes in white matter lesions (WMLs) on MRI in a sample of 179 older adults comprising 59 incident cases of Alzheimer disease, 60 persons with mild cognitive impairment, and 60 persons who remained cognitively stable over a median 5-year follow-up. Physical activity was not significantly associated with a decreased rate of periventricular or deep WML progression.
10aActivities of Daily Living10aAged10aAlzheimer Disease10aCognition Disorders10aCohort Studies10aDemyelinating Diseases10aDisease Progression10aFemale10aHumans10aMagnetic Resonance Imaging10aMale10aMotor Activity10aUnited States1 aPodewils, L, J1 aGuallar, E1 aBeauchamp, N1 aLyketsos, C, G1 aKuller, L H1 aScheltens, P uhttps://chs-nhlbi.org/node/95402586nas a2200421 4500008004100000022001400041245011700055210006900172260001300241300001000254490000700264520139000271653000901661653002201670653001001692653002101702653002001723653002301743653002801766653002501794653001101819653001101830653001701841653002101858653000901879653002601888653001201914653001501926653003201941653001701973653003001990100002502020700002102045700002102066700002202087700002002109856003502129 2007 eng d a1524-463600aSerum amyloid P and cardiovascular disease in older men and women: results from the Cardiovascular Health Study.0 aSerum amyloid P and cardiovascular disease in older men and wome c2007 Feb a352-80 v273 aOBJECTIVE: Serum amyloid P (SAP), a pentraxin like C-reactive protein (CRP), functions in innate immunity. However, associations of SAP with cardiovascular disease (CVD) are unknown.
METHODS AND RESULTS: We examined these associations in the Cardiovascular Health Study using a case-cohort design. Nonexclusive case groups were incident angina (n=523), myocardial infarction (MI; n=308), stroke (n=323), and CVD death (n=288). 786 participants had no events. SAP was correlated with CRP, CVD risk factors (obesity, blood pressure, lipids), common and internal carotid wall thickness, and ankle-brachial index (all P<0.02). In Cox regression models adjusted for age, sex, and ethnicity, a standard deviation increase in SAP (9.8 mg/L) was associated with angina (hazard ratio; 95% confidence interval 1.3; 1.2 to 1.5) and MI (1.3; 1.1 to 1.5), but not stroke (1.1; 0.9 to 1.3) or CVD death (1.1; 0.9 to 1.3). Adding CRP to the models had no significant effect on associations. Adjusting for CVD risk factors slightly attenuated SAP associations with CVD events; however, associations with angina and MI remained significant.
CONCLUSIONS: Although both are pentraxins, SAP and CRP may represent different facets of inflammation. The association of SAP with CVD in these older adults further supports the role of innate immunity in atherosclerosis.
10aAged10aAged, 80 and over10aAging10aAngina, Unstable10aAtherosclerosis10aC-Reactive Protein10aCardiovascular Diseases10aCase-Control Studies10aFemale10aHumans10aHypertension10aImmunity, Innate10aMale10aMyocardial Infarction10aObesity10aPrevalence10aProportional Hazards Models10aRisk Factors10aSerum Amyloid P-Component1 aJenny, Nancy, Swords1 aArnold, Alice, M1 aKuller, Lewis, H1 aTracy, Russell, P1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/93002445nas a2200397 4500008004100000022001400041245011400055210006900169260001600238300001000254490000800264520131600272653000901588653002101597653001101618653002201629653001901651653001101670653003001681653000901711653001501720653002401735653001701759653003101776653001701807653001801824100002401842700002201866700001801888700002101906700002001927700001801947700002301965700002401988856003502012 2008 eng d a1476-625600aAlcohol consumption and lower extremity arterial disease among older adults: the cardiovascular health study.0 aAlcohol consumption and lower extremity arterial disease among o c2008 Jan 01 a34-410 v1673 aFew studies of the relation of alcohol intake to lower-extremity arterial disease (LEAD) have included clinical events and objective measurements repeated longitudinally. As part of the Cardiovascular Health Study, a study of older adults from four US communities, 5,635 participants reported their use of beer, wine, and spirits yearly. Incident LEAD was identified by hospitalization surveillance. Technicians measured ankle-brachial index 6 years apart in 2,298 participants. A total of 172 cases of LEAD were documented during a mean of 7.5 years of follow-up between 1989 and 1999. Compared with abstention, the multivariable-adjusted hazard ratios were 1.10 (95% confidence interval (CI): 0.71, 1.71) for <1 alcoholic drink per week, 0.56 (95% CI: 0.33, 0.95) for 1-13 drinks per week, and 1.02 (95% CI: 0.53, 1.97) for > or =14 drinks per week (p for quadratic trend = 0.04). These relations were consistent within strata of sex, age, and apolipoprotein E genotype, and neither lipids nor inflammatory markers appeared to be important intermediates. Change in ankle-brachial index showed a similar relation (p for quadratic trend = 0.01). Alcohol consumption of 1-13 drinks per week in older adults may be associated with lower risk of LEAD, but heavier drinking is not associated with lower risk.
10aAged10aAlcohol Drinking10aFemale10aFollow-Up Studies10aHealth Surveys10aHumans10aIntermittent Claudication10aMale10aPrevalence10aProspective Studies10aRisk Factors10aSurveys and Questionnaires10aTime Factors10aUnited States1 aMukamal, Kenneth, J1 aKennedy, Margaret1 aCushman, Mary1 aKuller, Lewis, H1 aNewman, Anne, B1 aPolak, Joseph1 aCriqui, Michael, H1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/99405258nas a2200985 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520269500286653001002981653001602991653000903007653002203016653001003038653002003048653001903068653002003087653002803107653001903135653002503154653001103179653001803190653001103208653000903219653001603228653001503244653003003259653002003289653001703309653003003326110003903356700001903395700001703414700001503431700001603446700001403462700002003476700001703496700001703513700001503530700001603545700001903561700001703580700001703597700001503614700002203629700001903651700001403670700001603684700002103700700001903721700001703740700001603757700001503773700001703788700002103805700001703826700001703843700001603860700001503876700002203891700001603913700002003929700001903949700001503968700002103983700001304004700001504017700001804032700002104050700001904071700001404090700001704104700001704121700001404138700001604152700001404168700001804182700001604200700002004216856003604236 2008 eng d a1538-359800aAnkle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.0 aAnkle brachial index combined with Framingham Risk Score to pred c2008 Jul 09 a197-2080 v3003 aCONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction.
OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction.
DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.
STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality.
DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease.
RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women.
CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.
10aAdult10aAge Factors10aAged10aAged, 80 and over10aAnkle10aAtherosclerosis10aBlood Pressure10aBrachial Artery10aCardiovascular Diseases10aCohort Studies10aConfidence Intervals10aFemale10aGlobal Health10aHumans10aMale10aMiddle Aged10aOdds Ratio10aPredictive Value of Tests10aRisk Assessment10aRisk Factors10aSeverity of Illness Index1 aAnkle Brachial Index Collaboration1 aFowkes, F, G R1 aMurray, G, D1 aButcher, I1 aHeald, C, L1 aLee, R, J1 aChambless, L, E1 aFolsom, A, R1 aHirsch, A, T1 aDramaix, M1 adeBacker, G1 aWautrecht, J-C1 aKornitzer, M1 aNewman, A, B1 aCushman, M1 aSutton-Tyrrell, K1 aFowkes, F, G R1 aLee, A, J1 aPrice, J, F1 aD'Agostino, R, B1 aMurabito, J, M1 aNorman, P, E1 aJamrozik, K1 aCurb, J, D1 aMasaki, K, H1 aRodríguez, B, L1 aDekker, J, M1 aBouter, L, M1 aHeine, R, J1 aNijpels, G1 aStehouwer, C, D A1 aFerrucci, L1 aMcDermott, M, M1 aStoffers, H, E1 aHooi, J, D1 aKnottnerus, J, A1 aOgren, M1 aHedblad, B1 aWitteman, J C1 aBreteler, M, M B1 aHunink, M, G M1 aHofman, A1 aCriqui, M, H1 aLanger, R, D1 aFronek, A1 aHiatt, W, R1 aHamman, R1 aResnick, H, E1 aGuralnik, J1 aMcDermott, M, M uhttps://chs-nhlbi.org/node/103902878nas a2200517 4500008004100000022001400041245010500055210006900160260001300229300001000242490000700252520134800259653002201607653000901629653002201638653002101660653004001681653001101721653003801732653001101770653002501781653000901806653002601815653005301841653003601894653003201930653001801962100001801980700002201998700001902020700002402039700001902063700002302082700001902105700001802124700002002142700001702162700002302179700002002202700001802222700002202240700002202262700002102284700002002305856003502325 2008 eng d a1524-463600aAssociation of gene variants with incident myocardial infarction in the Cardiovascular Health Study.0 aAssociation of gene variants with incident myocardial infarction c2008 Jan a173-90 v283 aOBJECTIVE: We asked whether single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population-based prospective study of 4522 individuals aged 65 or older.
METHODS AND RESULTS: Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74 SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS). The prespecified risk alleles of 8 SNPs were nominally associated (1-sided P<0.05) with increased risk of MI in White CHS participants. The false discovery rate for these 8 was 0.43, suggesting that about 4 of these 8 are likely to be true positives. The 4 of these 8 SNPs that had the strongest evidence for association with cardiovascular disease before testing in CHS (association in 3 antecedent studies) were in KIF6 (CHS HR=1.29; 90%CI 1.1 to 1.52), VAMP8 (HR=1.2; 90%CI 1.02 to 1.41), TAS2R50 (HR=1.13; 90%CI 1 to 1.27), and LPA (HR=1.62; 90%CI 1.09 to 2.42).
CONCLUSIONS: Although most of the SNPs investigated were not associated with MI in CHS, evidence from this investigation combined with previous studies suggests that 4 of these SNPs are likely associated with MI.
10aAfrican Americans10aAged10aAged, 80 and over10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aHumans10aLongitudinal Studies10aMale10aMyocardial Infarction10aNational Heart, Lung, and Blood Institute (U.S.)10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aUnited States1 aShiffman, Dov1 aO'Meara, Ellen, S1 aBare, Lance, A1 aRowland, Charles, M1 aLouie, Judy, Z1 aArellano, Andre, R1 aLumley, Thomas1 aRice, Kenneth1 aIakoubova, Olga1 aLuke, May, M1 aYoung, Bradford, A1 aMalloy, Mary, J1 aKane, John, P1 aEllis, Stephen, G1 aTracy, Russell, P1 aDevlin, James, J1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/99502936nas a2200409 4500008004100000022001400041245011500055210006900170260001300239300001100252490000700263520173600270653003902006653000902045653001502054653002102069653002302090653001902113653004002132653001102172653001502183653001102198653001702209653001802226653003102244653000902275653003602284100002002320700001702340700002202357700002002379700002502399700002402424700002202448700002002470856003602490 2008 eng d a1524-462800aBiomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study.0 aBiomarkers of Inflammation and MRIDefined Small Vessel Disease o c2008 Jul a1952-90 v393 aBACKGROUND AND PURPOSE: To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study.
METHODS: Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (n=532) and Whites (n=2905).
RESULTS: Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the -174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: [1.02; 1.28]). The common haplotype tagged by the -572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race.
CONCLUSIONS: This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.
10aAfrican Continental Ancestry Group10aAged10aBiomarkers10aBrain Infarction10aC-Reactive Protein10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aHaplotypes10aHumans10aInflammation10aInterleukin-610aMagnetic Resonance Imaging10aMale10aPolymorphism, Single Nucleotide1 aFornage, Myriam1 aChiang, Aron1 aO'Meara, Ellen, S1 aPsaty, Bruce, M1 aReiner, Alexander, P1 aSiscovick, David, S1 aTracy, Russell, P1 aLongstreth, W T uhttps://chs-nhlbi.org/node/102703258nas a2200421 4500008004100000022001400041245016200055210006900217260001300286300001100299490000800310520205700318653000902375653002202384653001602406653001502422653001902437653002102456653002802477653001102505653001902516653001102535653000902546653003002555653000902585100001602594700001902610700002102629700001802650700002002668700001802688700002302706700001602729700001802745700002002763700001802783856003502801 2008 eng d a1879-148400aCardiovascular and mortality risk prediction and stratification using urinary albumin excretion in older adults ages 68-102: the Cardiovascular Health Study.0 aCardiovascular and mortality risk prediction and stratification c2008 Apr a806-130 v1973 aBACKGROUND: Elevated urinary albumin excretion (UAE) is associated with the risk of cardiovascular disease (CVD) and all-cause mortality. We tested the hypothesis that elevated UAE improves cardiovascular risk stratification in an elderly cohort aged 68-102 years.
METHODS: We evaluated UAE in 3112 participants of the Cardiovascular Health Study who attended the 1996-1997 examination and had median follow up of 5.4 years. Elevated UAE was defined as urinary albumin to creatinine ratio > or =30 microg/mg. Microalbuminuria and macroalbuminuria were defined as urinary albumin to creatinine ratio 30-300 microg/mg and >300 microg/mg, respectively. Outcomes included CVD (myocardial infarction, stroke, cardiovascular death) and all-cause mortality. Cox proportional hazards models were used to assess the risk of outcomes associated with elevated UAE.
RESULTS: The prevalence of elevated UAE was 14.3%, 17.1% and 26.9% in those aged 68-74, 75-84 and 85-102 years, respectively. CVD incidence and all-cause mortality were doubled (7.2% and 8.1% per year) in those with microalbuminuria and tripled (11.1% and 12.3% per year) in those with macroalbuminuria compared to those with normal UAE (3.3% and 3.8% per year). The increased CVD and mortality risks were observed in all age groups after adjustment for conventional risk factors. The adjusted population attributable risk percent of CVD and all-cause mortality for elevated UAE was 11% and 12%, respectively. When participants were cross-classified by UAE and Framingham Risk Score categories, the 5-year cumulative incidence of coronary heart disease among participants with elevated UAE and a 5-year predicted risk of 5-10% was 20%, substantially higher than 6.3% in those with UAE <30m microg/mg.
CONCLUSION: Elevated UAE was associated with an increased risk of CVD and all-cause mortality in all age groups from 68 to 102 years. Combining elevated UAE with the Framingham risk scores may improve risk stratification for CVD in the elderly.
10aAged10aAged, 80 and over10aAlbuminuria10aBiomarkers10aCohort Studies10aCoronary Disease10aCross-Sectional Studies10aFemale10aHealth Surveys10aHumans10aMale10aPredictive Value of Tests10aRisk1 aCao, Jie, J1 aBiggs, Mary, L1 aBarzilay, Joshua1 aKonen, Joseph1 aPsaty, Bruce, M1 aKuller, Lewis1 aBleyer, Anthony, J1 aOlson, Jean1 aWexler, Jason1 aSummerson, John1 aCushman, Mary uhttps://chs-nhlbi.org/node/98302746nas a2200373 4500008004100000022001400041245011500055210006900170260001300239300001000252490000600262520167500268653002401943653000901967653002801976653001102004653002202015653001102037653000902048653002402057653001702081100002402098700003202122700002402154700002002178700001602198700002102214700002102235700001902256700002002275700002002295700002102315856003602336 2008 eng d a1555-905X00aCardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study.0 aCardiovascular risk factors and incident acute renal failure in c2008 Mar a450-60 v33 aBACKGROUND AND OBJECTIVES: Although the elderly are at increased risk for acute renal failure, few prospective studies have identified risk factors for acute renal failure in the elderly.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The associations of cardiovascular disease risk factors, subclinical cardiovascular disease, and clinical coronary heart disease with the risk for development of acute renal failure were examined in older adults in the Cardiovascular Health Study, a prospective cohort study of community-dwelling older adults. Incident hospitalized cases of acute renal failure were identified through hospital discharge International Classification of Diseases, Ninth Revision codes and confirmed through physician diagnoses of acute renal failure in discharge summaries.
RESULTS: Acute renal failure developed in 225 (3.9%) of the 5731 patients during a median follow-up period of 10.2 yr. In multivariate analyses, diabetes, current smoking, hypertension, C-reactive protein, and fibrinogen were associated with acute renal failure. Prevalent coronary heart disease was associated with incident acute renal failure, and among patients without prevalent coronary heart disease, subclinical vascular disease measures were also associated with acute renal failure: Low ankle-arm index (< or =0.9), common carotid intima-media thickness, and internal carotid intima-media thickness.
CONCLUSIONS: In this large, population-based, prospective cohort study, cardiovascular risk factors and both subclinical and clinical vascular disease were associated with incident acute renal failure in the elderly.
10aAcute Kidney Injury10aAged10aCardiovascular Diseases10aFemale10aFollow-Up Studies10aHumans10aMale10aProspective Studies10aRisk Factors1 aMittalhenkle, Anuja1 aStehman-Breen, Catherine, O1 aShlipak, Michael, G1 aFried, Linda, F1 aKatz, Ronit1 aYoung, Bessie, A1 aSeliger, Stephen1 aGillen, Daniel1 aNewman, Anne, B1 aPsaty, Bruce, M1 aSiscovick, David uhttps://chs-nhlbi.org/node/101502806nas a2200493 4500008004100000022001400041245014000055210006900195260001300264300001100277490000800288520137300296653002201669653000901691653002301700653002801723653001901751653001901770653001101789653003801800653001501838653001101853653001801864653001401882653000901896653003601905653003201941653001801973100002301991700002102014700002102035700001702056700002002073700002002093700001402113700001402127700002502141700002402166700002002190700002202210700002002232700002502252856003502277 2008 eng d a1879-148400aCommon variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study.0 aCommon variants in the CRP gene in relation to longevity and cau c2008 Apr a922-300 v1973 aCommon polymorphisms in the CRP gene are associated with plasma CRP levels in population-based studies, but associations with age-related events are uncertain. A previous study of CRP haplotypes in older adults was broadened to include longevity and cause-specific mortality (all-cause, noncardiovascular (non-CV), and cardiovascular (CV)). Common haplotypes were inferred from four tagSNPs in 4512 whites and five tagSNPs in 812 blacks from the Cardiovascular Health Study, a longitudinal cohort of adults over age 65. Exploratory analyses addressed early versus late mortality. CRP haplotypes were not associated with all-cause mortality or longevity overall in either population, but associations with all-cause mortality differed during early and late periods. In blacks, the haplotype tagged by 3872A (rs1205) was associated with increased risk of non-CV mortality, relative to other haplotypes (adjusted hazard ratio for each additional copy: 1.42, 95% CI: 1.07, 1.87). Relative to other haplotypes, this haplotype was associated with decreased risk of early but not decreased risk of late CV mortality in blacks; among whites, a haplotype tagged by 2667C (rs1800947) gave similar but nonsignificant findings. If confirmed, CRP genetic variants may be weakly associated with CV and non-CV mortality in older adults, particularly in self-identified blacks.
10aAfrican Americans10aAged10aC-Reactive Protein10aCardiovascular Diseases10aCause of Death10aCohort Studies10aFemale10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aLinear Models10aLongevity10aMale10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aUnited States1 aHindorff, Lucia, A1 aRice, Kenneth, M1 aLange, Leslie, A1 aDiehr, Paula1 aHalder, Indrani1 aWalston, Jeremy1 aKwok, Pui1 aZiv, Elad1 aNievergelt, Caroline1 aCummings, Steven, R1 aNewman, Anne, B1 aTracy, Russell, P1 aPsaty, Bruce, M1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/98602801nas a2200505 4500008004100000022001400041245008500055210006900140260001300209300001000222490000700232520138800239653000901627653002201636653001501658653001901673653002501692653001501717653001401732653002101746653001101767653002901778653002801807653001101835653002501846653000901871653003001880653001601910653003201926653002001958653003201978653001802010653002202028100001802050700001602068700002202084700002002106700002002126700002402146700001702170700002402187700002402211700002402235856003602259 2008 eng d a1532-841400aCystatin C concentration as a predictor of systolic and diastolic heart failure.0 aCystatin C concentration as a predictor of systolic and diastoli c2008 Feb a19-260 v143 aBACKGROUND: Risk factors for heart failure (HF) may differ according to ejection fraction (EF). Higher cystatin C, a marker of kidney dysfunction, is associated with incident HF, but previous studies did not determine EF at diagnosis. We hypothesized that kidney dysfunction would predict diastolic HF (DHF) better than systolic HF (SHF) in the Cardiovascular Health Study.
METHODS AND RESULTS: Cystatin C was measured in 4453 participants without HF at baseline. Incident HF was categorized as DHF (EF > or = 50%) or SHF (EF < 50%). We compared the association of cystatin C with the risk for DHF and SHF, after adjustment for age, sex, race, medications, and HF risk factors. During 8 years of follow-up, 167 participants developed DHF and 206 participants developed SHF. After adjustment, sequentially higher quartiles of cystatin C were associated with risk for SHF (competing risks hazard ratios 1.0 [reference], 1.99 [95% confidence interval 1.14-3.48], 2.32 [1.32-4.07], 3.17 [1.82-5.50], P for trend < .001). The risk for DHF was apparent only at the highest cystatin C quartile (hazard ratios 1.0 [reference], 1.09 [0.62-1.89], 1.08 [0.61-1.93], and 1.83 [1.07-3.11]).
CONCLUSIONS: Cystatin C levels are linearly associated with the incidence of systolic HF, whereas only the highest concentrations of cystatin C predict diastolic HF.
10aAged10aAged, 80 and over10aBiomarkers10aCohort Studies10aConfidence Intervals10aCystatin C10aCystatins10aEchocardiography10aFemale10aHeart Failure, Diastolic10aHeart Failure, Systolic10aHumans10aLongitudinal Studies10aMale10aPredictive Value of Tests10aProbability10aProportional Hazards Models10aRisk Assessment10aSensitivity and Specificity10aStroke Volume10aSurvival Analysis1 aMoran, Andrew1 aKatz, Ronit1 aSmith, Nicolas, L1 aFried, Linda, F1 aSarnak, Mark, J1 aSeliger, Stephen, L1 aPsaty, Bruce1 aSiscovick, David, S1 aGottdiener, John, S1 aShlipak, Michael, G uhttps://chs-nhlbi.org/node/101203226nas a2200385 4500008004100000022001400041245009300055210006900148260001600217300001100233490000800244520217800252653000902430653002202439653001202461653002802473653001902501653002802520653002402548653002502572653001102597653001102608653001502619653001102634653000902645653001702654653001202671653000902683653001802692100002502710700002202735700002302757700002402780856003602804 2008 eng d a1524-453900aDietary fish and omega-3 fatty acid consumption and heart rate variability in US adults.0 aDietary fish and omega3 fatty acid consumption and heart rate va c2008 Mar 04 a1130-70 v1173 aBACKGROUND: Fish and omega-3 fatty acid consumption reduce risk of cardiac death, but mechanisms are not well established. Heart rate variability (HRV) predicts cardiac death and reflects specific electrophysiological pathways and influences. We hypothesized that habitual consumption of fish and marine omega-3 fatty acids would be associated with more favorable HRV, elucidating electrophysiological influences and supporting effects on clinical risk.
METHODS AND RESULTS: In a population-based cohort of older US adults, we evaluated cross-sectional associations of usual dietary fish and omega-3 consumption during the prior year and ECG-derived (n=4263) and 24-hour Holter monitor-derived (n=1152) HRV. After multivariable adjustment, consumption of tuna or other broiled/baked fish was associated with specific HRV components, including indices suggesting greater vagal predominance and moderated baroreceptor responses (eg, higher root mean square successive differences of normal-to-normal intervals [P=0.001]; higher normalized high-frequency power [P=0.008]; and lower low-frequency/high-frequency ratio [P=0.03]) and less erratic sinoatrial node firing (eg, lower Poincaré ratio [P=0.02] and higher short-term fractal scaling exponent [P=0.005]) but not measures of circadian fluctuations (eg, 24-hour standard deviation of normal-to-normal intervals). Findings were similar for estimated dietary consumption of marine omega-3 fatty acids. For magnitudes of observed differences in HRV comparing the highest to lowest category of fish intake, differences in relative risk of cardiac death during 10.8 years of follow-up ranged from 1.1% (for difference in standard deviation of normal-to-normal intervals) to 5.9% and 8.4% (for differences in Poincaré ratio and short-term fractal scaling exponent) lower risk.
CONCLUSIONS: Habitual tuna/other fish and marine omega-3 consumption are associated with specific HRV components in older adults, particularly indices of vagal activity, baroreceptor responses, and sinoatrial node function. Cellular mechanisms and implications for clinical risk deserve further investigation.
10aAged10aAged, 80 and over10aAnimals10aCardiovascular Diseases10aCohort Studies10aCross-Sectional Studies10aElectrocardiography10aFatty Acids, Omega-310aFemale10aFishes10aHeart Rate10aHumans10aMale10aRisk Factors10aSeafood10aTuna10aUnited States1 aMozaffarian, Dariush1 aStein, Phyllis, K1 aPrineas, Ronald, J1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/102003297nas a2200469 4500008004100000022001400041245013000055210006900185260001300254300001000267490000700277520190900284653005102193653000902244653002002253653002002273653002402293653002802317653002102345653002102366653001902387653002802406653002402434653001102458653001802469653001102487653003402498653002102532653000902553653002102562653002402583653001702607653002402624653001802648100002102666700002402687700001702711700001802728700002502746700002002771856003602791 2008 eng d a1532-541500aDistribution and correlates of lipoprotein-associated phospholipase A2 in an elderly cohort: the Cardiovascular Health Study.0 aDistribution and correlates of lipoproteinassociated phospholipa c2008 May a792-90 v563 aOBJECTIVES: To determine whether high levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with prevalent cardiovascular disease (CVD) and to evaluate factors most influencing Lp-PLA(2) levels in a community-based cohort of older adults.
DESIGN: Cross-sectional.
SETTING: The Cardiovascular Health Study (CHS), a population-based cohort study of men and women aged 65 and older.
PARTICIPANTS: Five thousand five hundred thirty-one CHS participants.
MEASUREMENTS: Levels of Lp-PLA(2) activity were determined using stored blood samples from the baseline examination.
RESULTS: Mean Lp-PLA(2) was higher in participants with electrocardiographically determined ventricular conduction defect and major Q-wave abnormality and was positively correlated with left ventricular (LV) mass. It was high in those with echocardiographically determined abnormal LV ejection fraction, which persisted after adjustment. Mean Lp-PLA(2) was also higher in participants with mild renal insufficiency and kidney disease. After multivariable adjustment, there was a modest but significant 27% greater risk of prevalent CHF per standard deviation increment of Lp-PLA(2) and a modest but significant 12% greater risk of prevalent myocardial infarction. Lp-PLA(2) was weakly but mainly most strongly correlated with cholesterol and lipoproteins, but those correlations were not especially strong. Lp-PLA(2) was weakly positively correlated with soluble intercellular adhesion molecule-1 but not interleukin-6. In total, all factors considered could explain only 29% of Lp-PLA(2) activity.
CONCLUSION: Novel findings in the study are the associations, in those aged 65 and older, between Lp-PLA(2) activity and LV dysfunction, CHF, and renal disease. CVD risk factors only minimally explain levels of Lp-PLA(2).
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aAtherosclerosis10aBody Mass Index10aCardiac Output, Low10aCardiovascular Diseases10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aCross-Sectional Studies10aElectrocardiography10aFemale10aHeart Failure10aHumans10aHypertrophy, Left Ventricular10aLong QT Syndrome10aMale10aReference Values10aRenal Insufficiency10aRisk Factors10aStatistics as Topic10aTriglycerides1 aFurberg, Curt, D1 aNelson, Jeanenne, J1 aSolomon, Cam1 aCushman, Mary1 aJenny, Nancy, Swords1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/102202839nas a2200469 4500008004100000022001400041245014000055210006900195260001300264300001000277490000700287520146600294653002201760653001601782653000901798653002201807653002201829653001401851653001901865653002501884653002301909653003001932653004001962653001102002653001302013653001102026653002502037653000902062653002902071653003202100653002402132653001702156653001602173100001702189700002802206700002002234700002102254700001602275700002002291700002202311856003602333 2008 eng d a0003-994200aEnhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study.0 aEnhanced risk for Alzheimer disease in persons with type 2 diabe c2008 Jan a89-930 v653 aBACKGROUND: Diabetes and the apolipoprotein E epsilon4 allele (APOE epsilon4) increase the risk for Alzheimer disease (AD). We hypothesize that APOE epsilon4 may modify the risk for AD in individuals with diabetes.
OBJECTIVE: To examine the joint effect of type 2 diabetes and APOE epsilon4 on the risk of AD, AD with vascular dementia (mixed AD), and vascular dementia without AD.
DESIGN: The Cardiovascular Health Study (CHS) Cognition Study (1992-2000) is a prospective study designed to identify all existing and new cases of dementia among study participants. Diagnoses were made according to international criteria for dementia and subtypes. There were 2547 dementia-free participants in the CHS Cognition Study cohort with complete information on APOE epsilon4 and type 2 diabetes status; among these, 411 new cases of dementia developed. Risk of dementia was estimated with a Cox proportional hazard model adjusted for age and other demographic and cardiovascular risk factors.
RESULTS: Compared with those who had neither type 2 diabetes nor APOE epsilon4, those with both factors had a significantly higher risk of AD (hazard ratio, 4.58; 95% confidence interval, 2.18-9.65) and mixed AD (hazard ratio, 3.89; 95% confidence interval, 1.46-10.40).
CONCLUSION: These data suggest that having both diabetes and APOE epsilon4 increases the risk of dementia, especially for AD and mixed AD.
10aAfrican Americans10aAge Factors10aAged10aAlzheimer Disease10aApolipoprotein E410aCognition10aCohort Studies10aConfidence Intervals10aDementia, Vascular10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGenotype10aHumans10aLongitudinal Studies10aMale10aNeuropsychological Tests10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSex Factors1 aIrie, Fumiko1 aFitzpatrick, Annette, L1 aLopez, Oscar, L1 aKuller, Lewis, H1 aPeila, Rita1 aNewman, Anne, B1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/100903455nas a2200421 4500008004100000022001400041245010600055210006900161260001300230300001200243490000700255520228800262653000902550653001802559653002002577653001902597653002802616653003002644653001202674653001102686653001102697653000902708653001602717653001502733653001102748653001902759653002002778653002102798653002902819100002602848700002102874700001702895700002402912700002102936700001702957700002302974856003602997 2008 eng d a0161-810500aFasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation.0 aFasting glycemia in sleep disordered breathing lowering the thre c2008 Jul a1018-240 v313 aSTUDY OBJECTIVES: Commonly used definitions of sleep-disordered breathing (SDB) are based on identifying discrete events of breathing abnormalities during sleep that are accompanied by an oxyhemoglobin desaturation (delta SaO2) of at least 4%. However, it is not known whether disordered breathing events with oxyhemoglobin desaturation less than 4% are associated with clinical sequelae such as abnormalities in fasting glycemia.
DESIGN: Cross-sectional study.
SUBJECTS AND SETTING: Participants from the Sleep Heart Health Study (SHHS) with a fasting glucose measurement made within a year of the baseline polysomnogram.
MEASUREMENTS AND RESULTS: SDB severity was defined using the apnea-hypopnea index (AHI) and the hypopnea index (HI) by counting events with different levels of oxyhemoglobin desaturation (0.0%-1.9%, 2.0%-2.9%, 3.0%-3.9%, > or = 4.0%). Fasting glucose levels were used to classify individuals into normal (<100 mg/dL), impaired (100-125 mg/dL), and diabetic (> or = 126 mg/dL) groups. Ordinal logistic regression was used to determine the adjusted relative odds of an abnormal glucose value across quartiles of the hypopnea index, independent of factors such as age, body mass index, waist circumference, and usual sleep duration. The prevalence of impaired and diabetic fasting glucose in the analytical sample was 32.9% and 5.8%, respectively. The covariate-adjusted relative odds of impaired or diabetic fasting glucose in the highest versus the lowest AHI quartile was 1.35 (95% CI: 1.04-1.76) for events with a delta SaO2 > or = 4.0%, 1.72 (95% CI: 1.20-2.48) for events with a delta SaO2 between 3.0%-3.9%, 1.41 (95% CI: 1.07-1.86) for events with a delta SaO2 between 2.0%-2.9%, and 1.07 (95% CI: 0.84-1.37) for events with a delta SaO2 between 0.0%-1.9%. The corresponding odds ratios for the HI were 1.47 (95% CI: 1.13-1.92), 2.25 (95% CI: 1.59-3.19), 1.44 (95% CI: 1.09-1.90), and 1.15 (95% CI: 0.90-1.47), respectively.
CONCLUSIONS: The results of this study indicate that SDB events accompanied by oxyhemoglobin desaturation of between 2% to 4% are associated with fasting hyperglycemia. These findings suggest that milder degrees of SDB may predispose to adverse metabolic outcomes.
10aAged10aBlood Glucose10aBody Mass Index10aCohort Studies10aCross-Sectional Studies10aDiabetes Mellitus, Type 210aFasting10aFemale10aHumans10aMale10aMiddle Aged10aOdds Ratio10aOxygen10aOxyhemoglobins10aPolysomnography10aReference Values10aSleep Apnea, Obstructive1 aStamatakis, Katherine1 aSanders, Mark, H1 aCaffo, Brian1 aResnick, Helaine, E1 aGottlieb, Dan, J1 aMehra, Reena1 aPunjabi, Naresh, M uhttps://chs-nhlbi.org/node/104303025nas a2200397 4500008004100000022001400041245011800055210006900173260001300242300001200255490000800267520183100275653000902106653002202115653001102137653001802148653001102166653001402177653004902191653004902240653003302289653000902322653003002331653002402361653001702385100002202402700002202424700002302446700001802469700002502487700002102512700002102533700001702554700002002571856003602591 2008 eng d a1097-674400aHigh insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly.0 aHigh insulinlike growth factor binding protein 1 level predicts c2008 Jun a1006-120 v1553 aBACKGROUND: Low levels of insulinlike growth factor 1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulinlike growth factor binding protein 1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in patients with CHF and has been associated prospectively with increased mortality among older adults and survivors of myocardial infarction. We investigated the association between fasting plasma levels of IGF-I, IGFBP-1, IGFBP-3, and insulin and risk of incident CHF in the prospective Cardiovascular Health Study.
METHODS: From among 5,888 adults 65 years old and older in the Cardiovascular Health Study, we studied 566 incident CHF cases and 1,072 comparison subjects after exclusion of underweight individuals (body mass index <18.5 kg/m(2)) and insulin users. Hazard ratios (HRs) with 95% CIs for CHF were estimated after adjustment for age, race, sex, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and body mass index.
RESULTS: High baseline IGFBP-1 level was a significant predictor of CHF, independent of established CHF risk factors and inflammation markers. The HR per SD of IGFBP-1 was 1.22 (95% CI 1.07-1.39, P < .01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95% CI 0.96-1.74, P = .09) for the second IGFBP-1 tertile and 1.47 (95% CI 1.06-2.04; P = .02) for the highest IGFBP-1 tertile (tertile cut points 19.5 and 35.8 ng/mL). Total IGF-I, IGFBP-3, or insulin levels had no association with CHF after adjustment for CHF risk factors.
CONCLUSIONS: High circulating IGFBP-1 level may be a CHF risk factor among older adults.
10aAged10aAged, 80 and over10aFemale10aHeart Failure10aHumans10aIncidence10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aPredictive Value of Tests10aProspective Studies10aRisk Factors1 aKaplan, Robert, C1 aMcGinn, Aileen, P1 aPollak, Michael, N1 aKuller, Lewis1 aStrickler, Howard, D1 aRohan, Thomas, E1 aCappola, Anne, R1 aXue, XiaoNan1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/103502753nas a2200421 4500008004100000022001400041245010100055210006900156260001300225300001100238490000700249520154500256653000901801653002201810653001901832653002801851653001101879653002401890653001101914653001701925653004801942653000901990653002401999653001702023100002602040700002202066700002502088700002102113700002002134700002102154700001802175700001702193700002002210700002402230700002002254700002202274856003502296 2008 eng d a1096-637400aInsulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults.0 aInsulinlike growth factorIGFaxis inflammation and glucose intole c2008 Apr a166-730 v183 aIncreasing evidence suggests that the insulin-like growth factor (IGF)-axis may play a role in glucose metabolism and may also be associated with systemic inflammation. The aim of this study was to evaluate the association of insulin-like growth factor-1 (IGF-I) and its binding proteins, IGFBP-1 and IGFBP-3, with glucose intolerance and inflammation among older adults. We conducted a cross-sectional analysis in a in a random subsample (n=922) of the Cardiovascular Health Study (CHS), a prospective cohort of men and women > or = 65 years. Mean IGFBP-1 levels were significantly lower in older adults with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes compared to those with normal fasting and post-load glucose. High IGFBP-1 was associated with a reduced prevalence of IGT and IFG; the multivariable OR between extreme quartiles of IGFBP-1 was 0.60 (95% CI: 0.37, 0.95; p-trend: 0.03) for IGT and 0.41 (95% CI: 0.26, 0.64; p-trend: <0.01) for IFG. We did not find any significant association between IGF-I and glucose intolerance in this study and the association for IGFBP-3 was less clear. However, low levels of IGF-I and IGFBP-3 were associated with increased levels of markers of inflammation including C-reactive protein and interleukin-6 levels. We conclude that among adults > or = 65 years, low IGFBP-1 levels are associated with increased prevalence of glucose intolerance. We did not confirm prior associations of low IGF-I with glucose intolerance in this cohort of older individuals.
10aAged10aAged, 80 and over10aCohort Studies10aCross-Sectional Studies10aFemale10aGlucose Intolerance10aHumans10aInflammation10aInsulin-Like Growth Factor Binding Proteins10aMale10aSignal Transduction10aSomatomedins1 aRajpathak, Swapnil, N1 aMcGinn, Aileen, P1 aStrickler, Howard, D1 aRohan, Thomas, E1 aPollak, Michael1 aCappola, Anne, R1 aKuller, Lewis1 aXue, XiaoNan1 aNewman, Anne, B1 aStrotmeyer, Elsa, S1 aPsaty, Bruce, M1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/99104908nas a2200757 4500008004100000022001400041245014800055210006900203260001600272300001800288490000800306520264500314653000902959653001102968653004902979653004903028653004803077653003303125653003403158653000903192653001603201653002403217653002403241653001703265653001703282100002203299700002003321700001803341700002003359700002003379700002303399700002003422700001403442700001903456700002503475700001803500700002003518700002203538700002003560700001703580700001803597700002703615700002303642700002403665700002403689700002003713700002403733700002403757700002803781700002403809700002103833700002303854700002103877700001803898700002103916700002303937700001803960700001603978700002203994700001904016700001904035700002104054700002204075700001704097856003604114 2008 eng d a1539-370400aInsulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies.0 aInsulinlike growth factors their binding proteins and prostate c c2008 Oct 07 a461-71, W83-80 v1493 aBACKGROUND: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer.
PURPOSE: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer.
DATA SOURCES: Studies identified in PubMed, Web of Science, and CancerLit.
STUDY SELECTION: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate.
DATA EXTRACTION: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom.
DATA SYNTHESIS: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake.
LIMITATIONS: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies.
CONCLUSION: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.
10aAged10aHumans10aInsulin-Like Growth Factor Binding Protein 210aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor Binding Proteins10aInsulin-Like Growth Factor I10aInsulin-Like Growth Factor II10aMale10aMiddle Aged10aProspective Studies10aProstatic Neoplasms10aRisk Factors10aSomatomedins1 aRoddam, Andrew, W1 aAllen, Naomi, E1 aAppleby, Paul1 aKey, Timothy, J1 aFerrucci, Luigi1 aCarter, Ballentine1 aMetter, Jeffrey1 aChen, Chu1 aWeiss, Noel, S1 aFitzpatrick, Annette1 aHsing, Ann, W1 aLacey, James, V1 aHelzlsouer, Kathy1 aRinaldi, Sabina1 aRiboli, Elio1 aKaaks, Rudolf1 aJanssen, Joop, A M J L1 aWildhagen, Mark, F1 aSchröder, Fritz, H1 aPlatz, Elizabeth, A1 aPollak, Michael1 aGiovannucci, Edward1 aSchaefer, Catherine1 aQuesenberry, Charles, P1 aVogelman, Joseph, H1 aSeveri, Gianluca1 aEnglish, Dallas, R1 aGiles, Graham, G1 aStattin, Pär1 aHallmans, Göran1 aJohansson, Mattias1 aChan, June, M1 aGann, Peter1 aOliver, Steven, E1 aHolly, Jeff, M1 aDonovan, Jenny1 aMeyer, François1 aBairati, Isabelle1 aGalan, Pilar uhttps://chs-nhlbi.org/node/105502223nas a2200325 4500008004100000022001400041245009100055210006900146260001300215300001000228490000700238520130400245653005101549653000901600653001101609653001101620653000901631653001701640653002201657100001601679700002201695700002001717700002101737700002101758700002101779700002301800700002001823700001801843856003601861 2008 eng d a1096-865200aLipoprotein-associated phospholipase A2 and risk of venous thrombosis in older adults.0 aLipoproteinassociated phospholipase A2 and risk of venous thromb c2008 Jul a524-70 v833 aLipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in inflammation and platelet function. Inherited deficiency and elevated levels are associated with atherosclerosis. Given potential common etiologies of atherosclerosis and venous thrombosis (VT), we hypothesized that low and high Lp-PLA2 would be associated with VT risk. Lp-PLA(2) mass and activity were measured in baseline samples of Cardiovascular Health Study participants (5,888 men and women age > or =65), excluding 354 reporting pre-baseline VT. The study endpoint was VT unrelated to cancer after 11.6 years follow-up. Hazard ratios were estimated using Cox proportional hazard models, adjusting for age, race, sex, and body-mass index. With 129 cases of VT, there was no association of Lp-PLA2 activity with risk. Adjusted hazard ratios were 1.19 (CI 0.62, 2.29) and 0.87 (CI 0.43, 1.76) for the lowest and highest decile, respectively, compared to the 10-25th percentile. Corresponding hazard ratios for Lp-PLA2 mass were 1.63 (CI 0.79, 3.34) and 1.33 (CI 0.61, 2.87). Results were robust to several definitions of low or high Lp-PLA2. While the association of Lp-PLA(2) levels with arterial disease events implies a role for this enzyme in atherogenesis, our findings suggest that it is not prothrombotic.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aFemale10aHumans10aMale10aRisk Factors10aVenous Thrombosis1 aOlson, Nels1 aO'Meara, Ellen, S1 aJenny, Nancy, S1 aFolsom, Aaron, R1 aBovill, Edwin, G1 aFurberg, Curt, D1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aCushman, Mary uhttps://chs-nhlbi.org/node/102303487nas a2200361 4500008004100000022001400041245008700055210006900142260001600211300001100227490000800238520247700246653000902723653002202732653001802754653001202772653001102784653002202795653001102817653001702828653000902845653002302854653002602877653003202903653002402935653002002959653001802979100002502997700002003022700002303042700002403065856003603089 2008 eng d a1538-367900aMetabolic syndrome and mortality in older adults: the Cardiovascular Health Study.0 aMetabolic syndrome and mortality in older adults the Cardiovascu c2008 May 12 a969-780 v1683 aBACKGROUND: The utility of metabolic syndrome (MetS) for predicting mortality among older adults, the highest-risk population, is not well established. In addition, few studies have compared the predictive utility of MetS to that of its individual risk factors.
METHODS: We evaluated relationships of MetS (as defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III (ATPIII)], International Diabetes Foundation [IDF], and World Health Organization [WHO]) and individual MetS criteria with mortality between 1989 and 2004 among 4258 US adults 65 years or older and free of prevalent cardiovascular disease (CVD) in the Cardiovascular Health Study, a multicenter, population-based, prospective cohort. Total, CVD, and non-CVD mortality were evaluated. Cox proportional hazards models were used to estimate the mortality hazard ratio (relative risk [RR]) predicted by MetS.
RESULTS: At baseline (mean age, 73 years), 31% of men and 38% of women had MetS (ATPIII). During 15 years of follow-up, 2116 deaths occurred. After multivariable adjustment, compared with persons without MetS, those with MetS had a 22% higher mortality (RR, 1.22; 95% confidence interval [CI], 1.11-1.34). Higher risk with MetS was confined to persons having elevated fasting glucose level (EFG) (defined as > or = 110 mg/dL [> or = 6.1 mmol/L] or treated diabetes mellitus) (RR, 1.41; 95% CI, 1.27-1.57) or hypertension (RR, 1.26; 95% CI, 1.15-1.39) as one of the criteria; persons having MetS without EFG (RR, 0.97; 95% CI, 0.85-1.11) or MetS without hypertension (RR, 0.92; 95% CI, 0.71-1.19) did not have higher risk. Evaluating MetS criteria individually, we found that only hypertension and EFG predicted higher mortality; persons having both hypertension and EFG had 82% higher mortality (RR, 1.82; 95% CI, 1.58-109). Substantially higher proportions of deaths were attributable to EFG and hypertension (population attributable risk fraction [PAR%], 22.2%) than to MetS (PAR%, 6.3%). Results were similar when we used WHO or IDF criteria, when we evaluated different cut points of each individual criterion, and when we evaluated CVD mortality.
CONCLUSION: These findings suggest limited utility of MetS for predicting total or CVD mortality in older adults compared with assessment of fasting glucose and blood pressure alone.
10aAged10aAged, 80 and over10aBlood Glucose10aFasting10aFemale10aFollow-Up Studies10aHumans10aHypertension10aMale10aMetabolic Syndrome10aMultivariate Analysis10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aUnited States1 aMozaffarian, Dariush1 aKamineni, Aruna1 aPrineas, Ronald, J1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/103303257nas a2200565 4500008004100000022001400041245011300055210006900168260001600237300001100253490000700264520171200271653001801983653001502001653001002016653000902026653002202035653002202057653002602079653002902105653004402134653001202178653001902190653001102209653001102220653000902231653001602240653002702256653002202283653003202305653002402337653001702361100001802378700001602396700002102412700001702433700001702450700001802467700001602485700001502501700001602516700001602532700001502548700001802563700001502581700002002596700002302616700001602639856003602655 2008 eng d a1526-632X00aNo advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.0 aNo advantage of A beta 42lowering NSAIDs for prevention of Alzhe c2008 Jun 10 a2291-80 v703 aINTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk.
METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs.
RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13).
CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.
10aAcetaminophen10aAdolescent10aAdult10aAged10aAged, 80 and over10aAlzheimer Disease10aAmyloid beta-Peptides10aAnalgesics, Non-Narcotic10aAnti-Inflammatory Agents, Non-Steroidal10aAspirin10aCohort Studies10aFemale10aHumans10aMale10aMiddle Aged10aNeuroprotective Agents10aPeptide Fragments10aProportional Hazards Models10aProspective Studies10aRisk Factors1 aSzekely, C, A1 aGreen, R, C1 aBreitner, J, C S1 astbye, T, Ø1 aBeiser, A, S1 aCorrada, M, M1 aDodge, H, H1 aGanguli, M1 aKawas, C, H1 aKuller, L H1 aPsaty, B M1 aResnick, S, M1 aWolf, P, A1 aZonderman, A, B1 aWelsh-Bohmer, K, A1 aZandi, P, P uhttps://chs-nhlbi.org/node/103402815nas a2200385 4500008004100000022001400041245009700055210006900152260001600221300001000237490000700247520174200254653000901996653002202005653002202027653004402049653002202093653002602115653001302141653001102154653001102165653001402176653000902190653003202199653002402231653001702255100001802272700002102290700002202311700001402333700001502347700001602362700001602378856003502394 2008 eng d a1526-632X00aNSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type.0 aNSAID use and dementia risk in the Cardiovascular Health Study r c2008 Jan 01 a17-240 v703 aBACKGROUND: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.
METHODS: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one epsilon 4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid-beta peptide variant A beta(42).
RESULTS: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% CI or CI 0.60-0.96) and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE epsilon 4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce A beta(42).
CONCLUSIONS: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE epsilon 4 allele, and there was no advantage for A beta(42)-lowering NSAIDs.
10aAged10aAged, 80 and over10aAlzheimer Disease10aAnti-Inflammatory Agents, Non-Steroidal10aApolipoproteins E10aCardiovascular System10aDementia10aFemale10aHumans10aIncidence10aMale10aProportional Hazards Models10aProspective Studies10aRisk Factors1 aSzekely, C, A1 aBreitner, J, C S1 aFitzpatrick, A, L1 aRea, T, D1 aPsaty, B M1 aKuller, L H1 aZandi, P, P uhttps://chs-nhlbi.org/node/99803085nas a2200325 4500008004100000022001400041245010900055210006900164260001600233300001000249490000800259520217800267653000902445653002202454653002402476653001302500653001102513653001102524653001402535653002302549653000902572653001902581653002402600653001202624100002502636700002102661700002002682700002102702856003602723 2008 eng d a1524-453900aPhysical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study.0 aPhysical activity and incidence of atrial fibrillation in older c2008 Aug 19 a800-70 v1183 aBACKGROUND: Vigorous exertion and endurance training have been reported to increase atrial fibrillation (AF). Associations of habitual light or moderate activity with AF incidence have not been evaluated.
METHODS AND RESULTS: We prospectively investigated associations of leisure-time activity, exercise intensity, and walking habits, assessed at baseline and updated during follow-up visits, with incident AF, diagnosed by annual 12-lead ECGs and hospital discharge records, from 1989 to 2001 among 5446 adults > or =65 years of age in the Cardiovascular Health Study. During 47 280 person-years of follow-up, 1061 new AF cases occurred (incidence 22.4/1000 person-years). In multivariable-adjusted analyses, leisure-time activity was associated with lower AF incidence in a graded manner, with 25% (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.61 to 0.90), 22% (HR 0.78, 95% CI 0.65 to 0.95), and 36% (HR 0.64, 95% CI 0.52 to 0.79) lower risk in quintiles 3, 4, and 5 versus quintile 1 (P for trend <0.001). Exercise intensity had a U-shaped relationship with AF (quadratic P=0.02): Versus no exercise, AF incidence was lower with moderate-intensity exercise (HR 0.72, 95% CI 0.58 to 0.89) but not with high-intensity exercise (HR 0.87, 95% CI 0.64 to 1.19). Walking distance and pace were each associated with lower AF risk in a graded manner (P for trend <0.001); when we assessed the combined effects of distance and pace, individuals in quartiles 2, 3, and 4 had 25% (HR 0.75, 95% CI 0.56 to 0.99), 32% (HR 0.68, 95% CI 0.50 to 0.92), and 44% (HR 0.56, 95% CI 0.38 to 0.82) lower AF incidence than individuals in quartile 1. Findings appeared unrelated to confounding by comorbidity or indication. After evaluation of cut points of moderate leisure-time activity (approximately 600 kcal/week), walking distance (12 blocks per week), and pace (2 mph), 26% of all new AF cases (95% CI 7% to 43%) appeared attributable to absence of these activities.
CONCLUSIONS: Light to moderate physical activities, particularly leisure-time activity and walking, are associated with significantly lower AF incidence in older adults.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aExercise10aFemale10aHumans10aIncidence10aLeisure Activities10aMale10aMotor Activity10aProspective Studies10aWalking1 aMozaffarian, Dariush1 aFurberg, Curt, D1 aPsaty, Bruce, M1 aSiscovick, David uhttps://chs-nhlbi.org/node/104502728nas a2200313 4500008004100000022001400041245007900055210006900134260001300203300001100216490000800227520186900235653002702104653001102131653001102142653002002153653000902173653001602182653002002198653001002218653001202228653004502240100001502285700002002300700001702320700001902337700002302356856003502379 2008 eng d a0012-369200aPower spectral analysis of EEG activity during sleep in cigarette smokers.0 aPower spectral analysis of EEG activity during sleep in cigarett c2008 Feb a427-320 v1333 aBACKGROUND: Research on the effects of cigarette smoking on sleep architecture is limited. The objective of this investigation was to examine differences in sleep EEG between smokers and nonsmokers.
METHODS: Smokers and nonsmokers who were free of all medical comorbidities were matched on different factors, including age, gender, race, body mass index, and anthropometric measures. Home polysomnography was conducted using a standard recording montage. Sleep architecture was assessed using visual sleep-stage scoring. The discrete fast Fourier transform was used to calculate the EEG power spectrum for the entire night within contiguous 30-s epochs of sleep for the following frequency bandwidths: delta (0.8 to 4.0 Hz); theta (4.1 to 8.0 Hz); alpha (8.1 to 13.0 Hz); and beta (13.1 to 20.0 Hz).
RESULTS: Conventional sleep stages were similar between the two groups. However, spectral analysis of the sleep EEG showed that, compared to nonsmokers, smokers had a lower percentage of EEG power in the delta-bandwidth (59.7% vs 62.6%, respectively; p < 0.04) and higher percentage of EEG power in alpha-bandwidth (15.6% vs 12.5%, respectively; p < 0.001). Differences in the EEG power spectrum between smokers and nonsmokers were greatest in the early part of the sleep period and decreased toward the end. Subjective complaints of lack of restful sleep were also more prevalent in smokers than in nonsmokers (22.5% vs 5.0%, respectively; p < 0.02) and were explained, in part, by the differences in EEG spectral power.
CONCLUSIONS: Cigarette smokers manifest disturbances in the sleep EEG that are not evident in conventional measures of sleep architecture. Nicotine in cigarette smoke and withdrawal from it during sleep may contribute to these changes and the subjective experience of nonrestorative sleep.
10aElectroencephalography10aFemale10aHumans10aLogistic Models10aMale10aMiddle Aged10aPolysomnography10aSleep10aSmoking10aSpectroscopy, Fourier Transform Infrared1 aZhang, Lin1 aSamet, Jonathan1 aCaffo, Brian1 aBankman, Isaac1 aPunjabi, Naresh, M uhttps://chs-nhlbi.org/node/99303076nas a2200385 4500008004100000022001400041245015600055210006900211260001600280300001100296490000800307520195300315653001602268653000902284653002502293653002802318653001902346653002402365653001102389653001802400653001102418653000902429653001602438653001502454653001402469653002402483100001702507700002302524700002102547700002002568700002102588700001802609700002702627856003602654 2008 eng d a1524-453900aPrevalence, prognosis, and implications of isolated minor nonspecific ST-segment and T-wave abnormalities in older adults: Cardiovascular Health Study.0 aPrevalence prognosis and implications of isolated minor nonspeci c2008 Dec 16 a2790-60 v1183 aBACKGROUND: The prevalence and prognostic significance of isolated minor nonspecific ST-segment and T-wave abnormalities (NSSTTAs) in older adults are poorly understood.
METHODS AND RESULTS: Cardiovascular Health Study participants free of both clinical cardiovascular disease and major ECG abnormalities were included. We examined the prospective association of isolated minor NSSTTAs (defined by Minnesota Codes 4-3, 4-4, 5-3, and 5-4) with total, cardiovascular, and coronary mortality and incident nonfatal myocardial infarction. Among 3224 participants (61.9% women; mean age, 72 years), 233 (7.2%) had isolated NSSTTAs at baseline. Covariates associated with isolated NSSTTAs included older age, nonwhite race (20.5% of blacks versus 4.8% of whites; P<0.001), diabetes, and higher blood pressure and body mass index but not the presence of subclinical cardiovascular disease. After 39 518 person-years of follow-up, the presence of isolated NSSTTAs was associated with significantly increased risk for coronary heart disease mortality (multivariable-adjusted hazards ratio, 1.76; 95% CI, 1.18 to 2.61) but not with incident nonfatal myocardial infarction (multivariable-adjusted hazards ratio, 0.71; 95% CI, 0.43 to 1.17). The association of isolated NSSTTAs with coronary death was independent of subclinical atherosclerosis and left ventricular mass measures. In secondary analyses, among those with cardiac death, there was a significantly higher rate of primary arrhythmic death (32.3% versus 15.4%; P=0.02) in participants with isolated NSSTTAs versus those without NSSTTAs.
CONCLUSIONS: Isolated NSSTTAs are common in older Americans and are associated with significantly increased risk for coronary death. However, isolated NSSTTAs are not associated with incident nonfatal myocardial infarction, suggesting that they are associated particularly with increased risk for primary arrhythmic death.
10aAge Factors10aAged10aArrhythmias, Cardiac10aCardiovascular Diseases10aCohort Studies10aElectrocardiography10aFemale10aHealth Status10aHumans10aMale10aMiddle Aged10aPrevalence10aPrognosis10aProspective Studies1 aKumar, Anita1 aPrineas, Ronald, J1 aArnold, Alice, M1 aPsaty, Bruce, M1 aFurberg, Curt, D1 aRobbins, John1 aLloyd-Jones, Donald, M uhttps://chs-nhlbi.org/node/106602453nas a2200337 4500008004100000022001400041245008900055210006900144260001300213300001100226490000800237520153300245653000901778653002101787653002801808653001101836653001101847653000901858653001601867653001501883653001701898653002601915653001801941653001701959653002001976100002701996700001702023700002302040700001702063856003502080 2008 eng d a1879-148400aRelation of sleep-disordered breathing to carotid plaque and intima-media thickness.0 aRelation of sleepdisordered breathing to carotid plaque and inti c2008 Mar a125-310 v1973 aBACKGROUND: Sleep-disordered breathing (SDB) is associated with clinical cardiovascular disease (CVD), but its relation to subclinical atherosclerosis remains to be determined.
METHODS: We analyzed the cross-sectional associations of SDB, measured by the respiratory disturbance index (RDI), a hypoxemia index, and an arousal index, with carotid plaque and carotid intima-media thickness (IMT), measured by ultrasound. The sample included 985 participants in the Sleep Heart Health Study (mean age-62, median RDI-8.7) with no history of coronary heart disease and stroke, of whom 396 had evidence of a carotid plaque.
RESULTS: As compared with the first quartile of the RDI (0-1.2), the crude odds ratio for carotid plaque was 1.14, 1.27, and 1.48 for the second (1.3-4.1), third (4.2-10.7), and fourth (>10.7) quartile, respectively. After adjustment for CVD risk factors, the corresponding odds ratios were reduced (1.00, 1.04, 1.07, and 1.25). Similarly, the unadjusted mean carotid IMT increased with RDI, but adjusted means (mm) were similar (0.84, 0.85, 0.84, 0.85). Spline regression models did not show monotonicity of the dose-response functions at the right end of the RDI distribution. Neither the hypoxemia index nor the arousal index was associated with carotid plaque or carotid IMT.
CONCLUSION: The results of this study suggest that crude, positive associations between SDB and subclinical atherosclerosis can be attributed to confounding by CVD risk factors.
10aAged10aCarotid Arteries10aCarotid Artery Diseases10aFemale10aHumans10aMale10aMiddle Aged10aOdds Ratio10aRisk Factors10aSleep Apnea Syndromes10aTunica Intima10aTunica Media10aUltrasonography1 aWattanakit, Keattiyoat1 aBoland, Lori1 aPunjabi, Naresh, M1 aShahar, Eyal uhttps://chs-nhlbi.org/node/95702767nas a2200397 4500008004100000022001400041245008700055210006900142260001300211300001100224490000700235520168000242653000901922653002201931653002501953653001901978653002201997653001302019653001102032653001102043653000902054653001502063653001702078653001802095653002202113100002802135700002402163700001902187700001802206700002102224700002002245700002102265700002402286700002302310856003602333 2008 eng d a1532-541500aThe relationship between exercise and risk of venous thrombosis in elderly people.0 arelationship between exercise and risk of venous thrombosis in e c2008 Mar a517-220 v563 aOBJECTIVES: To study whether exercise is associated with the risk of venous thrombosis in elderly people.
DESIGN: Observational study with a median follow-up of 11.6 years.
SETTING: The Cardiovascular Health Study in four U.S. communities.
PARTICIPANTS: People aged 65 and older without prior venous thrombosis (deep venous thrombosis or pulmonary embolism).
MEASUREMENTS: Self-reported exercise was measured two or three times during follow-up and was defined as expending more than 500 kcal/wk on exercise, including walking for exercise. Venous thrombosis cases were verified using medical record review.
RESULTS: Of 5,534 participants, 171 developed a first venous thrombosis. Self-reported exercise at baseline was not related to the risk of venous thrombosis after adjustment for sex, age, race, self-reported health, and body mass index (adjusted hazard ratio (HR(adj))=1.16, 95% confidence interval (CI)=0.84-1.61), although with exercise modeled as a time-varying exposure, overall results were in the direction of greater risk of venous thrombosis (HR(adj)=1.38, 95% CI=0.99-1.91). For mild-intensity exercise, such as walking, there was a nonsignificant finding in the direction of benefit (HR(adj)=0.75, 95% CI=0.49-1.16), but strenuous exercise, such as jogging, was associated with greater risk of venous thrombosis (HR(adj)=1.75, 95% CI=1.08-2.83) than no exercise at all.
CONCLUSION: In elderly people, strenuous exercise was associated with a higher risk of venous thrombosis than no exercise at all. Future studies are needed to explain this unexpected higher risk.
10aAged10aAged, 80 and over10aCase-Control Studies10aCohort Studies10aEnergy Metabolism10aExercise10aFemale10aHumans10aMale10aPrevalence10aRisk Factors10aUnited States10aVenous Thrombosis1 avan Stralen, Karlijn, J1 aDoggen, Carine, J M1 aLumley, Thomas1 aCushman, Mary1 aFolsom, Aaron, R1 aPsaty, Bruce, M1 aSiscovick, David1 aRosendaal, Frits, R1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/100702434nas a2200337 4500008004100000022001400041245010100055210006900156260001300225300001100238490000700249520148300256653003101739653000901770653002801779653002601807653001301833653001101846653000901857653001801866653001101884653000901895653001701904653001901921653003101940100002301971700002101994700002502015700002002040856003602060 2008 eng d a1532-821X00aThe reliability and validity of measures of gait variability in community-dwelling older adults.0 areliability and validity of measures of gait variability in comm c2008 Dec a2293-60 v893 aOBJECTIVE: To examine the test-retest reliability and concurrent validity of variability of gait characteristics.
DESIGN: Cross-sectional study.
SETTING: Research laboratory.
PARTICIPANTS: Older adults (N=558) from the Cardiovascular Health Study.
INTERVENTIONS: Not applicable.
MAIN OUTCOME MEASURES: Gait characteristics were measured using a 4-m computerized walkway. SD determined from the steps recorded were used as the measures of variability. Intraclass correlation coefficients (ICC) were calculated to examine test-retest reliability of a 4-m walk and two 4-m walks. To establish concurrent validity, the measures of gait variability were compared across levels of health, functional status, and physical activity using independent t tests and analysis of variances.
RESULTS: Gait variability measures from the two 4-m walks demonstrated greater test-retest reliability than those from the single 4-m walk (ICC=.22-.48 and ICC=.40-.63, respectively). Greater step length and stance time variability were associated with poorer health, functional status and physical activity (P<.05).
CONCLUSIONS: Gait variability calculated from a limited number of steps has fair to good test-retest reliability and concurrent validity. Reliability of gait variability calculated from a greater number of steps should be assessed to determine if the consistency can be improved.
10aActivities of Daily Living10aAged10aCross-Sectional Studies10aDisability Evaluation10aExercise10aFemale10aGait10aHealth Status10aHumans10aMale10aPennsylvania10aRehabilitation10aReproducibility of Results1 aBrach, Jennifer, S1 aPerera, Subashan1 aStudenski, Stephanie1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/106503134nas a2200349 4500008004100000022001400041245010100055210006900156260001600225300001100241490000800252520216200260653000902422653001002431653002802441653001902469653001102488653001102499653000902510653001602519653001502535653001902550653002002569653002602589653002502615100002302640700002002663700002002683700002402703700002102727856003602748 2008 eng d a1535-497000aSleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas.0 aSleepdisordered breathing and cardiovascular disease an outcomeb c2008 May 15 a1150-50 v1773 aRATIONALE: Epidemiologic studies on the consequences of sleep-disordered breathing invariably use the apnea-hypopnea index as the primary measure of disease severity. Although hypopneas constitute a majority of disordered breathing events, significant controversy remains about the best criteria used to define these events.
OBJECTIVES: The current investigation sought to assess the most appropriate definition for hypopneas that would be best correlated with cardiovascular disease.
METHODS: A community sample of middle-aged and older adults was recruited as part of the Sleep Heart Health Study. Full-montage polysomnography was conducted and hypopneas were defined using different thresholds of oxyhemoglobin desaturation with and without arousals. Prevalent cardiovascular disease was assessed based on self-report. Logistic regression analysis was used to characterize the independent association between the hypopnea index and prevalent cardiovascular disease.
MEASUREMENTS AND MAIN RESULTS: Using a sample of 6,106 adults with complete data on cardiovascular disease status and polysomnography, the current study found that hypopneas associated with an oxyhemoglobin desaturation of 4% or more were associated with prevalent cardiovascular disease independent of confounding covariates. The adjusted prevalent odds ratios for quartiles of the hypopnea index using a 4% desaturation criterion were as follows: 1.00 (<1.10 events/h), 1.10 (1.01-3.20 events/h), 1.33 (3.21-7.69 events/h), and 1.41 (>7.69 events/h). Hypopnea measures based on less than 4% oxyhemoglobin desaturation or presence of arousals showed no association with cardiovascular disease.
CONCLUSIONS: Hypopneas comprise a significant component of sleep-disordered breathing in the general community. By varying the criteria for defining hypopneas, this study demonstrates that hypopneas with a desaturation of at least 4% are independently associated with cardiovascular disease. In contrast, no association was observed between cardiovascular disease and hypopneas associated with milder desaturations or arousals.
10aAged10aApnea10aCardiovascular Diseases10aCohort Studies10aFemale10aHumans10aMale10aMiddle Aged10aOdds Ratio10aOxyhemoglobins10aPolysomnography10aSleep Apnea Syndromes10aTerminology as Topic1 aPunjabi, Naresh, M1 aNewman, Anne, B1 aYoung, Terry, B1 aResnick, Helaine, E1 aSanders, Mark, H uhttps://chs-nhlbi.org/node/101802979nas a2200433 4500008004100000022001400041245014400055210006900199260001300268300001100281490000700292520172800299653000902027653002202036653001602058653002802074653002802102653001102130653002402141653002702165653001102192653000902203653001602212653001202228653001502240653002002255653002102275653002502296100002202321700002102343700002402364700002302388700002102411700001802432700002102450700001902471700001902490856003602509 2008 eng d a1935-554800aSleep-disordered breathing and impaired glucose metabolism in normal-weight and overweight/obese individuals: the Sleep Heart Health Study.0 aSleepdisordered breathing and impaired glucose metabolism in nor c2008 May a1001-60 v313 aOBJECTIVE: To characterize the association between sleep-disordered breathing (SDB) and impaired fasting glucose (IFG), impaired glucose tolerance (IGT), combined IFG and IGT, and occult diabetes in individuals of different body habitus.
RESEARCH DESIGN AND METHODS: Cross-sectional analysis of 2,588 participants (aged 52-96 years; 46% men) without known diabetes. SDB was defined as respiratory disturbance index >or=10 events/h. IFG, IGT, occult diabetes, and body weight were classified according to recent accepted guidelines. Participants with and without SDB were compared on prevalence and odds ratios for measures of impaired glucose metabolism (IGM), adjusting for age, sex, race, BMI, and waist circumference.
RESULTS: SDB was observed in 209 nonoverweight and 1,036 overweight/obese participants. SDB groups had significantly higher adjusted prevalence and adjusted odds of IFG, IFG plus IGT, and occult diabetes. The adjusted odds ratio for all subjects was 1.3 (95% CI 1.1-1.6) for IFG, 1.2 (1.0-1.4) for IGT, 1.4 (1.1-2.7) for IFG plus IGT, and 1.7 (1.1-2.7) for occult diabetes.
CONCLUSIONS: SDB was associated with occult diabetes, IFG, and IFG plus IGT, after adjusting for age, sex, race, BMI, and waist circumference. The magnitude of these associations was similar in nonoverweight and overweight participants. The consistency of associations across all measures of IGM and body habitus groups and the significant association between SDB and IFG plus IGT, a risk factor for rapid progression to diabetes, cardiovascular disease, and mortality, suggests the importance of SDB as a risk factor for clinically important levels of metabolic dysfunction.
10aAged10aAged, 80 and over10aBody Weight10aCardiovascular Diseases10aCross-Sectional Studies10aFemale10aGlucose Intolerance10aGlucose Tolerance Test10aHumans10aMale10aMiddle Aged10aObesity10aOverweight10aPolysomnography10aReference Values10aSleep Wake Disorders1 aSeicean, Sinziana1 aKirchner, Lester1 aGottlieb, Daniel, J1 aPunjabi, Naresh, M1 aResnick, Helaine1 aSanders, Mark1 aBudhiraja, Rohit1 aSinger, Mendel1 aRedline, Susan uhttps://chs-nhlbi.org/node/101602899nas a2200361 4500008004100000022001400041245009800055210006900153260001300222300001000235490000700245520182900252653000902081653002202090653002802112653001102140653003102151653001102182653001802193653002502211653000902236653002902245653002102274653003102295653001702326653004102343100002302384700002502407700002102432700002902453700002002482856003502502 2008 eng d a0966-636200aStance time and step width variability have unique contributing impairments in older persons.0 aStance time and step width variability have unique contributing c2008 Apr a431-90 v273 aGait variability may have multiple causes. We hypothesized that central nervous system (CNS) impairments would affect motor control and be manifested as increased stance time and step length variability, while sensory impairments would affect balance and be manifested as increased step width variability. Older adults (mean+/-standard deviation (S.D.) age=79.4+/-4.1, n=558) from the Pittsburgh site of the Cardiovascular Health Study participated. The S.D. across steps was the indicator of gait variability, determined for three gait measures, step length, stance time and step width, using a computerized walkway. Impairment measures included CNS function (modified mini-mental state examination, Trails A and B, Digit Symbol Substitution, finger tapping), sensory function (lower extremity (LE) vibration, vision), strength (grip strength, repeated chair stands), mood, and LE pain. Linear regression models were fit for the three gait variability characteristics using impairment measures as independent variables, adjusted for age, race, gender, and height. Analyses were repeated stratified by gait speed. All measures of CNS impairment were directly related to stance time variability (p<0.01), with increased CNS impairment associated with increased stance time variability. CNS impairments were not related to step length or width variability. Both sensory impairments were inversely related to step width (p<0.01) but not step length or stance time variability. CNS impairments affected stance time variability especially in slow walkers while sensory impairments affected step width variability in fast walkers. Specific patterns of gait variability may imply different underlying causes. Types of gait variability should be specified. Interventions may be targeted at specific types of gait variability.
10aAged10aAged, 80 and over10aBiomechanical Phenomena10aFemale10aGait Disorders, Neurologic10aHumans10aLinear Models10aLongitudinal Studies10aMale10aNeuropsychological Tests10aPostural Balance10aRange of Motion, Articular10aRisk Factors10aSignal Processing, Computer-Assisted1 aBrach, Jennifer, S1 aStudenski, Stephanie1 aPerera, Subashan1 aVanSwearingen, Jessie, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/97003469nas a2200541 4500008004100000022001400041245016700055210006900222260001300291300001100304490000700315520191400322653000902236653002202245653002002267653002802287653002402315653001102339653002202350653001502372653001102387653001402398653002802412653000902440653001602449653001502465653001702480653002002497653001402517653001902531653002602550653001702576653003002593653001002623653002602633653003102659100001902690700002102709700001902730700002102749700002002770700001802790700002102808700002302829700001902852700002002871856003602891 2008 eng d a1523-683800aSubjective and objective sleep quality in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the sleep heart health study.0 aSubjective and objective sleep quality in patients on convention c2008 Aug a305-130 v523 aBACKGROUND: Studies examining sleep in the hemodialysis (HD) population have largely lacked an adequate comparison group. It therefore is uncertain whether poor sleep quality in the HD population reflects age, chronic health conditions, or effects of conventional HD therapy.
STUDY DESIGN: Cross-sectional matched-group study.
SETTING & PARTICIPANTS: Forty-six in-center HD patients were compared with 137 community participants participating in the Sleep Heart Health Study matched for age, sex, body mass index, and race.
PREDICTOR: HD patients compared with community-dwelling non-HD participants.
OUTCOMES & MEASUREMENTS: Home unattended polysomnography was performed and scored by using similar protocols. Sleep habits and sleepiness were assessed by using the Sleep Habits Questionnaire and Epworth Sleepiness Scale.
RESULTS: Average age of study samples was 63 years, 72% were white, and average body mass index was 28 +/- 5 kg/m(2). HD patients were significantly more likely than community participants to have short sleep (odds ratio, 3.27; 95% confidence interval, 1.16 to 9.25) and decreased sleep efficiency (odds ratio, 5.5; 95% confidence interval, 1.5 to 19.6). HD patients reported more difficulty getting back to sleep (odds ratio, 2.25; 95% confidence interval, 1.11 to 4.60) and waking up too early (odds ratio, 2.39; 95% confidence interval, 1.01 to 5.66). There was no association between polysomnography sleep time and self-reported sleep time (r = 0.09; P = 0.6) or between the Epworth Sleepiness Scale and severity of sleep apnea (r = 0.10; P = 0.5) in the HD population.
LIMITATIONS: The study was limited to participants older than 45 years.
CONCLUSIONS: Kidney failure treated with thrice-weekly HD is significantly associated with poor subjective and objective sleep quality.
10aAged10aAged, 80 and over10aBody Mass Index10aCross-Sectional Studies10aDisease Progression10aFemale10aFollow-Up Studies10aHeart Rate10aHumans10aIncidence10aKidney Failure, Chronic10aMale10aMiddle Aged10aOdds Ratio10aPennsylvania10aPolysomnography10aPrognosis10aRenal Dialysis10aRetrospective Studies10aRisk Factors10aSeverity of Illness Index10aSleep10aSleep Apnea Syndromes10aSurveys and Questionnaires1 aUnruh, Mark, L1 aSanders, Mark, H1 aRedline, Susan1 aPiraino, Beth, M1 aUmans, Jason, G1 aChami, Hassan1 aBudhiraja, Rohit1 aPunjabi, Naresh, M1 aBuysse, Daniel1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/104103435nas a2200529 4500008004100000022001400041245014200055210006900197260001300266300001100279490000700290520186600297653003102163653000902194653002202203653001502225653002802240653003802268653001202306653001102318653002202329653001802351653001102369653001402380653004902394653004902443653003302492653000902525653001602534653001402550653002402564653001702588653001802605653001802623653001202641100002202653700002202675700002302697700001802720700002502738700002102763700001702784700002802801700002002829700002002849856003602869 2008 eng d a1532-541500aTotal insulinlike growth factor 1 and insulinlike growth factor binding protein levels, functional status, and mortality in older adults.0 aTotal insulinlike growth factor 1 and insulinlike growth factor c2008 Apr a652-600 v563 aOBJECTIVES: To assess the association between total insulinlike growth factor (IGF)-1, IGF binding protein-1 (IGFBP-1), and IGFBP-3 levels and functioning and mortality in older adults.
DESIGN: Cohort study.
SETTING/PARTICIPANTS: One thousand one hundred twenty-two individuals aged 65 and older without prior cardiovascular disease events participating in the Cardiovascular Health Study.
MEASUREMENTS: Baseline fasting plasma levels of IGF-1, IGFBP-1, and IGFBP-3 (defined as tertiles, T1-T3) were examined in relationship to handgrip strength, time to walk 15 feet, development of new difficulties with activities of daily living (ADLs), and mortality.
RESULTS: Higher IGFBP-1 predicted worse handgrip strength (P-trend(T1-T3)<.01) and slower walking speed (P-trend(T1-T3)=.03), lower IGF-1 had a borderline significant association with worse handgrip strength (P-trend(T1-T3)=.06), and better grip strength was observed in the middle IGFBP-3 tertile than in the low or high tertiles (P=.03). Adjusted for age, sex, and race, high IGFBP-1 predicted greater mortality (P-trend(T1-T3)<.001, hazard ratio (HR)(T3vsT1)=1.48, 95% confidence interval (CI)=1.15-1.90); this association was borderline significant after additional confounder adjustment (P-trend(T1-T3)=.05, HR(T3vsT1)=1.35, 95% CI=0.98-1.87). High IGFBP-1 was associated with greater risk of incident ADL difficulties after adjustment for age, sex, race, and other confounders (P-trend(T1-T3)=.04, HR(T3vsT1)=1.40, CI=1.01-1.94). Neither IGF-1 nor IGFBP-3 level predicted mortality or incident ADL difficulties.
CONCLUSION: In adults aged 65 and older, high IGFBP-1 levels were associated with greater risk of mortality and poorer functional ability, whereas IGF-1 and IGFBP-3 had little association with these outcomes.
10aActivities of Daily Living10aAged10aAged, 80 and over10aBiomarkers10aCardiovascular Diseases10aEnzyme-Linked Immunosorbent Assay10aFasting10aFemale10aFollow-Up Studies10aHand Strength10aHumans10aIncidence10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aMiddle Aged10aPrognosis10aProspective Studies10aRisk Factors10aSurvival Rate10aUnited States10aWalking1 aKaplan, Robert, C1 aMcGinn, Aileen, P1 aPollak, Michael, N1 aKuller, Lewis1 aStrickler, Howard, D1 aRohan, Thomas, E1 aXue, XiaoNan1 aKritchevsky, Stephen, B1 aNewman, Anne, B1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/102102973nas a2200313 4500008004100000022001400041245011900055210006900174260001300243300001000256490000700266520207900273653000902352653002202361653001902383653002102402653002302423653001102446653003002457653001102487653002502498653000902523653001102532100001902543700002002562700002002582700002102602856003602623 2009 eng d a1532-541500aAgreement between nosologist and cardiovascular health study review of deaths: implications of coding differences.0 aAgreement between nosologist and cardiovascular health study rev c2009 Jan a133-90 v573 aOBJECTIVES: To compare nosologist coding of underlying cause of death according to the death certificate with adjudicated cause of death for subjects aged 65 and older in the Cardiovascular Health Study (CHS).
DESIGN: Observational.
SETTING: Four communities: Forsyth County, North Carolina (Wake Forest University); Sacramento County, California (University of California at Davis); Washington County, Maryland (Johns Hopkins University); and Pittsburgh, Pennsylvania (University of Pittsburgh).
PARTICIPANTS: Men and women aged 65 and older participating in CHS, a longitudinal study of coronary heart disease and stroke, who died through June 2004.
MEASUREMENTS: The CHS centrally adjudicated underlying cause of death for 3,194 fatal events from June 1989 to June 2004 using medical records, death certificates, proxy interviews, and autopsies, and results were compared with underlying cause of death assigned by a trained nosologist based on death certificate only.
RESULTS: Comparison of 3,194 CHS versus nosologist underlying cause of death revealed moderate agreement except for cancer (kappa=0.91, 95% confidence interval (CI)=0.89-0.93). kappas varied according to category (coronary heart disease, kappa=0.61, 95% CI=0.58-0.64; stroke, kappa=0.59, 95% CI=0.54-0.64; chronic obstructive pulmonary disease, kappa=0.58, 95% CI=0.51-0.65; dementia, kappa=0.40, 95% CI=0.34-0.45; and pneumonia, kappa=0.35, 95% CI=0.29-0.42). Differences between CHS and nosologist coding of dementia were found especially in older ages in the sex and race categories. CHS attributed 340 (10.6%) deaths due to dementia, whereas nosologist coding attributed only 113 (3.5%) to dementia as the underlying cause.
CONCLUSION: Studies that use only death certificates to determine cause of death may result in misclassification and potential bias. Changing trends in cause-specific mortality in older individuals may be a function of classification process rather than incidence and case fatality.
10aAged10aAged, 80 and over10aCause of Death10aCoronary Disease10aDeath Certificates10aFemale10aForms and Records Control10aHumans10aLongitudinal Studies10aMale10aStroke1 aIves, Diane, G1 aSamuel, Paulraj1 aPsaty, Bruce, M1 aKuller, Lewis, H uhttps://chs-nhlbi.org/node/106303350nas a2200421 4500008004100000022001400041245014800055210006900203260001600272300001300288490000800301520213900309653000902448653004502457653002402502653001402526653001302540653001102553653002202564653001102586653001702597653001402614653000902628653002402637653001702661100002002678700001802698700002102716700002802737700002002765700001802785700001702803700001802820700001802838700001702856700001902873856003602892 2009 eng d a1538-367900aAngiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study.0 aAngiotensinconverting enzyme inhibitors and cognitive decline in c2009 Jul 13 a1195-2020 v1693 aBACKGROUND: Hypertension (HTN) is a risk factor for dementia, and animal studies suggest that centrally active angiotensin-converting enzyme (ACE) inhibitors (those that cross the blood-brain barrier) may protect against dementia beyond HTN control.
METHODS: Participants in the Cardiovascular Health Study Cognition Substudy with treated HTN and no diagnosis of congestive heart failure (n = 1054; mean age, 75 years) were followed up for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared with other anti-HTN agents, was associated with a lower risk of incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs).
RESULTS: Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia. Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.88-1.15), difference in 3MSE scores (-0.32 points per year; P = .15), or odds of disability in IADLs (odds ratio [OR], 1.06; 95% CI, 0.99-1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (P = .01), and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20; 95% CI, 1.00-1.43 per year of exposure) and greater odds of disability in IADLs (adjusted OR, 1.16; 95% CI, 1.03-1.30 per year of exposure) compared with other anti-HTN drugs.
CONCLUSIONS: While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within-class differences in regard to these outcomes. These results should be confirmed with a randomized clinical trial of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.
10aAged10aAngiotensin-Converting Enzyme Inhibitors10aBlood-Brain Barrier10aCognition10aDementia10aFemale10aFollow-Up Studies10aHumans10aHypertension10aIncidence10aMale10aProspective Studies10aRisk Factors1 aSink, Kaycee, M1 aLeng, Xiaoyan1 aWilliamson, Jeff1 aKritchevsky, Stephen, B1 aYaffe, Kristine1 aKuller, Lewis1 aYasar, Sevil1 aAtkinson, Hal1 aRobbins, Mike1 aPsaty, Bruce1 aGoff, David, C uhttps://chs-nhlbi.org/node/111203039nas a2200553 4500008004100000022001400041245010400055210006900159260001300228300001100241490000600252520146700258653000901725653002201734653001101756653002201767653002801789653003501817653001801852653001301870653001101883653001201894653003301906653001401939653000901953653001701962653003601979653003402015653002402049100002502073700001602098700002002114700001702134700001902151700001702170700002502187700002402212700001902236700002502255700002002280700001602300700001802316700002402334700002302358700001802381700001402399710003602413856003602449 2009 eng d a1474-972600aAssociation of common genetic variation in the insulin/IGF1 signaling pathway with human longevity.0 aAssociation of common genetic variation in the insulinIGF1 signa c2009 Aug a460-720 v83 aThe insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.
10aAged10aAged, 80 and over10aFemale10aFollow-Up Studies10aForkhead Box Protein O310aForkhead Transcription Factors10aGenome, Human10aGenotype10aHumans10aInsulin10aInsulin-Like Growth Factor I10aLongevity10aMale10aOsteoporosis10aPolymorphism, Single Nucleotide10aProto-Oncogene Proteins c-akt10aSignal Transduction1 aPawlikowska, Ludmila1 aHu, Donglei1 aHuntsman, Scott1 aSung, Andrew1 aChu, Catherine1 aChen, Justin1 aJoyner, Alexander, H1 aSchork, Nicholas, J1 aHsueh, Wen-Chi1 aReiner, Alexander, P1 aPsaty, Bruce, M1 aAtzmon, Gil1 aBarzilai, Nir1 aCummings, Steven, R1 aBrowner, Warren, S1 aKwok, Pui-Yan1 aZiv, Elad1 aStudy of Osteoporotic Fractures uhttps://chs-nhlbi.org/node/110403838nas a2200829 4500008004100000022001400041245013700055210006900192260001300261300001100274490000600285520145100291653001001742653000901752653002201761653002801783653001901811653004001830653001101870653001501881653001701896653003401913653001101947653000901958653001601967653001301983653003601996653001602032100001902048700001602067700002002083700001702103700001902120700002402139700002002163700002002183700001802203700002202221700002202243700001802265700002002283700002202303700002302325700002202348700001902370700002102389700001902410700002302429700002602452700001802478700002002496700002302516700002202539700001802561700002402579700002102603700002302624700002802647700002402675700002202699700002002721700002102741700002102762700002102783700003002804700002802834700002302862700002302885700002102908710004302929856003602972 2009 eng d a1942-326800aAssociation of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.0 aAssociation of novel genetic Loci with circulating fibrinogen le c2009 Apr a125-330 v23 aBACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.
METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).
CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPedigree10aPolymorphism, Single Nucleotide10aYoung Adult1 aDehghan, Abbas1 aYang, Qiong1 aPeters, Annette1 aBasu, Saonli1 aBis, Joshua, C1 aRudnicka, Alicja, R1 aKavousi, Maryam1 aChen, Ming-Huei1 aBaumert, Jens1 aLowe, Gordon, D O1 aMcKnight, Barbara1 aTang, Weihong1 ade Maat, Moniek1 aLarson, Martin, G1 aEyhermendy, Susana1 aMcArdle, Wendy, L1 aLumley, Thomas1 aPankow, James, S1 aHofman, Albert1 aMassaro, Joseph, M1 aRivadeneira, Fernando1 aKolz, Melanie1 aTaylor, Kent, D1 aDuijn, Cornelia, M1 aKathiresan, Sekar1 aIllig, Thomas1 aAulchenko, Yurii, S1 aVolcik, Kelly, A1 aJohnson, Andrew, D1 aUitterlinden, André, G1 aTofler, Geoffrey, H1 aGieger, Christian1 aPsaty, Bruce, M1 aCouper, David, J1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aO'Donnell, Christopher, J1 aWitteman, Jacqueline, C1 aStrachan, David, P1 aSmith, Nicholas, L1 aFolsom, Aaron, R1 aWellcome Trust Case Control Consortium uhttps://chs-nhlbi.org/node/115302610nas a2200433 4500008004100000022001400041245011400055210006900169260001300238300001000251490000700261520136200268653000901630653001501639653002301654653002801677653002501705653001101730653001901741653001101760653002701771653001801798653000901816653003001825653003201855653002401887653002001911653001701931653003001948653001701978653001801995653001802013100002502031700002102056700002102077700002202098700002002120856003602140 2009 eng d a1524-463600aAssociations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study.0 aAssociations of pentraxin 3 with cardiovascular disease and allc c2009 Apr a594-90 v293 aOBJECTIVE: We examined associations of pentraxin 3 (PTX3), a vascular inflammation marker, with incident cardiovascular disease (CVD) and all-cause death.
METHODS AND RESULTS: 1583 Cardiovascular Health Study participants free of prevalent CVD were included. Nonexclusive case groups were angina (n=476), myocardial infarction (MI; n=237), stroke (n=310), CVD death (n=282), and all-cause death (n=772). 535 participants had no events. PTX3 levels were higher in those with subclinical CVD (1.90+/-1.89 ng/mL) than those without (1.71+/-1.88 ng/mL; P=0.001). Using Cox regression adjusted for age, sex, and ethnicity, a standard deviation increase in PTX3 (1.89 ng/mL) was associated with CVD death (hazard ratio 1.11; 95% confidence interval 1.02 to 1.21) and all-cause death (1.08; 1.02 to 1.15). PTX3 was not associated with angina (1.09; 0.98 to 1.20), MI (0.96; 0.81 to 1.12), or stroke (1.06; 0.95 to 1.18). Adding C-reactive protein (CRP) or CVD risk factors to the models had no significant effects on associations.
CONCLUSIONS: In these older adults, PTX3 was associated with CVD and all-cause death independent of CRP and CVD risk factors. PTX3 likely reflects different aspects of inflammation than CRP and may provide insight into vascular health in aging and chronic diseases of aging that lead to death.
10aAged10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aCase-Control Studies10aFemale10aHealth Surveys10aHumans10aInflammation Mediators10aLinear Models10aMale10aPredictive Value of Tests10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aSerum Amyloid P-Component10aTime Factors10aUnited States10aUp-Regulation1 aJenny, Nancy, Swords1 aArnold, Alice, M1 aKuller, Lewis, H1 aTracy, Russell, P1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/107203253nas a2200457 4500008004100000022001400041245017300055210006900228260001300297300001000310490000600320520189200326653001002218653000902228653001002237653001902247653001102266653003802277653003402315653001302349653001902362653001102381653000902392653002702401653001602428653001402444653002002458653001702478100002002495700003002515700002402545700002402569700002102593700002202614700002802636700002202664700003002686700002102716710002202737856003602759 2009 eng d a1942-326800aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts.0 aCohorts for Heart and Aging Research in Genomic Epidemiology CHA c2009 Feb a73-800 v23 aBACKGROUND: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.
CONCLUSIONS: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.
10aAdult10aAged10aAging10aCohort Studies10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHeart Diseases10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPhenotype10aResearch Design10aRisk Factors1 aPsaty, Bruce, M1 aO'Donnell, Christopher, J1 aGudnason, Vilmundur1 aLunetta, Kathryn, L1 aFolsom, Aaron, R1 aRotter, Jerome, I1 aUitterlinden, André, G1 aHarris, Tamara, B1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aCHARGE Consortium uhttps://chs-nhlbi.org/node/115203137nas a2200673 4500008004100000022001400041245008300055210006900138260001300207300001200220490000700232520108000239653004101319653001001360653000901370653002501379653002301404653002701427653002701454653002701481653003701508653004001545653003801585653002201623653001801645653001101663653002801674653002701702653002001729653004001749653003601789653003801825653001701863653002001880100002901900700002201929700002101951700002501972700001701997700001902014700001902033700002302052700002602075700002502101700002202126700002302148700002202171700001702193700003002210700001902240700002302259700003002282700002802312700002002340700001902360700002202379700002602401856003602427 2009 eng d a1546-171800aCommon variants at ten loci influence QT interval duration in the QTGEN Study.0 aCommon variants at ten loci influence QT interval duration in th c2009 Apr a399-4060 v413 aQT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.
10aAdaptor Proteins, Signal Transducing10aAdult10aAged10aArrhythmias, Cardiac10aChromosome Mapping10aDeath, Sudden, Cardiac10aElectroencephalography10aERG1 Potassium Channel10aEther-A-Go-Go Potassium Channels10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenetic Variation10aGenome, Human10aHumans10aKCNQ1 Potassium Channel10aMeta-Analysis as Topic10aMuscle Proteins10aNAV1.5 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aPotassium Channels, Voltage-Gated10aRisk Factors10aSodium Channels1 aNewton-Cheh, Christopher1 aEijgelsheim, Mark1 aRice, Kenneth, M1 ade Bakker, Paul, I W1 aYin, Xiaoyan1 aEstrada, Karol1 aBis, Joshua, C1 aMarciante, Kristin1 aRivadeneira, Fernando1 aNoseworthy, Peter, A1 aSotoodehnia, Nona1 aSmith, Nicholas, L1 aRotter, Jerome, I1 aKors, Jan, A1 aWitteman, Jacqueline, C M1 aHofman, Albert1 aHeckbert, Susan, R1 aO'Donnell, Christopher, J1 aUitterlinden, André, G1 aPsaty, Bruce, M1 aLumley, Thomas1 aLarson, Martin, G1 aStricker, Bruno, H Ch uhttps://chs-nhlbi.org/node/108702448nas a2200409 4500008004100000022001400041245009600055210006900151260001300220300001300233490000700246520125300253653002201506653000901528653002201537653001501559653002301574653004001597653001101637653001701648653001801665653000901683653003601692653002401728653002401752653001701776100002301793700001901816700002301835700002501858700002001883700002501903700002801928700002301956700002301979856003602002 2009 eng d a1573-722500aC-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older.0 aCreactive protein interleukin6 and prostate cancer risk in men a c2009 Sep a1193-2030 v203 aInflammation is believed to play a role in prostate cancer (PCa) etiology, but it is unclear whether inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) associate with PCa risk in older men. Using Cox regression, we assessed the relationship between baseline concentrations of CRP and IL-6 and the subsequent PCa risk in the Cardiovascular Health Study, a population-based cohort study of mostly European American men of ages >64 years (n = 2,234; mean follow-up = 8.7 years; 215 incident PCa cases). We also tested associations between CRP and IL-6 tagSNPs and PCa risk, focusing on SNPs that are known to associate with circulating CRP and/or IL-6. Neither CRP nor IL-6 blood concentrations was associated with PCa risk. The C allele of IL-6 SNP rs1800795 (-174), a known functional variant, was associated with increased risk in a dominant model (HR = 1.44; 95% CI = 1.03-2.01; p = 0.03), but was not statistically significant after accounting for multiple tests (permutation p = 0.21). Our results suggest that circulating CRP and IL-6 do not influence PCa risk. SNPs at the CRP locus are not associated with PCa risk in this cohort, while the association between rs1800795 and PCa risk warrants further investigation.
10aAfrican Americans10aAged10aAged, 80 and over10aBiomarkers10aC-Reactive Protein10aEuropean Continental Ancestry Group10aHumans10aInflammation10aInterleukin-610aMale10aPolymorphism, Single Nucleotide10aProspective Studies10aProstatic Neoplasms10aRisk Factors1 aPierce, Brandon, L1 aBiggs, Mary, L1 aDeCambre, Marvalyn1 aReiner, Alexander, P1 aLi, Christopher1 aFitzpatrick, Annette1 aCarlson, Christopher, S1 aStanford, Janet, L1 aAustin, Melissa, A uhttps://chs-nhlbi.org/node/108402807nas a2200361 4500008004100000022001400041245010100055210006900156260001300225300001100238490000700249520176500256653000902021653002802030653001902058653001602077653001102093653001102104653000902115653001302124653004202137653003102179653002602210653001802236100002302254700002402277700002202301700002402323700002102347700001802368700002302386856003602409 2009 eng d a1537-194800aExternal validity of the cardiovascular health study: a comparison with the Medicare population.0 aExternal validity of the cardiovascular health study a compariso c2009 Aug a916-230 v473 aBACKGROUND: The Cardiovascular Health Study (CHS), a population-based prospective cohort study, has been used to identify major risk factors associated with cardiovascular disease and stroke in the elderly.
OBJECTIVE: To assess the external validity of the CHS.
RESEARCH DESIGN: Comparison of the CHS cohort to a national cohort of Medicare beneficiaries and to Medicare beneficiaries residing in the CHS geographic regions.
SUBJECTS: CHS participants and a 5% sample of Medicare beneficiaries.
MEASURES: Demographic and administrative characteristics, comorbid conditions, resource use, and mortality.
RESULTS: Compared with both Medicare cohorts, the CHS cohort was older and included more men and African American participants. CHS participants were more likely to be enrolled in Medicare managed care than beneficiaries in the national Medicare cohort. Compared with the Medicare cohorts, mortality in the CHS was more than 40% lower at 1 year, approximately 25% lower at 5 years, and approximately 15% lower at 10 years. There were minimal differences in comorbid conditions and health care resource use.
CONCLUSION: The CHS cohort is comparable with the Medicare population, particularly with regard to comorbid conditions and resource use, but had lower mortality. The difference in mortality may reflect the CHS recruitment strategy or volunteer bias. These findings suggest it may not be appropriate to project absolute rates of disease and outcomes based on CHS data to the entire Medicare population. However, there is no reason to expect that the relative risks associated with physiologic processes identified by CHS data would differ for nonparticipants.
10aAged10aCardiovascular Diseases10aCohort Studies10aComorbidity10aFemale10aHumans10aMale10aMedicare10aRandomized Controlled Trials as Topic10aReproducibility of Results10aSocioeconomic Factors10aUnited States1 aDiMartino, Lisa, D1 aHammill, Bradley, G1 aCurtis, Lesley, H1 aGottdiener, John, S1 aManolio, Teri, A1 aPowe, Neil, R1 aSchulman, Kevin, A uhttps://chs-nhlbi.org/node/111303092nas a2200505 4500008004100000022001400041245008400055210006900139260001300208300001000221490000700231520167900238653003901917653000901956653001201965653001901977653002801996653002102024653001802045653004002063653001102103653001902114653002202133653001102155653002602166653000902192653003602201653002402237653001702261653001102278653001802289100001702307700002202324700002402346700001802370700001902388700002302407700002002430700001902450700001802469700002202487700002102509700002002530856003602550 2009 eng d a1524-462800aGene variants associated with ischemic stroke: the cardiovascular health study.0 aGene variants associated with ischemic stroke the cardiovascular c2009 Feb a363-80 v403 aBACKGROUND AND PURPOSE: The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke.
METHODS: Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS).
RESULTS: In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS.
CONCLUSIONS: The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.
10aAfrican Continental Ancestry Group10aAged10aAlleles10aBrain Ischemia10aCardiovascular Diseases10aCoronary Disease10aEthnic Groups10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Variation10aHumans10aKaplan-Meier Estimate10aMale10aPolymorphism, Single Nucleotide10aProspective Studies10aRisk Factors10aStroke10aUnited States1 aLuke, May, M1 aO'Meara, Ellen, S1 aRowland, Charles, M1 aShiffman, Dov1 aBare, Lance, A1 aArellano, Andre, R1 aLongstreth, W T1 aLumley, Thomas1 aRice, Kenneth1 aTracy, Russell, P1 aDevlin, James, J1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/106405728nas a2201213 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520227000293653001002563653000902573653002202582653001002604653002802614653002102642653004002663653001102703653003402714653001302748653001602761653002102777653001102798653000902809653001602818653001502834653001402849653003602863653001702899653003402916653003102950100002702981700002203008700002103030700001903051700002103070700002203091700002303113700002203136700002303158700001903181700002303200700002003223700002203243700002203265700002203287700001903309700002403328700002003352700001803372700001803390700002303408700002103431700001903452700002603471700002203497700002403519700001803543700002003561700001503581700002703596700002703623700001703650700002303667700002103690700001803711700002103729700001703750700002003767700002003787700002303807700003003830700002303860700002303883700002103906700002503927700002603952700001703978700002203995700001804017700002104035700001904056700002404075700002804099700002204127700002004149700002004169700002004189700002004209700002304229700002204252700002204274700002104296700002404317700002204341700002804363700002404391700002004415700001904435700002404454856003604478 2009 eng d a1538-359800aGenetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.0 aGenetic variants associated with cardiac structure and function c2009 Jul 08 a168-780 v3023 aCONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.
OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.
DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.
MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.
RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).
CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aAorta10aCardiovascular Diseases10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHeart Ventricles10aHumans10aMale10aMiddle Aged10aOrgan Size10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aVentricular Dysfunction, Left10aVentricular Function, Left1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aFelix, Janine, F1 aLieb, Wolfgang1 aWild, Philipp, S1 aFelix, Stephan, B1 aWatzinger, Norbert1 aLarson, Martin, G1 aSmith, Nicholas, L1 aDehghan, Abbas1 aGrosshennig, Anika1 aSchillert, Arne1 aTeumer, Alexander1 aSchmidt, Reinhold1 aKathiresan, Sekar1 aLumley, Thomas1 aAulchenko, Yurii, S1 aKönig, Inke, R1 aZeller, Tanja1 aHomuth, Georg1 aStruchalin, Maksim1 aAragam, Jayashri1 aBis, Joshua, C1 aRivadeneira, Fernando1 aErdmann, Jeanette1 aSchnabel, Renate, B1 aDörr, Marcus1 aZweiker, Robert1 aLind, Lars1 aRodeheffer, Richard, J1 aGreiser, Karin, Halina1 aLevy, Daniel1 aHaritunians, Talin1 aDeckers, Jaap, W1 aStritzke, Jan1 aLackner, Karl, J1 aVölker, Uwe1 aIngelsson, Erik1 aKullo, Iftikhar1 aHaerting, Johannes1 aO'Donnell, Christopher, J1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aZiegler, Andreas1 aReffelmann, Thorsten1 aRedfield, Margaret, M1 aWerdan, Karl1 aMitchell, Gary, F1 aRice, Kenneth1 aArnett, Donna, K1 aHofman, Albert1 aGottdiener, John, S1 aUitterlinden, André, G1 aMeitinger, Thomas1 aBlettner, Maria1 aFriedrich, Nele1 aWang, Thomas, J1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aMunzel, Thomas, F1 aKroemer, Heyo, K1 aBenjamin, Emelia, J1 aRotter, Jerome, I1 aWitteman, Jacqueline, C1 aSchunkert, Heribert1 aSchmidt, Helena1 aVölzke, Henry1 aBlankenberg, Stefan uhttps://chs-nhlbi.org/node/110803647nas a2200457 4500008004100000022001400041245014800055210006900203260001600272300001100288490000800299520225800307653004102565653000902606653002702615653002402642653004002666653001302706653001102719653001602730653003602746653001702782100002002799700001902819700001602838700001902854700002202873700002302895700001702918700001902935700002102954700002002975700002502995700001803020700002403038700002103062700002203083700002203105700002603127856003603153 2009 eng d a1524-453900aGenetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations.0 aGenetic variations in nitric oxide synthase 1 adaptor protein ar c2009 Feb 24 a940-510 v1193 aBACKGROUND: The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOS1AP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOS1AP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study.
METHODS AND RESULTS: We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs10494366 and rs4657139 in NOS1AP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOS1AP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs12567209, which was not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs16847548 and SCD, and such adjustment had no effect on the association between rs12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOS1AP and either QT interval or SCD were observed in blacks.
CONCLUSIONS: In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white US adults.
10aAdaptor Proteins, Signal Transducing10aAged10aDeath, Sudden, Cardiac10aElectrocardiography10aEuropean Continental Ancestry Group10aGenotype10aHumans10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aKao, Linda, W H1 aArking, Dan, E1 aPost, Wendy1 aRea, Thomas, D1 aSotoodehnia, Nona1 aPrineas, Ronald, J1 aBishe, Bryan1 aDoan, Betty, Q1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aTomaselli, Gordon, F1 aCoresh, Josef1 aSiscovick, David, S1 aMarbán, Eduardo1 aSpooner, Peter, M1 aBurke, Gregory, L1 aChakravarti, Aravinda uhttps://chs-nhlbi.org/node/107701824nas a2200241 4500008004100000022001400041245010400055210006900159260001300228300001100241490001400252520108000266653002801346653003801374653003401412653001101446653002801457653001701485100001301502700001601515700001501531856003601546 2009 eng d a1538-783600aGenome-wide association studies of cardiovascular risk factors: design, conduct and interpretation.0 aGenomewide association studies of cardiovascular risk factors de c2009 Jul a308-110 v7 Suppl 13 aRelying on known biology, candidate-gene studies have been only modestly successful in identifying genetic variants associated with cardiovascular risk factors. Genome-wide association (GWA) studies, in contrast, allow broad scans across millions of loci in search of unsuspected genetic associations with phenotypes. The large numbers of statistical tests in GWA studies and the large sample sizes required to detect modest-sized associations have served as a powerful incentive for the development of large collaborative efforts such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. This article uses published data on three phenotypes, fibrinogen, uric acid, and electrocardiographic QT interval duration, from the CHARGE Consortium to describe several methodologic issues in the design, conduct, and interpretation of GWA studies, including the use of imputation and the need for additional genotyping. Even with large studies, novel genetic loci explain only a small proportion of the variance of cardiovascular phenotypes.
10aCardiovascular Diseases10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aQuantitative Trait Loci10aRisk Factors1 aBis, J C1 aGlazer, N L1 aPsaty, B M uhttps://chs-nhlbi.org/node/111704313nas a2200889 4500008004100000022001400041245004600055210004500101260001600146300001200162490000800174520183800182653003902020653000902059653003202068653001902100653004002119653001102159653002002170653003802190653003402228653001302262653001102275653000902286653001602295653003602311653003202347653001702379653001102396100002002407700002002427700001902447700002002466700002402486700002402510700002302534700001902557700002102576700002802597700002002625700001802645700001802663700002202681700001702703700002302720700001702743700002202760700002302782700002602805700002602831700002002857700001802877700001902895700002102914700002302935700002402958700001602982700002302998700002003021700001803041700002303059700001703082700002303099700002003122700002303142700001903165700002803184700002203212700002103234700002003255700002203275700002303297700002703320700002003347700002003367856003603387 2009 eng d a1533-440600aGenomewide association studies of stroke.0 aGenomewide association studies of stroke c2009 Apr 23 a1718-280 v3603 aBACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.
METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.
RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.
CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
10aAfrican Continental Ancestry Group10aAged10aChromosomes, Human, Pair 1210aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aRisk Factors10aStroke1 aIkram, Arfan, M1 aSeshadri, Sudha1 aBis, Joshua, C1 aFornage, Myriam1 aDeStefano, Anita, L1 aAulchenko, Yurii, S1 aDebette, Stephanie1 aLumley, Thomas1 aFolsom, Aaron, R1 avan den Herik, Evita, G1 aBos, Michiel, J1 aBeiser, Alexa1 aCushman, Mary1 aLauner, Lenore, J1 aShahar, Eyal1 aStruchalin, Maksim1 aDu, Yangchun1 aGlazer, Nicole, L1 aRosamond, Wayne, D1 aRivadeneira, Fernando1 aKelly-Hayes, Margaret1 aLopez, Oscar, L1 aCoresh, Josef1 aHofman, Albert1 aDeCarli, Charles1 aHeckbert, Susan, R1 aKoudstaal, Peter, J1 aYang, Qiong1 aSmith, Nicholas, L1 aKase, Carlos, S1 aRice, Kenneth1 aHaritunians, Talin1 aRoks, Gerwin1 ade Kort, Paul, L M1 aTaylor, Kent, D1 ade Lau, Lonneke, M1 aOostra, Ben, A1 aUitterlinden, André, G1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aMosley, Thomas, H1 aDuijn, Cornelia, M1 aBreteler, Monique, M B1 aLongstreth, W T1 aWolf, Philip, A uhttps://chs-nhlbi.org/node/109203588nas a2200877 4500008004100000022001400041245007000055210006800125260001300193300001100206490000700217520113400224653001901358653001401377653002301391653002301414653001301437653003101450653003201481653003401513653001101547653001701558653001001575653001601585653002701601653001501628653001401643653001501657653002001672653001201692100001701704700002001721700001801741700002601759700002201785700001901807700002201826700002401848700002301872700001901895700002101914700001901935700001901954700002701973700002602000700002402026700001702050700001902067700002202086700003302108700002102141700001702162700002302179700002002202700002502222700001602247700002202263700002202285700003002307700001902337700002202356700001802378700002402396700002802420700001902448700002102467700003002488700002102518700002002539700002402559700002202583700002602605700002002631700002302651856003602674 2009 eng d a1546-171800aGenome-wide association study of blood pressure and hypertension.0 aGenomewide association study of blood pressure and hypertension c2009 Jun a677-870 v413 aBlood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
10aBlood Pressure10aCell Line10aChromosome Mapping10aChromosomes, Human10aDiastole10aGene Expression Regulation10aGenetic Association Studies10aGenome-Wide Association Study10aHumans10aHypertension10aLiver10aLymphocytes10aMeta-Analysis as Topic10aOdds Ratio10aPhenotype10aPrevalence10aRisk Assessment10aSystole1 aLevy, Daniel1 aEhret, Georg, B1 aRice, Kenneth1 aVerwoert, Germaine, C1 aLauner, Lenore, J1 aDehghan, Abbas1 aGlazer, Nicole, L1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aAspelund, Thor1 aAulchenko, Yurii1 aLumley, Thomas1 aKöttgen, Anna1 aVasan, Ramachandran, S1 aRivadeneira, Fernando1 aEiriksdottir, Gudny1 aGuo, Xiuqing1 aArking, Dan, E1 aMitchell, Gary, F1 aMattace-Raso, Francesco, U S1 aSmith, Albert, V1 aTaylor, Kent1 aScharpf, Robert, B1 aHwang, Shih-Jen1 aSijbrands, Eric, J G1 aBis, Joshua1 aHarris, Tamara, B1 aGanesh, Santhi, K1 aO'Donnell, Christopher, J1 aHofman, Albert1 aRotter, Jerome, I1 aCoresh, Josef1 aBenjamin, Emelia, J1 aUitterlinden, André, G1 aHeiss, Gerardo1 aFox, Caroline, S1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aWang, Thomas, J1 aGudnason, Vilmundur1 aLarson, Martin, G1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aDuijn, Cornelia, M uhttps://chs-nhlbi.org/node/109803110nas a2200445 4500008004100000022001400041245014600055210006900201260001300270300001200283490000700295520180900302653000902111653002202120653001802142653002802160653002102188653001102209653001102220653001202231653002302243653002302266653001502289653002102304653002602325653001702351653002202368100002102390700002402411700002402435700002202459700002202481700002202503700002002525700002402545700001802569700002002587700002102607856003602628 2009 eng d a1945-719700aHigher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease.0 aHigher serum testosterone concentration in older women is associ c2009 Dec a4776-840 v943 aCONTEXT: Early postmenopausal women with higher testosterone (T) levels have increased insulin resistance (IR) and cardiovascular risk factors, but whether this translates into increased cardiovascular disease later in life is unknown.
OBJECTIVE: The objective of the study was to determine whether higher T levels are associated with IR, the metabolic syndrome (MetSyn), and coronary heart disease (CHD) in elderly women.
DESIGN: Total T and free T by equilibrium dialysis were measured using ultrasensitive assays in 344 women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to examine the associations between total and free T and IR, MetSyn, and CHD.
RESULTS: There was a stepwise increase in the homeostasis model assessment of insulin resistance with increasing total (P = 0.0.003) and free T (P = 0.02) level and a corresponding decrease in Quantitative Insulin Sensitivity Check Index (P < 0.001 and P = 0.002, respectively). In adjusted models, higher levels of both total and free T were strongly associated with abdominal obesity and high fasting glucose, the two MetSyn components most strongly linked to IR. After adjustment, women in the top quartile of total T levels had a 3-fold greater odds of MetSyn (odds ratio 3.15, 95% confidence interval 1.57-6.35) than those in the bottom quartile and a 3-fold greater odds of CHD (odds ratio 2.95, 95% confidence interval 1.2-7.3) than those in second quartile, whereas free T was not significantly associated with MetSyn or CHD.
CONCLUSIONS: Higher levels of T are associated with IR, MetSyn, and CHD in elderly women. Whether T is a marker or mediator of cardiovascular disease in this population merits further investigation.
10aAged10aAged, 80 and over10aBlood Glucose10aCardiovascular Diseases10aCoronary Disease10aFemale10aHumans10aInsulin10aInsulin Resistance10aMetabolic Syndrome10aOdds Ratio10aRadioimmunoassay10aSocioeconomic Factors10aTestosterone10aTreatment Outcome1 aPatel, Shrita, M1 aRatcliffe, Sarah, J1 aReilly, Muredach, P1 aWeinstein, Rachel1 aBhasin, Shalender1 aBlackman, Marc, R1 aCauley, Jane, A1 aSutton-Tyrrell, Kim1 aRobbins, John1 aFried, Linda, P1 aCappola, Anne, R uhttps://chs-nhlbi.org/node/113902825nas a2200529 4500008004100000022001400041245011300055210006900168260001300237300001000250490000700260520135800267653000901625653002201634653001001656653002801666653002501694653001101719653002201730653001301752653001101765653001701776653001801793653001401811653000901825653001401834653003501848653003301883653001701916100002301933700002101956700002501977700002102002700002002023700001802043700001402061700002502075700001402100700002302114700002402137700002002161700002202181700001602203700002002219700002002239856003602259 2009 eng d a1873-681500aInflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults.0 aInflammation and stressrelated candidate genes plasma interleuki c2009 May a350-50 v443 aInterleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10(-4)). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415--longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the "risk" of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62-1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.
10aAged10aAged, 80 and over10aAging10aCardiovascular Diseases10aCase-Control Studies10aFemale10aGenetic Variation10aGenotype10aHumans10aInflammation10aInterleukin-610aLongevity10aMale10aPhenotype10aPoly (ADP-Ribose) Polymerase-110aPoly(ADP-ribose) Polymerases10aRisk Factors1 aWalston, Jeremy, D1 aMatteini, Amy, M1 aNievergelt, Caroline1 aLange, Leslie, A1 aFallin, Dani, M1 aBarzilai, Nir1 aZiv, Elad1 aPawlikowska, Ludmila1 aKwok, Pui1 aCummings, Steve, R1 aKooperberg, Charles1 aLaCroix, Andrea1 aTracy, Russell, P1 aAtzmon, Gil1 aLange, Ethan, M1 aReiner, Alex, P uhttps://chs-nhlbi.org/node/108102796nas a2200361 4500008004100000022001400041245010300055210006900158260001300227300001000240490000700250520173200257653002201989653000902011653001902020653001602039653004002055653001102095653002202106653001902128653001102147653001702158653000902175653002402184653001702208653004702225653001802272100002202290700002102312700001802333710004702351856003602398 2009 eng d a0161-810500aInsomnia did not predict incident hypertension in older adults in the cardiovascular health study.0 aInsomnia did not predict incident hypertension in older adults i c2009 Jan a65-720 v323 aSTUDY OBJECTIVE: We hypothesized that the sleep complaints of insomnia predict incident hypertension, particularly in African Americans. The purpose of this study was to analyze insomnia complaints as predictors of incident hypertension in the Cardiovascular Health Study (CHS), stratifying by gender and allowing for race and sleep variable interaction.
DESIGN: This is a prospective cohort study over a 6-year period of follow-up.
SETTING: This is a community-based study of participants in Forsyth County, North Carolina; Pittsburgh, Pennsylvania; Sacramento County, California; and Washington County, Maryland.
PARTICIPANTS: The study analyzed data from 1419 older individuals (baseline mean age 73.4 +/- 4.4 years) from the Cardiovascular Health Study who were not hypertensive at baseline.
INTERVENTIONS: none.
MEASUREMENTS: We constructed relative risks of incident hypertension over a 6-year period for insomnia complaints singly and in combination.
RESULTS: Difficulty falling asleep, singly or in combination with other sleep complaints, predicted a statistically significant reduction of risk for incident hypertension for non-African American men in 6 years of follow-up. Insomnia complaints did not predict incident hypertension in 6 years of follow-up in women or in African Americans, although there may not have been enough power to show a significant association for African Americans.
CONCLUSIONS: Insomnia did not predict hypertension in this older cohort which was free of hypertension at baseline. Difficulty falling asleep was associated with reduced risk of hypertension in non-African American men.
10aAfrican Americans10aAged10aCohort Studies10aComorbidity10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHealth Surveys10aHumans10aHypertension10aMale10aProspective Studies10aRisk Factors10aSleep Initiation and Maintenance Disorders10aUnited States1 aPhillips, Barbara1 aBůzková, Petra1 aEnright, Paul1 aCardiovascular Health Study Research Group uhttps://chs-nhlbi.org/node/107602317nas a2200433 4500008004100000022001400041245009600055210006900151260001300220300001100233490000700244520102500251653000901276653001001285653002801295653001101323653001101334653004901345653004901394653004801443653003301491653001501524653001801539653000901557653002401566653001301590100002201603700002801625700002301653700002401676700002001700700002201720700002101742700002501763700002101788700002001809700001801829856003601847 2009 eng d a1758-535X00aInsulin-like growth factors and leukocyte telomere length: the cardiovascular health study.0 aInsulinlike growth factors and leukocyte telomere length the car c2009 Nov a1103-60 v643 aThe insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.
10aAged10aAging10aCross-Sectional Studies10aFemale10aHumans10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor Binding Proteins10aInsulin-Like Growth Factor I10aLeukocytes10aLinear Models10aMale10aSex Characteristics10aTelomere1 aKaplan, Robert, C1 aFitzpatrick, Annette, L1 aPollak, Michael, N1 aGardner, Jeffrey, P1 aJenny, Nancy, S1 aMcGinn, Aileen, P1 aKuller, Lewis, H1 aStrickler, Howard, D1 aKimura, Masayuki1 aPsaty, Bruce, M1 aAviv, Abraham uhttps://chs-nhlbi.org/node/108803609nas a2200337 4500008004100000022001400041245010800055210006900163260001600232300001100248490000800259520261400267653001902881653002102900653001102921653001902932653001702951653001102968110004002979700001803019700002103037700002103058700003003079700002403109700001803133700002603151700001803177700002303195700001703218856003603235 2009 eng d a1538-359800aLipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.0 aLipoproteina concentration and the risk of coronary heart diseas c2009 Jul 22 a412-230 v3023 aCONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke.
OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.
STUDY SELECTION: Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators.
DATA EXTRACTION: Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline.
DATA SYNTHESIS: Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer.
CONCLUSION: Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.
10aCause of Death10aCoronary Disease10aHumans10aLipoprotein(a)10aRisk Factors10aStroke1 aEmerging Risk Factors Collaboration1 aErqou, Sebhat1 aKaptoge, Stephen1 aPerry, Philip, L1 aDi Angelantonio, Emanuele1 aThompson, Alexander1 aWhite, Ian, R1 aMarcovina, Santica, M1 aCollins, Rory1 aThompson, Simon, G1 aDanesh, John uhttps://chs-nhlbi.org/node/111603185nas a2200469 4500008004100000022001400041245013300055210006900188260001300257300001100270490000600281520182900287653005102116653000902167653001502176653002302191653001102214653001502225653001802240653001102258653001402269653002702283653001802310653002602328653000902354653002802363653003202391653002402423653002002447653001702467653001702484653001802501100001902519700001702538700002502555700001902580700002402599700002002623700001802643700001802661856003602679 2009 eng d a1941-329700aLipoprotein-associated phospholipase A(2) and risk of congestive heart failure in older adults: the Cardiovascular Health Study.0 aLipoproteinassociated phospholipase A2 and risk of congestive he c2009 Sep a429-360 v23 aBACKGROUND: Inflammation may be a causative factor in congestive heart failure (CHF). Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammation marker associated with vascular risk. One previous study showed an association of Lp-PLA(2) activity with CHF risk, but there were only 94 CHF cases and Lp-PLA(2) antigen, which is available clinically in the United States, was not measured.
METHODS AND RESULTS: We measured baseline Lp-PLA(2) antigen and activity in 3991 men and women without baseline CHF or cardiovascular disease who were participating in the Cardiovascular Health Study, a prospective observational study of adults 65 years or older. Cox proportional hazards models adjusted for age, sex, clinic site, race, low-density and high-density lipoprotein cholesterol, body mass index, systolic and diastolic blood pressure, hypertension, smoking status, pack-years, and diabetes were used to calculate hazard ratios and 95% CIs for incident CHF. Further models adjusted for coronary disease events during follow-up and C-reactive protein. Eight hundred twenty-nine participants developed CHF during 12.1 years. Adjusted hazard ratios for CHF with Lp-PLA(2) in the fourth compared with the first quartile were 1.44 (95% CI, 1.16 to 1.79) for Lp-PLA(2) antigen and 1.06 (95% CI, 0.84 to 1.32) for activity. Adjustment for incident coronary disease attenuated the hazard ratio for Lp-PLA(2) antigen to 1.26 (95% CI, 1.02 to 1.57), adjustment for C-reactive protein had minimal impact.
CONCLUSIONS: Lp-PLA(2) antigen was associated with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events. Further clinical and basic research is needed to better understand the role of Lp-PLA(2) in CHF.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aBiomarkers10aC-Reactive Protein10aFemale10aFibrinogen10aHeart Failure10aHumans10aIncidence10aInflammation Mediators10aInterleukin-610aKaplan-Meier Estimate10aMale10aPopulation Surveillance10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aTime Factors10aUnited States1 aSuzuki, Takeki1 aSolomon, Cam1 aJenny, Nancy, Swords1 aTracy, Russell1 aNelson, Jeanenne, J1 aPsaty, Bruce, M1 aFurberg, Curt1 aCushman, Mary uhttps://chs-nhlbi.org/node/113502923nas a2200397 4500008004100000022001400041245011500055210006900170260001300239300001100252490000600263520181100269653003002080653001802110653001902128653002002147653001902167653001102186653001502197653001102212653001102223653002502234653000902259653002302268653003202291653001702323653002702340100001802367700001502385700001802400700001802418700001702436700001902453700001702472856003602489 2009 eng d a1538-783600aMetabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology.0 aMetabolic syndrome and risk of venous thromboembolism Longitudin c2009 May a746-510 v73 aSUMMARY BACKGROUND: In a recent case-control study, the odds of metabolic syndrome (MetSyn) among deep vein thrombosis cases were almost twice those among controls. We tested the hypothesis that the incidence of non-cancer-related venous thromboembolism (VTE) is higher among adults with MetSyn and further, that associations are stronger for idiopathic than secondary VTE.
METHODS: A total of 20 374 middle-aged and elderly adults were followed for over 12 years for incident VTE in the Longitudinal Investigation of Thromboembolism Etiology (LITE). All hospitalizations were identified and VTEs validated by chart review. Baseline MetSyn was defined using ATP III guidelines, including >or=3 of the following components: abdominal obesity, elevated blood pressure, low HDL-cholesterol, high triglycerides and high glucose. Because sex modified the relation between MetSyn and VTE (p(interaction) = 0.001), proportional hazards regression analyses were stratified by sex to assess the associations of MetSyn and its components with risk of incident non-cancer-related VTE, adjusting for potential confounders.
RESULTS: Incident VTE (n = 358) included 196 idiopathic events. Baseline MetSyn was associated with risk of total VTE (hazard ratio (HR) = 1.84, 95% CI = 1.30, 2.59) and idiopathic VTE (HR = 1.59, 95% CI = 1.02, 2.47) among men, but not women. The association was largely attributable to abdominal obesity (HR of VTE = 2.10, 95% CI = 1.51, 2.93, in men; HR of VTE = 1.70, 95% CI = 1.24, 2.34, in women), with no additional contribution by the other MetSyn components.
CONCLUSION: Although abdominal obesity was associated with increased risk of VTE in both men and women, MetSyn and its other components do not seem important in VTE etiology.
10aBlood Coagulation Factors10aBlood Glucose10aBlood Pressure10aBody Mass Index10aCohort Studies10aFemale10aFibrinogen10aHumans10aLipids10aLongitudinal Studies10aMale10aMetabolic Syndrome10aProportional Hazards Models10aRisk Factors10aVenous Thromboembolism1 aSteffen, L, M1 aCushman, M1 aPeacock, J, M1 aHeckbert, S R1 aJacobs, D, R1 aRosamond, W, D1 aFolsom, A, R uhttps://chs-nhlbi.org/node/107303239nas a2200481 4500008004100000022001400041245010600055210006900161260000900230300001000239490000600249520187600255653004102131653001502172653001002187653002202197653000902219653002702228653002402255653001802279653004002297653001102337653003402348653001902382653001502401653002302416653001102439653001802450653002702468653000902495653001602504653003602520653001602556653001602572100001902588700001602607700001502623700002002638700001602658700002102674700002602695856003602721 2009 eng d a1932-620300aMultiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.0 aMultiple independent genetic factors at NOS1AP modulate the QT i c2009 ae43330 v43 aExtremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.
10aAdaptor Proteins, Signal Transducing10aAdolescent10aAdult10aAfrican Americans10aAged10aDeath, Sudden, Cardiac10aElectrocardiography10aEthnic Groups10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHeart Diseases10aHeart Rate10aHispanic Americans10aHumans10aLinear Models10aLinkage Disequilibrium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSex Factors10aYoung Adult1 aArking, Dan, E1 aKhera, Amit1 aXing, Chao1 aKao, Linda, W H1 aPost, Wendy1 aBoerwinkle, Eric1 aChakravarti, Aravinda uhttps://chs-nhlbi.org/node/107403209nas a2200769 4500008004100000022001400041245008800055210006900143260001300212300001000225490000700235520104200242653002301284653001901307653002201326653003401348653003101382653001101413653001101424653002801435653002701463653001701490653001601507653003601523653001501559653001501574100001901589700002201608700001901630700002001649700001601669700001201685700001601697700002401713700002201737700002201759700002101781700001901802700001901821700002101840700002001861700002001881700002301901700002201924700002001946700002301966700001901989700001702008700002102025700002402046700001702070700002102087700002402108700001902132700002602151700002802177700002302205700002302228700002102251700002002272700002002292700002802312700001802340700002402358700002102382856003602403 2009 eng d a1546-171800aMultiple loci associated with indices of renal function and chronic kidney disease.0 aMultiple loci associated with indices of renal function and chro c2009 Jun a712-70 v413 aChronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.
10aChromosome Mapping10aCohort Studies10aGenetic Variation10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aMeta-Analysis as Topic10aMucoproteins10aNetherlands10aPolymorphism, Single Nucleotide10aPrevalence10aUromodulin1 aKöttgen, Anna1 aGlazer, Nicole, L1 aDehghan, Abbas1 aHwang, Shih-Jen1 aKatz, Ronit1 aLi, Man1 aYang, Qiong1 aGudnason, Vilmundur1 aLauner, Lenore, J1 aHarris, Tamara, B1 aSmith, Albert, V1 aArking, Dan, E1 aAstor, Brad, C1 aBoerwinkle, Eric1 aEhret, Georg, B1 aRuczinski, Ingo1 aScharpf, Robert, B1 aChen, Yii-Der Ida1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSarnak, Mark1 aSiscovick, David1 aBenjamin, Emelia, J1 aLevy, Daniel1 aUpadhyay, Ashish1 aAulchenko, Yurii, S1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aChasman, Daniel, I1 aParé, Guillaume1 aRidker, Paul, M1 aKao, Linda, W H1 aWitteman, Jacqueline, C1 aCoresh, Josef1 aShlipak, Michael, G1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/109904054nas a2201033 4500008004100000022001400041245007700055210006900132260001300201300001100214490000700225520114900232653001901381653001401400653001901414653002201433653001701455653002001472653001801492653003401510653001101544653001701555653001401572653003601586653002801622100002201650700001901672700002601691700002001717700002101737700002201758700002001780700001901800700002201819700001901841700002101860700001901881700001601900700002001916700001801936700002101954700002601975700002202001700002102023700002202044700002002066700001802086700002102104700002002125700002402145700001702169700002202186700002102208700002202229700001902251700002602270700002302296700001602319700002502335700002502360700001802385700001902403700002802422700002302450700002202473700002502495700001902520700002302539700002402562700002002586700002302606700002002629700002002649700002002669700002202689700002402711700002302735700002002758700002002778700002602798700002402824700003002848700003002878700001702908700001802925700002202943700001902965856003602984 2009 eng d a1546-171800aMultiple loci influence erythrocyte phenotypes in the CHARGE Consortium.0 aMultiple loci influence erythrocyte phenotypes in the CHARGE Con c2009 Nov a1191-80 v413 aMeasurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
10aBlood Pressure10aCell Line10aCohort Studies10aEndothelial Cells10aErythrocytes10aGene Expression10aGenome, Human10aGenome-Wide Association Study10aHumans10aHypertension10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aGanesh, Santhi, K1 aZakai, Neil, A1 avan Rooij, Frank, J A1 aSoranzo, Nicole1 aSmith, Albert, V1 aNalls, Michael, A1 aChen, Ming-Huei1 aKöttgen, Anna1 aGlazer, Nicole, L1 aDehghan, Abbas1 aKuhnel, Brigitte1 aAspelund, Thor1 aYang, Qiong1 aTanaka, Toshiko1 aJaffe, Andrew1 aBis, Joshua, C M1 aVerwoert, Germaine, C1 aTeumer, Alexander1 aFox, Caroline, S1 aGuralnik, Jack, M1 aEhret, Georg, B1 aRice, Kenneth1 aFelix, Janine, F1 aRendon, Augusto1 aEiriksdottir, Gudny1 aLevy, Daniel1 aPatel, Kushang, V1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aHofman, Albert1 aSambrook, Jennifer, G1 aHernandez, Dena, G1 aZheng, Gang1 aBandinelli, Stefania1 aSingleton, Andrew, B1 aCoresh, Josef1 aLumley, Thomas1 aUitterlinden, André, G1 aVangils, Janine, M1 aLauner, Lenore, J1 aCupples, Adrienne, L1 aOostra, Ben, A1 aZwaginga, Jaap-Jan1 aOuwehand, Willem, H1 aThein, Swee-Lay1 aMeisinger, Christa1 aDeloukas, Panos1 aNauck, Matthias1 aSpector, Tim, D1 aGieger, Christian1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aFerrucci, Luigi1 aChakravarti, Aravinda1 aGreinacher, Andreas1 aO'Donnell, Christopher, J1 aWitteman, Jacqueline, C M1 aFurth, Susan1 aCushman, Mary1 aHarris, Tamara, B1 aLin, Jing-Ping uhttps://chs-nhlbi.org/node/114104323nas a2201033 4500008004100000022001400041245011200055210006900167260001300236300001300249490000600262520134000268653000901608653002001617653001901637653004001656653001101696653003801707653003401745653001101779653000901790653001601799653002601815653001201841653003601853653002401889100002601913700002501939700001901964700001901983700002202002700001202024700002302036700002102059700001902080700002402099700002002123700002202143700002102165700002502186700002402211700002302235700002602258700002102284700001902305700002302324700002102347700002102368700002202389700002202411700002202433700002002455700002202475700001602497700002002513700002002533700002202553700002602575700001602601700002302617700002202640700001602662700001602678700002502694700001902719700002102738700001902759700002402778700002402802700003002826700002702856700002202883700002402905700001902929700001902948700002602967700002802993700003003021700001903051700002203070700002403092700002603116700002303142700002303165700002503188700002103213700001903234856003603253 2009 eng d a1553-740400aNRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.0 aNRXN3 is a novel locus for waist circumference a genomewide asso c2009 Jun ae10005390 v53 aCentral abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
10aAged10aBody Mass Index10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aObesity10aPolymorphism, Single Nucleotide10aWaist Circumference1 aHeard-Costa, Nancy, L1 aZillikens, Carola, M1 aMonda, Keri, L1 aJohansson, Asa1 aHarris, Tamara, B1 aFu, Mao1 aHaritunians, Talin1 aFeitosa, Mary, F1 aAspelund, Thor1 aEiriksdottir, Gudny1 aGarcia, Melissa1 aLauner, Lenore, J1 aSmith, Albert, V1 aMitchell, Braxton, D1 aMcArdle, Patrick, F1 aShuldiner, Alan, R1 aBielinski, Suzette, J1 aBoerwinkle, Eric1 aBrancati, Fred1 aDemerath, Ellen, W1 aPankow, James, S1 aArnold, Alice, M1 aChen, Yii-Der Ida1 aGlazer, Nicole, L1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aAmin, Najaf1 aCampbell, Harry1 aGyllensten, Ulf1 aPattaro, Cristian1 aPramstaller, Peter, P1 aRudan, Igor1 aStruchalin, Maksim1 aVitart, Veronique1 aGao, Xiaoyi1 aKraja, Aldi1 aProvince, Michael, A1 aZhang, Qunyuan1 aAtwood, Larry, D1 aDupuis, Josée1 aHirschhorn, Joel, N1 aJaquish, Cashell, E1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWhite, Charles, C1 aAulchenko, Yurii, S1 aEstrada, Karol1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aOostra, Ben, A1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aCupples, Adrienne, L1 aFox, Caroline, S1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/110702964nas a2200385 4500008004100000022001400041245014300055210006900198260001600267300001200283490000800295520179300303653000902096653002202105653002402127653001102151653001102162653001602173653002502189653000902214653003102223653002202254653003002276653001502306653003202321653001702353100002302370700002402393700002302417700002702440700002702467700002402494700002402518856003602542 2009 eng d a1524-453900aN-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study.0 aNterminal proBtype natriuretic peptide is a major predictor of t c2009 Nov 03 a1768-740 v1203 aBACKGROUND: Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and healthcare expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, AF, and mortality.
METHODS AND RESULTS: The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5445 Cardiovascular Health Study participants with the use of relative risk regression for predicting prevalent AF and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95% confidence interval, 17.9 to 913.3; P<0.001) and adjusted prevalence ratio of 147 for the highest quintile (95% confidence interval, 20.4 to 1064.3; P<0.001) compared with the lowest. After a median follow-up of 10 years (maximum of 16 years), there were 1126 cases of incident AF (a rate of 2.2 per 100 person-years). NT-proBNP was highly predictive of incident AF, with an unadjusted hazard ratio of 5.2 (95% confidence interval, 4.3 to 6.4; P<0.001) for the development of AF for the highest quintile compared with the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes mellitus, and heart failure, with an adjusted hazard ratio of 4.0 (95% confidence interval, 3.2 to 5.0; P<0.001).
CONCLUSIONS: In a community-based population of older adults, NT-proBNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aFemale10aHumans10aImmunoassay10aLongitudinal Studies10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aPrevalence10aProportional Hazards Models10aRisk Factors1 aPatton, Kristen, K1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aChristenson, Robert, H1 aDeFilippi, Christopher1 aGottdiener, John, S1 aKronmal, Richard, A uhttps://chs-nhlbi.org/node/113802476nas a2200397 4500008004100000022001400041245007300055210006900128260001300197300001200210490000600222520144700228653000901675653002201684653001901706653002401725653001101749653001101760653000901771653002601780653001901806653000901825653001101834653002201845653001501867653002201882100002201904700001801926700001401944700001701958700001501975700001701990700002002007700001502027856003602042 2009 eng d a1538-783600aPlatelet count and the risk for thrombosis and death in the elderly.0 aPlatelet count and the risk for thrombosis and death in the elde c2009 Mar a399-4050 v73 aAIM: Our aim was to examine the association between platelet count and the incidence of myocardial infarction, ischemic stroke, hemorrhagic stroke, venous thrombosis, and mortality.
METHODS AND RESULTS: Platelet count was measured at baseline in 1989-1990 and at 3 years follow-up, or at baseline (for a newly recruited group) in 1992-1993 in 5766 community-dwelling individuals aged 65 years and older (mean age at baseline, 73 years). During 12-15 years of follow-up, there were 821 incident myocardial infarctions, 807 ischemic strokes, 161 hemorrhagic strokes, 159 venous thrombotic events, and 3413 participants died. Platelet count was not associated with the occurrence of myocardial infarction, ischemic or hemorrhagic stroke, venous thrombosis, or cardiovascular mortality. Non-cardiovascular mortality was higher among both participants with low and with high platelet count. Adjusted non-cardiovascular mortality rates for platelet counts below 100, 100-199, 300-399, and above 400 x 10(9) L(-1) relative to the reference mortality rate in participants with platelet count values between 200 and 299 x 10(9) L(-1) were 1.89 (1.21-2.96), 1.08 (0.98-1.20), 1.20 (1.06-1.37), and 1.47 (1.14-1.90), respectively.
CONCLUSION: Platelet counts were not associated with vascular outcomes but low and high platelet counts were associated with non-cardiovascular mortality, including cancer mortality.
10aAged10aAged, 80 and over10aCause of Death10aCerebral Hemorrhage10aFemale10aHumans10aMale10aMyocardial Infarction10aPlatelet Count10aRisk10aStroke10aSurvival Analysis10aThrombosis10aVenous Thrombosis1 avan der Bom, J, G1 aHeckbert, S R1 aLumley, T1 aHolmes, C, E1 aCushman, M1 aFolsom, A, R1 aRosendaal, F, R1 aPsaty, B M uhttps://chs-nhlbi.org/node/106802919nas a2200445 4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520167600257653002201933653000901955653002201964653001001986653002301996653002802019653001902047653002802066653004002094653001102134653001702145653001802162653001102180653000902191653001602200653001502216653002402231653001202255653002602267653001802293100002102311700001802332700002302350700002602373700002202399700001602421856003602437 2009 eng d a1092-438800aPrevalence of hearing loss in Black and White elders: results of the Cardiovascular Health Study.0 aPrevalence of hearing loss in Black and White elders results of c2009 Aug a973-890 v523 aPURPOSE: The goal of this study was to determine the impact of age, gender, and race on the prevalence and severity of hearing loss in elder adults, aged 72-96 years, after accounting for income, education, smoking, and clinical and subclinical cardiovascular disease. Methods Air-conduction thresholds for standard and extended high-frequency pure-tones were obtained from a cohort of 548 (out of 717) elderly adults (ages 72-96 years) who were recruited during the Year 11 clinical visit (1999-2000) of the Cardiovascular Health Study (CHS) at the Pittsburgh, Pennsylvania site. Participant smoking, income, education, and cardiovascular disease histories were obtained from the CHS database and were included as factors.
RESULTS: Hearing loss was more common and more severe for the participants in their 80s than for those in their 70s-the men more than the women and the White participants more than the Black participants. The inclusion of education, income, smoking, and cardiovascular disease (clinical and subclinical) histories as factors did not substantively impact the overall results.
CONCLUSION: Although the data reported in this article were cross-sectional and a cohort phenomenon might have been operational, they suggested that hearing loss is more substantive in the 8th than the 7th decade of life and that race and gender influence this decline in audition. Given the high prevalence in the aging population and the differences across groups, there is a clear need to understand the nature and causes of hearing loss across various groups in order to improve prevention and develop appropriate interventions.
10aAfrican Americans10aAged10aAged, 80 and over10aAging10aAuditory Threshold10aCardiovascular Diseases10aCohort Studies10aCross-Sectional Studies10aEuropean Continental Ancestry Group10aFemale10aHearing Loss10aHearing Tests10aHumans10aMale10aOccupations10aPrevalence10aSex Characteristics10aSmoking10aSocioeconomic Factors10aUnited States1 aPratt, Sheila, R1 aKuller, Lewis1 aTalbott, Evelyn, O1 aMcHugh-Pemu, Kathleen1 aBuhari, Alhaji, M1 aXu, Xiaohui uhttps://chs-nhlbi.org/node/109302978nas a2200397 4500008004100000022001400041245013200055210006900187260001600256300001100272490000800283520181200291653002202103653001602125653000902141653002202150653001902172653003402191653004002225653001102265653001802276653001102294653001402305653000902319653003202328653001602360653001802376100002202394700001602416700002302432700002102455700002102476700002302497700002402520856003602544 2009 eng d a1879-191300aRace, gender, and mortality in adults > or =65 years of age with incident heart failure (from the Cardiovascular Health Study).0 aRace gender and mortality in adults or 65 years of age with inci c2009 Apr 15 a1120-70 v1033 aIn patients with heart failure (HF), mortality is lower in women versus men. However, it is unknown whether the survival advantage in women compared with men is present in both whites and African Americans with HF. The inception cohort consisted of adults > or =65 years with incident HF after enrollment in the CHS, a prospective population-based study of cardiovascular disease. Of 5,888 CHS subjects, 1,264 developed new HF and were followed up for 3 years. Subjects were categorized into 4 race-gender groups, and Cox proportional hazard regression models were used to examine whether 3-year total and cardiovascular mortality differed among the 4 groups after adjusting for sociodemographic factors, co-morbidities, and treatment. A gender-race interaction was also tested for each outcome. In subjects with incident HF, African Americans had more hypertension and diabetes than whites, and white men had more coronary heart disease than other gender-race groups. Receipt of cardiovascular treatments among the 4 groups was similar. Mortality rates after HF were lower in women compared with men (for white women, African-American women, African-American men, and white men, total mortality was 35.5, 33.6, 44.4, and 40.5/100 person-years, and cardiovascular mortality was 18.4, 19.5, 20.2, and 22.7/100 person-years, respectively). After adjusting for covariates, women had a 15% to 20% lower risk of total and cardiovascular mortality compared with men, but there was no significant difference in outcome by race. The gender-race interaction for either outcome was not significant. In conclusion, in older adults with HF, women had significantly better survival than men irrespective of race, suggesting that gender-based survival differences may be more important than race-based differences.
10aAfrican Americans10aAge Factors10aAged10aAged, 80 and over10aCohort Studies10aContinental Population Groups10aEuropean Continental Ancestry Group10aFemale10aHeart Failure10aHumans10aIncidence10aMale10aProportional Hazards Models10aSex Factors10aUnited States1 aParashar, Susmita1 aKatz, Ronit1 aSmith, Nicholas, L1 aArnold, Alice, M1 aVaccarino, Viola1 aWenger, Nanette, K1 aGottdiener, John, S uhttps://chs-nhlbi.org/node/109001428nas a2200517 4500008004100000022001400041245013100055210006900186260001300255300001100268490000600279653001500285653001000300653000900310653002200319653002500341653001900366653001100385653003200396653003800428653002200466653001500488653001500503653001100518653001400529653000900543653001400552653001600566653003600582653003100618653000900649653001800658653002200676653001600698100001500714700001800729700001700747700001600764700001500780700001800795700001400813700001500827700001700842700001500859856003600874 2009 eng d a1538-783600aReplication of findings on the association of genetic variation in 24 hemostasis genes and risk of incident venous thrombosis.0 aReplication of findings on the association of genetic variation c2009 Oct a1743-60 v710aAdolescent10aAdult10aAged10aAged, 80 and over10aCase-Control Studies10aCohort Studies10aFemale10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenetic Variation10aHaplotypes10aHemostasis10aHumans10aIncidence10aMale10aMenopause10aMiddle Aged10aPolymorphism, Single Nucleotide10aReproducibility of Results10aRisk10aThrombophilia10aVenous Thrombosis10aYoung Adult1 aSmith, N L1 aWiggins, K, L1 aReiner, A, P1 aLange, L, A1 aCushman, M1 aHeckbert, S R1 aLumley, T1 aRice, K, M1 aFolsom, A, R1 aPsaty, B M uhttps://chs-nhlbi.org/node/112102551nas a2200385 4500008004100000022001400041245013900055210006900194260001300263300001100276490000700287520145000294653000901744653002001753653001101773653003801784653001101822653001401833653000901847653002601856653001501882653001501897653002401912653001701936653001301953653001101966653001801977100001701995700002202012700001802034700002202052700001802074710003702092856003602129 2009 eng d a1873-258500aSibling history of myocardial infarction or stroke and risk of cardiovascular disease in the elderly: the Cardiovascular Health Study.0 aSibling history of myocardial infarction or stroke and risk of c c2009 Dec a858-660 v193 aPURPOSE: To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults.
METHODS: Prospective cohort study of 5,888 older adults participating in the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle-brachial index), CVD risk factors differed between groups.
RESULTS: More than 91% (n = 5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile.
CONCLUSIONS: Sibling history of MI and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention.
10aAged10aAtherosclerosis10aFemale10aGenetic Predisposition to Disease10aHumans10aIncidence10aMale10aMyocardial Infarction10aOdds Ratio10aPrevalence10aProspective Studies10aRisk Factors10aSiblings10aStroke10aUnited States1 aYanez, David1 aBurke, Gregory, L1 aManolio, Teri1 aGardin, Julius, M1 aPolak, Joseph1 aCHS Collaborative Research Group uhttps://chs-nhlbi.org/node/114603483nas a2200457 4500008004100000022001400041245007400055210006900129260001300198300001300211490000600224520223200230653000902462653002802471653001102499653001102510653001202521653000902533653001602542653001502558653003202573653002402605653001702629653001602646653002602662653002202688100002302710700002002733700002202753700002402775700002002799700002402819700002302843700001902866700002402885700002102909700001702930700001902947700002302966856003602989 2009 eng d a1549-167600aSleep-disordered breathing and mortality: a prospective cohort study.0 aSleepdisordered breathing and mortality a prospective cohort stu c2009 Aug ae10001320 v63 aBACKGROUND: Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.
METHODS AND FINDINGS: We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea-hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0-14.9 events/h), moderate (AHI: 15.0-29.9 events/h), and severe (AHI: >or=30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80-1.08), 1.17 (95% CI: 0.97-1.42), and 1.46 (95% CI: 1.14-1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40-70 y (hazard ratio: 2.09; 95% CI: 1.31-3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease-related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.
CONCLUSIONS: Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40-70 y with severe sleep-disordered breathing. Please see later in the article for the Editors' Summary.
10aAged10aCoronary Artery Disease10aFemale10aHumans10aHypoxia10aMale10aMiddle Aged10aOdds Ratio10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSex Factors10aSleep Apnea Syndromes10aSurvival Analysis1 aPunjabi, Naresh, M1 aCaffo, Brian, S1 aGoodwin, James, L1 aGottlieb, Daniel, J1 aNewman, Anne, B1 aO'Connor, George, T1 aRapoport, David, M1 aRedline, Susan1 aResnick, Helaine, E1 aRobbins, John, A1 aShahar, Eyal1 aUnruh, Mark, L1 aSamet, Jonathan, M uhttps://chs-nhlbi.org/node/112205120nas a2201681 4500008004100000022001400041245011700055210006900172260001600241300001200257490000700269520098300276653001901259653002401278653002101302653003701323653001101360653001501371653001101386653000901397653002701406653002401433110003701457700001701494700001501511700001701526700001701543700001701560700001001577700001701587700001601604700001701620700001501637700001401652700002001666700001901686700001701705700001501722700001501737700001501752700002301767700001701790700002001807700001901827700001901846700001401865700001601879700001501895700001401910700001201924700001501936700001801951700001801969700001701987700001902004700001402023700001202037700001702049700001702066700001702083700001802100700001402118700001602132700001402148700001302162700001502175700001702190700001202207700001802219700001802237700001902255700001502274700001602289700001602305700001402321700001402335700001602349700001602365700001702381700001802398700001902416700001702435700001702452700001602469700002002485700001202505700001602517700001302533700001102546700001502557700001402572700001202586700001502598700001802613700001502631700001902646700001502665700001602680700001602696700001702712700001902729700001502748700001502763700001502778700001402793700001602807700001802823700001902841700002202860700001702882700001602899700001802915700001902933700001602952700001402968700001602982700001602998700001503014700001903029700001703048700001403065700001803079700001503097700001603112700001703128700001203145700001703157700001503174700001503189700002003204700002303224700001503247700001703262700001703279700001403296700001903310700001403329700001403343700001603357700001503373700001403388856003603402 2009 eng d a0277-671500aSystematically missing confounders in individual participant data meta-analysis of observational cohort studies.0 aSystematically missing confounders in individual participant dat c2009 Apr 15 a1218-370 v283 aOne difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts
10aCohort Studies10aComputer Simulation10aCoronary Disease10aData Interpretation, Statistical10aFemale10aFibrinogen10aHumans10aMale10aMeta-Analysis as Topic10aModels, Statistical1 aFibrinogen Studies Collaboration1 aJackson, Dan1 aWhite, Ian1 aKostis, J, B1 aWilson, A, C1 aFolsom, A, R1 aWu, K1 aChambless, L1 aBenderly, M1 aGoldbourt, U1 aWilleit, J1 aKiechl, S1 aYarnell, J, W G1 aSweetnam, P, M1 aElwood, P, C1 aCushman, M1 aPsaty, B M1 aTracy, R P1 aTybjaerg-Hansen, A1 aHaverkate, F1 ade Maat, M, P M1 aThompson, S, G1 aFowkes, F, G R1 aLee, A, J1 aSmith, F, B1 aSalomaa, V1 aHarald, K1 aRasi, V1 aVahtera, E1 aJousilahti, P1 aD'Agostino, R1 aKannel, W, B1 aWilson, P, W F1 aTofler, G1 aLevy, D1 aMarchioli, R1 aValagussa, F1 aRosengren, A1 aWilhelmsen, L1 aLappas, G1 aEriksson, H1 aCremer, P1 aNagel, D1 aCurb, J, D1 aRodriguez, B1 aYano, K1 aSalonen, J, T1 aNyyssönen, K1 aTuomainen, T-P1 aHedblad, B1 aEngstrom, G1 aBerglund, G1 aLoewel, H1 aKoenig, W1 aHense, H, W1 aMeade, T, W1 aCooper, J, A1 aDe Stavola, B1 aKnottenbelt, C1 aMiller, G, J1 aCooper, J, A1 aBauer, K, A1 aRosenberg, R, D1 aSato, S1 aKitamura, A1 aNaito, Y1 aIso, H1 aSalomaa, V1 aHarald, K1 aRasi, V1 aVahtera, E1 aJousilahti, P1 aPalosuo, T1 aDucimetiere, P1 aAmouyel, P1 aArveiler, D1 aEvans, A, E1 aFerrieres, J1 aJuhan-Vague, I1 aBingham, A1 aSchulte, H1 aAssmann, G1 aCantin, B1 aLamarche, B1 aDesprés, J-P1 aDagenais, G, R1 aTunstall-Pedoe, H1 aLowe, G, D O1 aWoodward, M1 aBen-Shlomo, Y1 aDavey Smith, G1 aPalmieri, V1 aYeh, J, L1 aMeade, T, W1 aRudnicka, A1 aBrennan, P1 aKnottenbelt, C1 aCooper, J, A1 aRidker, P1 aRodeghiero, F1 aTosetto, A1 aShepherd, J1 aLowe, G, D O1 aFord, I1 aRobertson, M1 aBrunner, E1 aShipley, M1 aFeskens, E, J M1 aDi Angelantonio, E1 aKaptoge, S1 aLewington, S1 aLowe, G, D O1 aSarwar, N1 aThompson, S, G1 aWalker, M1 aWatson, S1 aWhite, I, R1 aWood, A, M1 aDanesh, J uhttps://chs-nhlbi.org/node/107903160nas a2200541 4500008004100000022001400041245007500055210006900130260001300199300001200212490000700224520168000231653001601911653000901927653002201936653001001958653002801968653001901996653002002015653001902035653001102054653002502065653001902090653001102109653002602120653000902146653001602155653003202171653002602203653002002229653003002249653001602279653002202295653001802317100002002335700002202355700002102377700002002398700002102418700001802439700002002457700002202477700002102499700002202520700002102542700001902563856003602582 2009 eng d a1758-535X00aTotal and cause-specific mortality in the cardiovascular health study.0 aTotal and causespecific mortality in the cardiovascular health s c2009 Dec a1251-610 v643 aBACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.
METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.
RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.
CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.
10aAge Factors10aAged10aAged, 80 and over10aAging10aCardiovascular Diseases10aCause of Death10aChronic Disease10aCohort Studies10aFemale10aGeriatric Assessment10aHealth Surveys10aHumans10aKaplan-Meier Estimate10aMale10aProbability10aProportional Hazards Models10aRetrospective Studies10aRisk Assessment10aSeverity of Illness Index10aSex Factors10aSurvival Analysis10aUnited States1 aNewman, Anne, B1 aSachs, Michael, C1 aArnold, Alice, M1 aFried, Linda, P1 aKronmal, Richard1 aCushman, Mary1 aPsaty, Bruce, M1 aHarris, Tamara, B1 aRobbins, John, A1 aBurke, Gregory, L1 aKuller, Lewis, H1 aLumley, Thomas uhttps://chs-nhlbi.org/node/112402966nas a2200445 4500008004100000022001400041245011400055210006900169260001600238300001200254490000800266520170200274653001601976653000901992653002202001653001502023653002402038653001102062653002502073653001802098653001102116653002502127653000902152653001502161653003002176653001602206653001402222653002002236653003202256653003002288653001602318100002202334700001602356700002502372700002302397700002202420700002002442700002202462856003602484 2009 eng d a1879-191300aUsefulness of myeloperoxidase levels in healthy elderly subjects to predict risk of developing heart failure.0 aUsefulness of myeloperoxidase levels in healthy elderly subjects c2009 May 01 a1269-740 v1033 aIncreased systemic myeloperoxidase (MPO) has been associated with both the presence and severity of heart failure (HF). This study tested the hypothesis that increased systemic MPO in apparently healthy elderly subjects may predict increased risk of developing HF. Systemic MPO was measured in all available samples from the 1992 to 1993 visit of the Cardiovascular Health Study (CHS). After excluding subjects without available blood samples or with a history of prevalent HF, myocardial infarction (MI), or stroke, 3,733 subjects were included. A total of 569 subjects developed incident HF during 7.2 +/- 2.3 years of follow-up. Patients in the highest MPO quartile (>432 pmol/L) showed higher risk of developing incident HF after adjusting for MI, age, gender, systolic blood pressure, smoking, low-density lipoprotein cholesterol, diabetes mellitus, and any subclinical cardiovascular disease (hazard ratio 1.34, 95% confidence interval 1.06 to 1.72, p = 0.013). However, the relation was more apparent after censoring subjects with incident MI before incident HF, even when adjusted for C-reactive protein and cystatin C (hazard ratio 1.46, 95% confidence interval 1.08 to 1.97, p = 0.02). Interestingly, stratified analyses showed that the relation between increased MPO and HF risk was stronger in subjects without traditional cardiovascular risk factors (10aAge Factors10aAged10aAged, 80 and over10aBiomarkers10aDisease Progression10aFemale10aGeriatric Assessment10aHeart Failure10aHumans10aLongitudinal Studies10aMale10aPeroxidase10aPredictive Value of Tests10aProbability10aPrognosis10aRisk Assessment10aSensitivity and Specificity10aSeverity of Illness Index10aSex Factors1 aTang, W, H Wilson1 aKatz, Ronit1 aBrennan, Marie-Luise1 aAviles, Ronnier, J1 aTracy, Russell, P1 aPsaty, Bruce, M1 aHazen, Stanley, L uhttps://chs-nhlbi.org/node/109603278nas a2200937 4500008004100000022001400041245009900055210006900154260001300223300001100236490000700247520051100254653002400765653003200789653004000821653003800861653003400899653002500933653001100958653002700969653001300996653003601009653003101045100002401076700002101100700001901121700001801140700002501158700002101183700002401204700001901228700002101247700002201268700001901290700002201309700002501331700001901356700002001375700001801395700001901413700002901432700002201461700002601483700002401509700002601533700002001559700002401579700001701603700002001620700001201640700002701652700001901679700002701698700002201725700002201747700002001769700002201789700002601811700001301837700002201850700002301872700002601895700002801921700002001949700002201969700001901991700002302010700002202033700002102055700002002076700002302096700002202119700002402141700002302165700002402188700001902212700001902231700002402250700003002274856003602304 2009 eng d a1546-171800aVariants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.0 aVariants in ZFHX3 are associated with atrial fibrillation in ind c2009 Aug a879-810 v413 aWe conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).
10aAtrial Fibrillation10aChromosomes, Human, Pair 1610aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeodomain Proteins10aHumans10aMeta-Analysis as Topic10aMutation10aPolymorphism, Single Nucleotide10aReproducibility of Results1 aBenjamin, Emelia, J1 aRice, Kenneth, M1 aArking, Dan, E1 aPfeufer, Arne1 avan Noord, Charlotte1 aSmith, Albert, V1 aSchnabel, Renate, B1 aBis, Joshua, C1 aBoerwinkle, Eric1 aSinner, Moritz, F1 aDehghan, Abbas1 aLubitz, Steven, A1 aD'Agostino, Ralph, B1 aLumley, Thomas1 aEhret, Georg, B1 aHeeringa, Jan1 aAspelund, Thor1 aNewton-Cheh, Christopher1 aLarson, Martin, G1 aMarciante, Kristin, D1 aSoliman, Elsayed, Z1 aRivadeneira, Fernando1 aWang, Thomas, J1 aEiriksdottir, Gudny1 aLevy, Daniel1 aPsaty, Bruce, M1 aLi, Man1 aChamberlain, Alanna, M1 aHofman, Albert1 aVasan, Ramachandran, S1 aHarris, Tamara, B1 aRotter, Jerome, I1 aKao, Linda, W H1 aAgarwal, Sunil, K1 aStricker, Bruno, H Ch1 aWang, Ke1 aLauner, Lenore, J1 aSmith, Nicholas, L1 aChakravarti, Aravinda1 aUitterlinden, André, G1 aWolf, Philip, A1 aSotoodehnia, Nona1 aKöttgen, Anna1 aDuijn, Cornelia, M1 aMeitinger, Thomas1 aMueller, Martina1 aPerz, Siegfried1 aSteinbeck, Gerhard1 aWichmann, H-Erich1 aLunetta, Kathryn, L1 aHeckbert, Susan, R1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aKääb, Stefan1 aEllinor, Patrick, T1 aWitteman, Jacqueline, C M uhttps://chs-nhlbi.org/node/111403169nas a2200517 4500008004100000022001400041245012300055210006900178260001300247300000800260490000700268520180100275653002202076653000902098653002502107653002302132653003202155653001102187653001702198653001302215653001102228653000902239653001502248653003302263653003602296100001802332700001602350700001902366700001102385700001602396700001602412700001002428700002202438700001802460700001502478700001702493700001402510700001102524700001402535700001202549700001002561700001302571700001702584700001402601856003602615 2010 eng d a1468-624400aAdmixture mapping of ankle-arm index: identification of a candidate locus associated with peripheral arterial disease.0 aAdmixture mapping of anklearm index identification of a candidat c2010 Jan a1-70 v473 aBACKGROUND: Peripheral arterial disease (PAD) is associated with significant morbidity and mortality, and has a higher prevalence in African Americans than Caucasians. Ankle-arm index (AAI) is the ratio of systolic blood pressure in the leg to that in the arm, and, when low, is a marker of PAD.
METHODS: The authors used an admixture mapping approach to search for genetic loci associated with low AAI. Using data from 1040 African American participants in the observational, population based Health, Aging, and Body Composition Study who were genotyped at 1322 single nucleotide polymorphisms (SNPs) that are informative for African versus European ancestry and span the entire genome, we estimated genetic ancestry in each chromosomal region and then tested the association between AAI and genetic ancestry at each locus.
RESULTS: The authors found a region of chromosome 11 that reaches its peak between 80 and 82 Mb associated with low AAI (p<0.001 for rs12289502 and rs9665943, both within this region). 753 African American participants in the observational, population based Cardiovascular Health Study were genotyped at rs9665943 to test the reproducibility of this association, and this association was also statistically significant (odds ratio (OR) for homozygous African genotype 1.59, 95% confidence interval (CI) 1.12 to 2.27). Another candidate SNP (rs1042602) in the same genomic region was tested in both populations, and was also found to be significantly associated with low AAI in both populations (OR for homozygous African genotype 1.89, 95% CI 1.29 to 2.76).
CONCLUSION: This study identifies a novel region of chromosome 11 representing an area with a potential candidate gene associated with PAD in African Americans.
10aAfrican Americans10aAged10aAnkle Brachial Index10aChromosome Mapping10aChromosomes, Human, Pair 1110aFemale10aGenetic Loci10aGenotype10aHumans10aMale10aOdds Ratio10aPeripheral Vascular Diseases10aPolymorphism, Single Nucleotide1 aScherer, M, L1 aNalls, M, A1 aPawlikowska, L1 aZiv, E1 aMitchell, G1 aHuntsman, S1 aHu, D1 aSutton-Tyrrell, K1 aLakatta, E, G1 aHsueh, W-C1 aNewman, A, B1 aTandon, A1 aKim, L1 aKwok, P-Y1 aSung, A1 aLi, R1 aPsaty, B1 aReiner, A, P1 aHarris, T uhttps://chs-nhlbi.org/node/110902951nas a2200445 4500008004100000022001400041245008200055210006900137260001600206300001200222490000700234520174700241653000901988653002201997653001602019653003002035653002502065653001102090653002502101653003102126653001102157653001402168653002502182653000902207653003202216653002602248653001702274653001102291100001802302700001802320700001502338700002002353700001502373700001802388700001702406700001202423700001702435700001702452856003602469 2010 eng d a1526-632X00aAlbuminuria and the risk of incident stroke and stroke types in older adults.0 aAlbuminuria and the risk of incident stroke and stroke types in c2010 Oct 12 a1343-500 v753 aBACKGROUND: The kidney biomarker that best reflects risk of stroke is unknown. We sought to evaluate the association of stroke with 3 kidney biomarkers: albuminuria, cystatin C, and glomerular filtration rate.
METHODS: These 3 biomarkers were determined in 3,287 participants without history of stroke from the Cardiovascular Health Study, a longitudinal cohort study of men and women age 65 years and older from 4 US communities. The biomarkers were albuminuria ascertained using urinary albumin-to-creatinine ratio (UACR) from morning spot urine, creatinine-based estimated glomerular filtration rate (eGFR), and cystatin C. Outcomes were incident stroke (any, ischemic, or hemorrhagic) during follow-up between 1996 and 2006.
RESULTS: A total of 390 participants had an incident stroke: 81% ischemic, 12% hemorrhagic, and 7% unclassified. In adjusted Cox regression models, UACR was more strongly related to any stroke, ischemic stroke, and hemorrhagic stroke than eGFR and cystatin C. The hazard ratio (HR) of any stroke comparing the top to bottom quintile of UACR was 2.10 (95% confidence interval [CI] 1.47-3.00), while HR for eGFR was 1.29 (95% CI 0.91-1.84) and for cystatin C was 1.22 (95% CI 0.85-1.74). When considering clinically relevant categories, elevated UACR was associated with increased hazard of any stroke and ischemic stroke regardless of eGFR or cystatin C categories.
CONCLUSIONS: UACR was the kidney biomarker most strongly associated with risk of incident stroke. Results in this elderly cohort may not be applicable to younger populations. These findings suggest that measures of glomerular filtration and permeability have differential effects on stroke risk.
10aAged10aAged, 80 and over10aAlbuminuria10aCommunity Health Services10aConfidence Intervals10aFemale10aGeriatric Assessment10aGlomerular Filtration Rate10aHumans10aIncidence10aLongitudinal Studies10aMale10aProportional Hazards Models10aRetrospective Studies10aRisk Factors10aStroke1 aAguilar, M, I1 aO'Meara, E, S1 aSeliger, S1 aLongstreth, W T1 aHart, R, G1 aPergola, P, E1 aShlipak, M G1 aKatz, R1 aSarnak, M, J1 aRifkin, D, E uhttps://chs-nhlbi.org/node/122814196nas a2204789 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2010 eng d a1546-171800aAssociation analyses of 249,796 individuals reveal 18 new loci associated with body mass index.0 aAssociation analyses of 249796 individuals reveal 18 new loci as c2010 Nov a937-480 v423 aObesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
10aBody Height10aBody Mass Index10aBody Size10aBody Weight10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aObesity10aPolymorphism, Single Nucleotide1 aSpeliotes, Elizabeth, K1 aWiller, Cristen, J1 aBerndt, Sonja, I1 aMonda, Keri, L1 aThorleifsson, Gudmar1 aJackson, Anne, U1 aAllen, Hana, Lango1 aLindgren, Cecilia, M1 aLuan, Jian'an1 aMägi, Reedik1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWinkler, Thomas, W1 aQi, Lu1 aWorkalemahu, Tsegaselassie1 aHeid, Iris, M1 aSteinthorsdottir, Valgerdur1 aStringham, Heather, M1 aWeedon, Michael, N1 aWheeler, Eleanor1 aWood, Andrew, R1 aFerreira, Teresa1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aEstrada, Karol1 aLiang, Liming1 aNemesh, James1 aPark, Ju-Hyun1 aGustafsson, Stefan1 aKilpeläinen, Tuomas, O1 aYang, Jian1 aBouatia-Naji, Nabila1 aEsko, Tõnu1 aFeitosa, Mary, F1 aKutalik, Zoltán1 aMangino, Massimo1 aRaychaudhuri, Soumya1 aScherag, Andre1 aSmith, Albert, Vernon1 aWelch, Ryan1 aZhao, Jing Hua1 aAben, Katja, K1 aAbsher, Devin, M1 aAmin, Najaf1 aDixon, Anna, L1 aFisher, Eva1 aGlazer, Nicole, L1 aGoddard, Michael, E1 aHeard-Costa, Nancy, L1 aHoesel, Volker1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJohnson, Toby1 aKetkar, Shamika1 aLamina, Claudia1 aLi, Shengxu1 aMoffatt, Miriam, F1 aMyers, Richard, H1 aNarisu, Narisu1 aPerry, John, R B1 aPeters, Marjolein, J1 aPreuss, Michael1 aRipatti, Samuli1 aRivadeneira, Fernando1 aSandholt, Camilla1 aScott, Laura, J1 aTimpson, Nicholas, J1 aTyrer, Jonathan, P1 avan Wingerden, Sophie1 aWatanabe, Richard, M1 aWhite, Charles, C1 aWiklund, Fredrik1 aBarlassina, Christina1 aChasman, Daniel, I1 aCooper, Matthew, N1 aJansson, John-Olov1 aLawrence, Robert, W1 aPellikka, Niina1 aProkopenko, Inga1 aShi, Jianxin1 aThiering, Elisabeth1 aAlavere, Helene1 aAlibrandi, Maria, T S1 aAlmgren, Peter1 aArnold, Alice, M1 aAspelund, Thor1 aAtwood, Larry, D1 aBalkau, Beverley1 aBalmforth, Anthony, J1 aBennett, Amanda, J1 aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBergmann, Sven1 aBiebermann, Heike1 aBlakemore, Alexandra, I F1 aBoes, Tanja1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBrown, Morris, J1 aBuchanan, Thomas, A1 aBusonero, Fabio1 aCampbell, Harry1 aCappuccio, Francesco, P1 aCavalcanti-Proença, Christine1 aChen, Yii-Der Ida1 aChen, Chih-Mei1 aChines, Peter, S1 aClarke, Robert1 aCoin, Lachlan1 aConnell, John1 aDay, Ian, N M1 aHeijer, Martin, den1 aDuan, Jubao1 aEbrahim, Shah1 aElliott, Paul1 aElosua, Roberto1 aEiriksdottir, Gudny1 aErdos, Michael, R1 aEriksson, Johan, G1 aFacheris, Maurizio, F1 aFelix, Stephan, B1 aFischer-Posovszky, Pamela1 aFolsom, Aaron, R1 aFriedrich, Nele1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGejman, Pablo, V1 aGeus, Eco, J C1 aGieger, Christian1 aGjesing, Anette, P1 aGoel, Anuj1 aGoyette, Philippe1 aGrallert, Harald1 aGrässler, Jürgen1 aGreenawalt, Danielle, M1 aGroves, Christopher, J1 aGudnason, Vilmundur1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHall, Alistair, S1 aHavulinna, Aki, S1 aHayward, Caroline1 aHeath, Andrew, C1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHinney, Anke1 aHofman, Albert1 aHomuth, Georg1 aHui, Jennie1 aIgl, Wilmar1 aIribarren, Carlos1 aIsomaa, Bo1 aJacobs, Kevin, B1 aJarick, Ivonne1 aJewell, Elizabeth1 aJohn, Ulrich1 aJørgensen, Torben1 aJousilahti, Pekka1 aJula, Antti1 aKaakinen, Marika1 aKajantie, Eero1 aKaplan, Lee, M1 aKathiresan, Sekar1 aKettunen, Johannes1 aKinnunen, Leena1 aKnowles, Joshua, W1 aKolcic, Ivana1 aKönig, Inke, R1 aKoskinen, Seppo1 aKovacs, Peter1 aKuusisto, Johanna1 aKraft, Peter1 aKvaløy, Kirsti1 aLaitinen, Jaana1 aLantieri, Olivier1 aLanzani, Chiara1 aLauner, Lenore, J1 aLecoeur, Cécile1 aLehtimäki, Terho1 aLettre, Guillaume1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aLuben, Robert, N1 aLudwig, Barbara1 aManunta, Paolo1 aMarek, Diana1 aMarre, Michel1 aMartin, Nicholas, G1 aMcArdle, Wendy, L1 aMcCarthy, Anne1 aMcKnight, Barbara1 aMeitinger, Thomas1 aMelander, Olle1 aMeyre, David1 aMidthjell, Kristian1 aMontgomery, Grant, W1 aMorken, Mario, A1 aMorris, Andrew, P1 aMulic, Rosanda1 aNgwa, Julius, S1 aNelis, Mari1 aNeville, Matt, J1 aNyholt, Dale, R1 aO'Donnell, Christopher, J1 aO'Rahilly, Stephen1 aOng, Ken, K1 aOostra, Ben1 aParé, Guillaume1 aParker, Alex, N1 aPerola, Markus1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPlatou, Carl, G P1 aPolasek, Ozren1 aPouta, Anneli1 aRafelt, Suzanne1 aRaitakari, Olli1 aRayner, Nigel, W1 aRidderstråle, Martin1 aRief, Winfried1 aRuokonen, Aimo1 aRobertson, Neil, R1 aRzehak, Peter1 aSalomaa, Veikko1 aSanders, Alan, R1 aSandhu, Manjinder, S1 aSanna, Serena1 aSaramies, Jouko1 aSavolainen, Markku, J1 aScherag, Susann1 aSchipf, Sabine1 aSchreiber, Stefan1 aSchunkert, Heribert1 aSilander, Kaisa1 aSinisalo, Juha1 aSiscovick, David, S1 aSmit, Jan, H1 aSoranzo, Nicole1 aSovio, Ulla1 aStephens, Jonathan1 aSurakka, Ida1 aSwift, Amy, J1 aTammesoo, Mari-Liis1 aTardif, Jean-Claude1 aTeder-Laving, Maris1 aTeslovich, Tanya, M1 aThompson, John, R1 aThomson, Brian1 aTönjes, Anke1 aTuomi, Tiinamaija1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aViikari, Jorma1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogel, Carla, I G1 aVoight, Benjamin, F1 aWaite, Lindsay, L1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWiegand, Susanna1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aWitteman, Jacqueline, C1 aXu, Jianfeng1 aZhang, Qunyuan1 aZgaga, Lina1 aZiegler, Andreas1 aZitting, Paavo1 aBeilby, John, P1 aFarooqi, Sadaf1 aHebebrand, Johannes1 aHuikuri, Heikki, V1 aJames, Alan, L1 aKähönen, Mika1 aLevinson, Douglas, F1 aMacciardi, Fabio1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRidker, Paul, M1 aStumvoll, Michael1 aBeckmann, Jacques, S1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCollins, Francis, S1 aCupples, Adrienne, L1 aSmith, George Davey1 aErdmann, Jeanette1 aFroguel, Philippe1 aGrönberg, Henrik1 aGyllensten, Ulf1 aHall, Per1 aHansen, Torben1 aHarris, Tamara, B1 aHattersley, Andrew, T1 aHayes, Richard, B1 aHeinrich, Joachim1 aHu, Frank, B1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aKaprio, Jaakko1 aKarpe, Fredrik1 aKhaw, Kay-Tee1 aKiemeney, Lambertus, A1 aKrude, Heiko1 aLaakso, Markku1 aLawlor, Debbie, A1 aMetspalu, Andres1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPedersen, Oluf1 aPenninx, Brenda, W1 aPeters, Annette1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aReinehr, Thomas1 aRissanen, Aila1 aRudan, Igor1 aSamani, Nilesh, J1 aSchwarz, Peter, E H1 aShuldiner, Alan, R1 aSpector, Timothy, D1 aTuomilehto, Jaakko1 aUda, Manuela1 aUitterlinden, Andre1 aValle, Timo, T1 aWabitsch, Martin1 aWaeber, Gérard1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWilson, James, F1 aWright, Alan, F1 aZillikens, Carola, M1 aChatterjee, Nilanjan1 aMcCarroll, Steven, A1 aPurcell, Shaun1 aSchadt, Eric, E1 aVisscher, Peter, M1 aAssimes, Themistocles, L1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aFrayling, Timothy, M1 aThorsteinsdottir, Unnur1 aAbecasis, Goncalo, R1 aBarroso, Inês1 aBoehnke, Michael1 aStefansson, Kari1 aNorth, Kari, E1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aIngelsson, Erik1 aLoos, Ruth, J F1 aMAGIC1 aProcardis Consortium uhttps://chs-nhlbi.org/node/123704239nas a2200781 4500008004100000022001400041245024400055210006900299260001300368300001100381490000600392520185900398653002202257653000902279653002202288653001902310653001902329653004002348653001102388653003402399653001802433653001102451653001402462653000902476653001602485653003602501653000902537653003302546100002302579700002102602700002402623700002302647700002202670700002002692700002502712700001902737700001902756700002302775700001902798700002602817700001902843700002102862700002102883700002402904700002302928700001802951700002102969700001802990700002303008700002403031700002303055700002003078700002103098700001903119700002303138700001803161700003003179700002803209700002203237700002403259700001703283700002303300700002003323700003003343700002103373700002703394856003603421 2010 eng d a1942-326800aAssociation of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.0 aAssociation of genomewide variation with the risk of incident he c2010 Jun a256-660 v33 aBACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.
CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.
10aAfrican Americans10aAged10aAged, 80 and over10aCohort Studies10aEndopeptidases10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHeart Failure10aHumans10aIncidence10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk10aUbiquitin-Specific Proteases1 aSmith, Nicholas, L1 aFelix, Janine, F1 aMorrison, Alanna, C1 aDemissie, Serkalem1 aGlazer, Nicole, L1 aLoehr, Laura, R1 aCupples, Adrienne, L1 aDehghan, Abbas1 aLumley, Thomas1 aRosamond, Wayne, D1 aLieb, Wolfgang1 aRivadeneira, Fernando1 aBis, Joshua, C1 aFolsom, Aaron, R1 aBenjamin, Emelia1 aAulchenko, Yurii, S1 aHaritunians, Talin1 aCouper, David1 aMurabito, Joanne1 aWang, Ying, A1 aStricker, Bruno, H1 aGottdiener, John, S1 aChang, Patricia, P1 aWang, Thomas, J1 aRice, Kenneth, M1 aHofman, Albert1 aHeckbert, Susan, R1 aFox, Ervin, R1 aO'Donnell, Christopher, J1 aUitterlinden, André, G1 aRotter, Jerome, I1 aWillerson, James, T1 aLevy, Daniel1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/119704577nas a2200337 4500008004100000022001400041245012700055210006900182260001300251300001100264490000700275520357600282653000903858653002803867653001903895653001103914653001103925653002003936653000903956653001703965653001703982653003703999100002304036700002304059700002404082700002504106700002504131700002204156700002504178856003604203 2010 eng d a1523-683800aAssociations between renal duplex parameters and adverse cardiovascular events in the elderly: a prospective cohort study.0 aAssociations between renal duplex parameters and adverse cardiov c2010 Feb a281-900 v553 aBACKGROUND: Atherosclerotic renovascular disease is associated with an increased risk of cardiovascular disease (CVD) events. This study examines associations between Doppler-derived parameters from the renal artery and renal parenchyma and all-cause mortality and fatal and nonfatal CVD events in a cohort of elderly Americans.
STUDY DESIGN: Cohort study.
SETTING: A subset of participants from the Cardiovascular Health Study (CHS). Through an ancillary study, 870 (70% recruitment) Forsyth County, NC, CHS participants consented to undergo renal duplex sonography to define the prevalence of renovascular disease in the elderly, resulting in 726 (36% men; mean age, 77 years) technically adequate complete studies included in this investigation.
PREDICTOR: Renal duplex sonography-derived Doppler signals from the main renal arteries and renal parenchyma. Spectral analysis from Doppler-shifted frequencies and angle of insonation were used to estimate renal artery peak systolic and end diastolic velocity (both in meters per second). Color Doppler was used to identify the corticomedullary junction. Using a 3-mm Doppler sample, the parenchymal peak systolic and end diastolic frequency shift (both in kilohertz) were obtained. Resistive index was calculated as (1 - [end diastolic frequency shift/peak systolic frequency shift]) using Doppler samples from the hilar arteries of the left or right kidney with the higher main renal artery peak systolic velocity.
OUTCOMES & MEASUREMENTS: Proportional hazard regression analysis was used to determine associations between renal duplex sonography-derived Doppler signals and CVD events and all-cause mortality adjusted for accepted cardiovascular risk factors. Index CVD outcomes were defined as coronary events (angina, myocardial infarction, and coronary artery bypass grafting/percutaneous coronary intervention), cerebrovascular events (stroke or transient ischemic attack), and any CVD event (angina, congestive heart failure, myocardial infarction, stroke, transient ischemic attack, and coronary artery bypass grafting [CABG]/percutaneous transluminal coronary intervention [PTCI]).
RESULTS: During follow-up, 221 deaths (31%), 229 CVD events (32%), 122 coronary events (17%), and 92 cerebrovascular events (13%) were observed. Renal duplex sonography-derived Doppler signals from the renal parenchyma were associated independently with all-cause mortality and CVD outcomes. In particular, increased parenchymal end diastolic frequency shift was associated significantly with any CVD event (HR, 0.73; 95% CI, 0.62-0.87; P < 0.001). Marginally significant associations were observed between increases in parenchymal end diastolic frequency shift and decreased risk of death (HR, 0.86; 95% CI, 0.73-1.00; P = 0.06) and decreased risk of cerebrovascular events (HR, 0.78; 95% CI, 0.61-1.01; P = 0.06). Parenchymal end diastolic frequency shift was not significantly predictive of coronary events (HR, 0.84; 95% CI, 0.67-1.06; P = 0.1).
LIMITATIONS: CHS participants showed a "healthy cohort" effect that may underestimate the rate of CVD events in the general population.
CONCLUSION: Renal duplex sonographic Doppler signals from the renal parenchyma showed significant associations with subsequent CVD events after controlling for other significant risk factors. In particular, a standard deviation increase in parenchymal end diastolic frequency shift was associated with 27% risk reduction in any CVD event.
10aAged10aCardiovascular Diseases10aCohort Studies10aFemale10aHumans10aKidney Diseases10aMale10aRenal Artery10aRisk Factors10aUltrasonography, Doppler, Duplex1 aPearce, Jeffrey, D1 aCraven, Timothy, E1 aEdwards, Matthew, S1 aCorriere, Matthew, A1 aCrutchley, Teresa, A1 aFleming, Shawn, H1 aHansen, Kimberley, J uhttps://chs-nhlbi.org/node/116303234nas a2200505 4500008004100000022001400041245010600055210006900161260001600230300001100246490000800257520186500265653001002130653000902140653002202149653001902171653001802190653001102208653001902219653001102238653001102249653000902260653001602269653003302285653001802318653002302336653002002359653001202379653003002391653001002421653002602431653001602457653001802473653001702491100002502508700001902533700001902552700001802571700001802589700002402607700002202631700002002653700001902673856003602692 2010 eng d a1535-497000aAssociations of PM10 with sleep and sleep-disordered breathing in adults from seven U.S. urban areas.0 aAssociations of PM10 with sleep and sleepdisordered breathing in c2010 Sep 15 a819-250 v1823 aRATIONALE: Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17% of U.S. adults, and may be more prevalent in poor urban environments. SDB and air pollution have been linked to increased cardiovascular diseases and mortality, but the association between pollution and SDB is poorly understood.
OBJECTIVES: We used data from the Sleep Heart Health Study (SHHS), a U.S. multicenter cohort study assessing cardiovascular and other consequences of SDB, to examine whether particulate air matter less than 10 μm in aerodynamic diameter (PM(10)) was associated with SDB among persons 39 years of age and older.
METHODS: Using baseline data from SHHS urban sites, outcomes included the following: the respiratory disturbance index (RDI); percentage of sleep time at less than 90% O(2) saturation; and sleep efficiency, measured by overnight in-home polysomnography. We applied a fixed-effect model containing a city effect, controlling for potential predictors. In all models we included both the 365-day moving averages of PM(10) and temperature (long-term effects) and the differences between the daily measures of these two predictors and their 365-day average (short-term effects).
MEASUREMENTS AND MAIN RESULTS: In summer, increases in RDI or percentage of sleep time at less than 90% O(2) saturation, and decreases in sleep efficiency, were all associated with increases in short-term variation in PM(10). Over all seasons, we found that increased RDI was associated with an 11.5% (95% confidence interval: 1.96, 22.01) increase per interquartile range increase (25.5°F) in temperature.
CONCLUSIONS: Reduction in air pollution exposure may decrease the severity of SDB and nocturnal hypoxemia and may improve cardiac risk.
10aAdult10aAged10aAged, 80 and over10aAir Pollutants10aAir Pollution10aCities10aCohort Studies10aFemale10aHumans10aMale10aMiddle Aged10aMulticenter Studies as Topic10aParticle Size10aParticulate Matter10aPolysomnography10aSeasons10aSeverity of Illness Index10aSleep10aSleep Apnea Syndromes10aTemperature10aUnited States10aUrban Health1 aZanobetti, Antonella1 aRedline, Susan1 aSchwartz, Joel1 aRosen, Dennis1 aPatel, Sanjay1 aO'Connor, George, T1 aLebowitz, Michael1 aCoull, Brent, A1 aGold, Diane, R uhttps://chs-nhlbi.org/node/120205486nas a2201657 4500008004100000022001400041245011100055210006900166260001600235300001300251490000700264520147400271653001801745653001801763653002301781653001501804653002001819653001101839653002701850653002401877653001401901653003601915100002101951700002301972700001501995700001902010700001502029700001602044700001202060700001502072700001402087700001602101700001902117700001502136700001502151700001802166700001902184700001502203700001302218700001602231700001402247700001402261700001302275700001302288700001502301700001202316700001602328700001402344700001802358700001702376700002302393700002302416700001302439700001002452700001202462700001602474700001402490700001402504700001902518700001602537700001602553700001702569700001602586700001402602700001202616700001102628700001302639700001602652700001102668700001302679700001402692700001502706700001402721700001602735700001602751700001702767700001702784700001702801700001602818700001702834700001702851700001202868700001402880700001102894700001502905700001402920700001602934700001602950700001602966700001402982700001402996700001703010700001603027700001603043700001403059700002103073700001403094700001803108700001903126700001503145700001603160700001403176700001403190700001203204700001503216700001403231700001403245700002203259700002503281700001303306700001503319700001603334700001403350700001903364700001603383700001703399700001603416700001403432700002303446700001603469700001403485700001403499700001503513700001303528700001403541700001503555700001603570700002303586700001403609700001103623700001203634700001403646700001903660700001603679700001403695700001703709700001703726700001403743710003503757856003603792 2010 eng d a1097-025800aBayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.0 aBayesian methods for metaanalysis of causal relationships estima c2010 May 30 a1298-3110 v293 aGenetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.
10aBayes Theorem10aBiostatistics10aC-Reactive Protein10aFibrinogen10aGenetic Markers10aHumans10aMeta-Analysis as Topic10aModels, Statistical10aPhenotype10aPolymorphism, Single Nucleotide1 aBurgess, Stephen1 aThompson, Simon, G1 aBurgess, S1 aThompson, S, G1 aAndrews, G1 aSamani, N J1 aHall, A1 aWhincup, P1 aMorris, R1 aLawlor, D A1 aDavey Smith, G1 aTimpson, N1 aEbrahim, S1 aBen-Shlomo, Y1 aDavey Smith, G1 aTimpson, N1 aBrown, M1 aRicketts, S1 aSandhu, M1 aReiner, A1 aPsaty, B1 aLange, L1 aCushman, M1 aHung, J1 aThompson, P1 aBeilby, J1 aWarrington, N1 aPalmer, L, J1 aNordestgaard, B, G1 aTybjaerg-Hansen, A1 aZacho, J1 aWu, C1 aLowe, G1 aTzoulaki, I1 aKumari, M1 aSandhu, M1 aYamamoto, J, F1 aChiodini, B1 aFranzosi, M1 aHankey, G, J1 aJamrozik, K1 aPalmer, L1 aRimm, E1 aPai, J1 aPsaty, B1 aHeckbert, S1 aBis, J1 aAnand, S1 aEngert, J1 aCollins, R1 aClarke, R1 aMelander, O1 aBerglund, G1 aLadenvall, P1 aJohansson, L1 aJansson, J-H1 aHallmans, G1 aHingorani, A1 aHumphries, S1 aRimm, E1 aManson, J1 aPai, J1 aWatkins, H1 aClarke, R1 aHopewell, J1 aSaleheen, D1 aFrossard, R1 aDanesh, J1 aSattar, N1 aRobertson, M1 aShepherd, J1 aSchaefer, E1 aHofman, A1 aWitteman, J, C M1 aKardys, I1 aBen-Shlomo, Y1 aDavey Smith, G1 aTimpson, N1 ade Faire, U1 aBennet, A1 aSattar, N1 aFord, I1 aPackard, C1 aKumari, M1 aManson, J1 aLawlor, Debbie, A1 aSmith, George, Davey1 aAnand, S1 aCollins, R1 aCasas, J, P1 aDanesh, J1 aDavey Smith, G1 aFranzosi, M1 aHingorani, A1 aLawlor, D A1 aManson, J1 aNordestgaard, B, G1 aSamani, N J1 aSandhu, M1 aSmeeth, L1 aWensley, F1 aAnand, S1 aBowden, J1 aBurgess, S1 aCasas, J, P1 aDi Angelantonio, E1 aEngert, J1 aGao, P1 aShah, T1 aSmeeth, L1 aThompson, S, G1 aVerzilli, C1 aWalker, M1 aWhittaker, J1 aHingorani, A1 aDanesh, J1 aCRP CHD Genetics Collaboration uhttps://chs-nhlbi.org/node/117109616nas a2202929 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2010 eng d a1476-468700aBiological, clinical and population relevance of 95 loci for blood lipids.0 aBiological clinical and population relevance of 95 loci for bloo c2010 Aug 05 a707-130 v4663 aPlasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
10aAfrican Americans10aAnimals10aAsian Continental Ancestry Group10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aLipid Metabolism10aLipids10aLiver10aMale10aMice10aN-Acetylgalactosaminyltransferases10aPhenotype10aPolymorphism, Single Nucleotide10aProtein Phosphatase 110aReproducibility of Results10aTriglycerides1 aTeslovich, Tanya, M1 aMusunuru, Kiran1 aSmith, Albert, V1 aEdmondson, Andrew, C1 aStylianou, Ioannis, M1 aKoseki, Masahiro1 aPirruccello, James, P1 aRipatti, Samuli1 aChasman, Daniel, I1 aWiller, Cristen, J1 aJohansen, Christopher, T1 aFouchier, Sigrid, W1 aIsaacs, Aaron1 aPeloso, Gina, M1 aBarbalic, Maja1 aRicketts, Sally, L1 aBis, Joshua, C1 aAulchenko, Yurii, S1 aThorleifsson, Gudmar1 aFeitosa, Mary, F1 aChambers, John1 aOrho-Melander, Marju1 aMelander, Olle1 aJohnson, Toby1 aLi, Xiaohui1 aGuo, Xiuqing1 aLi, Mingyao1 aCho, Yoon, Shin1 aGo, Min, Jin1 aKim, Young, Jin1 aLee, Jong-Young1 aPark, Taesung1 aKim, Kyunga1 aSim, Xueling1 aOng, Rick, Twee-Hee1 aCroteau-Chonka, Damien, C1 aLange, Leslie, A1 aSmith, Joshua, D1 aSong, Kijoung1 aZhao, Jing, Hua1 aYuan, Xin1 aLuan, Jian'an1 aLamina, Claudia1 aZiegler, Andreas1 aZhang, Weihua1 aZee, Robert, Y L1 aWright, Alan, F1 aWitteman, Jacqueline, C M1 aWilson, James, F1 aWillemsen, Gonneke1 aWichmann, H-Erich1 aWhitfield, John, B1 aWaterworth, Dawn, M1 aWareham, Nicholas, J1 aWaeber, Gérard1 aVollenweider, Peter1 aVoight, Benjamin, F1 aVitart, Veronique1 aUitterlinden, André, G1 aUda, Manuela1 aTuomilehto, Jaakko1 aThompson, John, R1 aTanaka, Toshiko1 aSurakka, Ida1 aStringham, Heather, M1 aSpector, Tim, D1 aSoranzo, Nicole1 aSmit, Johannes, H1 aSinisalo, Juha1 aSilander, Kaisa1 aSijbrands, Eric, J G1 aScuteri, Angelo1 aScott, James1 aSchlessinger, David1 aSanna, Serena1 aSalomaa, Veikko1 aSaharinen, Juha1 aSabatti, Chiara1 aRuokonen, Aimo1 aRudan, Igor1 aRose, Lynda, M1 aRoberts, Robert1 aRieder, Mark1 aPsaty, Bruce, M1 aPramstaller, Peter, P1 aPichler, Irene1 aPerola, Markus1 aPenninx, Brenda, W J H1 aPedersen, Nancy, L1 aPattaro, Cristian1 aParker, Alex, N1 aParé, Guillaume1 aOostra, Ben, A1 aO'Donnell, Christopher, J1 aNieminen, Markku, S1 aNickerson, Deborah, A1 aMontgomery, Grant, W1 aMeitinger, Thomas1 aMcPherson, Ruth1 aMcCarthy, Mark, I1 aMcArdle, Wendy1 aMasson, David1 aMartin, Nicholas, G1 aMarroni, Fabio1 aMangino, Massimo1 aMagnusson, Patrik, K E1 aLucas, Gavin1 aLuben, Robert1 aLoos, Ruth, J F1 aLokki, Marja-Liisa1 aLettre, Guillaume1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLakatta, Edward, G1 aLaaksonen, Reijo1 aKyvik, Kirsten, O1 aKronenberg, Florian1 aKönig, Inke, R1 aKhaw, Kay-Tee1 aKaprio, Jaakko1 aKaplan, Lee, M1 aJohansson, Asa1 aJarvelin, Marjo-Riitta1 aJanssens, Cecile, J W1 aIngelsson, Erik1 aIgl, Wilmar1 aHovingh, Kees1 aHottenga, Jouke-Jan1 aHofman, Albert1 aHicks, Andrew, A1 aHengstenberg, Christian1 aHeid, Iris, M1 aHayward, Caroline1 aHavulinna, Aki, S1 aHastie, Nicholas, D1 aHarris, Tamara, B1 aHaritunians, Talin1 aHall, Alistair, S1 aGyllensten, Ulf1 aGuiducci, Candace1 aGroop, Leif, C1 aGonzalez, Elena1 aGieger, Christian1 aFreimer, Nelson, B1 aFerrucci, Luigi1 aErdmann, Jeanette1 aElliott, Paul1 aEjebe, Kenechi, G1 aDöring, Angela1 aDominiczak, Anna, F1 aDemissie, Serkalem1 aDeloukas, Panagiotis1 aGeus, Eco, J C1 ade Faire, Ulf1 aCrawford, Gabriel1 aCollins, Francis, S1 aChen, Yii-der, I1 aCaulfield, Mark, J1 aCampbell, Harry1 aBurtt, Noel, P1 aBonnycastle, Lori, L1 aBoomsma, Dorret, I1 aBoekholdt, Matthijs1 aBergman, Richard, N1 aBarroso, Inês1 aBandinelli, Stefania1 aBallantyne, Christie, M1 aAssimes, Themistocles, L1 aQuertermous, Thomas1 aAltshuler, David1 aSeielstad, Mark1 aWong, Tien, Y1 aTai, E-Shyong1 aFeranil, Alan, B1 aKuzawa, Christopher, W1 aAdair, Linda, S1 aTaylor, Herman, A1 aBorecki, Ingrid, B1 aGabriel, Stacey, B1 aWilson, James, G1 aHolm, Hilma1 aThorsteinsdottir, Unnur1 aGudnason, Vilmundur1 aKrauss, Ronald, M1 aMohlke, Karen, L1 aOrdovas, Jose, M1 aMunroe, Patricia, B1 aKooner, Jaspal, S1 aTall, Alan, R1 aHegele, Robert, A1 aKastelein, John, J P1 aSchadt, Eric, E1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aStrachan, David, P1 aMooser, Vincent1 aStefansson, Kari1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aDuijn, Cornelia, M1 aPeltonen, Leena1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/122102888nas a2200481 4500008004100000022001400041245003300055210003200088260001300120300001100133490000700144520166400151653001601815653000901831653002501840653002001865653001001885653003401895653003001929653001201959653001101971653001101982653001201993653003102005653000902036653002902045653003102074653001202105653001502117653002402132653001602156100001902172700001702191700002702208700002102235700002002256700002102276700001302297700001802310700002002328700002202348856003602370 2010 eng d a1097-019300aBrain structure and obesity.0 aBrain structure and obesity c2010 Mar a353-640 v313 aObesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects.
10aAge Factors10aAged10aAnalysis of Variance10aBody Mass Index10aBrain10aContinental Population Groups10aDiabetes Mellitus, Type 210aFasting10aFemale10aHumans10aInsulin10aMagnetic Resonance Imaging10aMale10aNerve Fibers, Myelinated10aNerve Fibers, Unmyelinated10aObesity10aOrgan Size10aRegression Analysis10aSex Factors1 aRaji, Cyrus, A1 aHo, April, J1 aParikshak, Neelroop, N1 aBecker, James, T1 aLopez, Oscar, L1 aKuller, Lewis, H1 aHua, Xue1 aLeow, Alex, D1 aToga, Arthur, W1 aThompson, Paul, M uhttps://chs-nhlbi.org/node/112004142nas a2200757 4500008004100000022001400041245008700055210006900142260001300211300001100224490000600235520194100241653002202182653002102204653002102225653001902246653002302265653004002288653003202328653001302360653001102373653001402384653001902398653003602417653002002453653001802473100002002491700002202511700001802533700002302551700002602574700002202600700002402622700001602646700002002662700001802682700002102700700001902721700002202740700002402762700002502786700002002811700001802831700002302849700002402872700002902896700002302925700002002948700002802968700002102996700002003017700002103037700001903058700002103077700002203098700002203120700002203142700002703164700002103191700002203212700002403234700002103258700002303279710004603302856003603348 2010 eng d a1942-326800aCandidate gene association resource (CARe): design, methods, and proof of concept.0 aCandidate gene association resource CARe design methods and proo c2010 Jun a267-750 v33 aBACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.
METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.
CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.
10aAfrican Americans10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenotype10aHumans10aPhenotype10aPilot Projects10aPolymorphism, Single Nucleotide10aResearch Design10aTriglycerides1 aMusunuru, Kiran1 aLettre, Guillaume1 aYoung, Taylor1 aFarlow, Deborah, N1 aPirruccello, James, P1 aEjebe, Kenechi, G1 aKeating, Brendan, J1 aYang, Qiong1 aChen, Ming-Huei1 aLapchyk, Nina1 aCrenshaw, Andrew1 aZiaugra, Liuda1 aRachupka, Anthony1 aBenjamin, Emelia, J1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, R1 aHeckbert, Susan, R1 aHirschhorn, Joel, N1 aNewton-Cheh, Christopher1 aNizzari, Marcia, M1 aPaltoo, Dina, N1 aPapanicolaou, George, J1 aPatel, Sanjay, R1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aTaylor, Herman, A1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aWilson, James, G1 aKathiresan, Sekar1 aFabsitz, Richard, R1 aBoerwinkle, Eric1 aGabriel, Stacey, B1 aNHLBI Candidate Gene Association Resource uhttps://chs-nhlbi.org/node/118802933nas a2200397 4500008004100000022001400041245010700055210006900162260001300231300001200244490000700256520183200263653000902095653001402104653002802118653002002146653001902166653001602185653002802201653002102229653001402250653001102264653002202275653001102297653000902308653001202317653001502329653002102344100002402365700002702389700002002416700002002436700002002456700002302476856003602499 2010 eng d a1758-535X00aChronic medical conditions and the sex-based disparity in disability: the Cardiovascular Health Study.0 aChronic medical conditions and the sexbased disparity in disabil c2010 Dec a1325-310 v653 aBACKGROUND: Older women experience disability more commonly than their male peers. This disparity may be due, in part, to sex-based differences in the prevalence or the disabling effects of common medical conditions. The objectives of this analysis were to (a) quantify the extent to which excess disability in women is explained by higher prevalence of selected medical conditions and (b) evaluate whether the same conditions have differing effects on disability in men and women.
METHODS: We analyzed cross-sectional data from 5,888 community-dwelling older men and women. Disability was defined as difficulty with greater than or equal to one activity of daily living. Thirteen medical conditions were assessed by self-report, testing, or record review.
RESULTS: Controlling for age, race, education, and marital status, women were more likely to experience disability (odds ratio = 1.70, 95% confidence interval = 1.36-2.11). Higher prevalence of arthritis and obesity in women explained 30.2% and 12.9%, respectively, of the sex-based difference in disability rates, whereas male prevalent diseases like vascular conditions and emphysema narrowed the disability gap. Women with arthritis, hearing problems, coronary artery disease, congestive heart failure, stroke, and claudication were more likely to exhibit disability compared with men with the same conditions (p < .001).
CONCLUSIONS: Efforts to lessen sex-based inequality in disability should focus on reducing the prevalence of arthritis and obesity. Future generations may see greater functional disparity if rates of vascular disease and emphysema rise among women. Several conditions were more often associated with disability in women, suggesting additional sex-based differences in the disablement process.
10aAged10aArthritis10aCardiovascular Diseases10aChronic Disease10aCohort Studies10aComorbidity10aCross-Sectional Studies10aDisabled Persons10aEmphysema10aFemale10aHearing Disorders10aHumans10aMale10aObesity10aPrevalence10aSex Distribution1 aWhitson, Heather, E1 aLanderman, Lawrence, R1 aNewman, Anne, B1 aFried, Linda, P1 aPieper, Carl, F1 aCohen, Harvey, Jay uhttps://chs-nhlbi.org/node/122003132nas a2200469 4500008004100000022001400041245015000055210006900205260001300274300001000287490000700297520179300304653001602097653000902113653002202122653001902144653002802163653002102191653002102212653002202233653001102255653001902266653001102285653002502296653001102321653000902332653003202341653001602373653001202389653002602401653001802427100002002445700002102465700002202486700002202508700002202530700001802552700001902570700001702589700002002606856003602626 2010 eng d a1941-722500aCombined association of lipids and blood pressure in relation to incident cardiovascular disease in the elderly: the cardiovascular health study.0 aCombined association of lipids and blood pressure in relation to c2010 Feb a161-70 v233 aBACKGROUND: Hypertension and dyslipidemia are highly prevalent in the elderly. We studied the combined impact of both conditions on cardiovascular disease (CVD) events.
METHODS: We studied 4,311 participants aged 65-98 (61.2% female) from the Cardiovascular Health Study (CHS), a longitudinal epidemiologic study, with no prior CVD. We evaluated the relation of low-density lipoprotein (LDL), high-density lipoprotein (HDL), or non-HDL-cholesterol combined with blood pressure (BP) categories to incident CVD-including coronary heart disease (CHD) (angina, myocardial infarction (MI), angioplasty, coronary bypass surgery, or CHD death), stroke, claudication, and CVD death over 15 years.
RESULTS: CVD incidence (per 1,000 person years) ranged from 38.4 when BP <120/80 mm Hg and LDL-C <100 mg/dl to 94.8 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl, and from 28.9 when BP <120/80 mm Hg and HDL >60 mg/dl to 87.1 for a BP >or=160/100 and HDL-C <40 mg/dl. Compared with those with BP <120/80 mm Hg with either LDL-C <100 mg/dl or HDL-C >60 mg/dl, hazard ratios (HRs) for CVD events were 2.1 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl and 2.1 when BP >or=160/100 and HDL-C <40 mg/dl (all P < 0.01), with similar results for non-HDL-C. Elevated BP was associated with increased risk across all lipid levels. Increased LDL-C added risk mainly when BP <140/90 mm Hg, but lower HDL-C also predicted CVD in those with higher BP.
CONCLUSION: Increased BP confers increased risks for CVD in elderly persons across all lipid levels. Although increased LDL-C added risk mainly when BP <140/90 mm Hg, low HDL-C added risk also in those with hypertension. These results document the importance of combined hypertension and dyslipidemia.
10aAge Factors10aAged10aAged, 80 and over10aBlood Pressure10aCardiovascular Diseases10aCholesterol, HDL10aCholesterol, LDL10aDiabetes Mellitus10aFemale10aHealth Surveys10aHumans10aLikelihood Functions10aLipids10aMale10aProportional Hazards Models10aSex Factors10aSmoking10aSocioeconomic Factors10aUnited States1 aWong, Nathan, D1 aLopez, Victor, A1 aRoberts, Craig, S1 aSolomon, Henry, A1 aBurke, Gregory, L1 aKuller, Lewis1 aTracy, Russell1 aYanez, David1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/114505927nas a2201285 4500008004100000022001400041245009300055210006900148260001600217300001000233490000800243520230500251653001102556653003202567653003102599653001902630653002402649653001102673653004002684653003802724653003402762653001702796653001502813653001102828653001602839653003002855653002702885653003602912653001202948653001802960653001402978653002502992100002003017700001603037700002003053700002203073700002403095700001703119700002103136700002703157700001903184700002203203700002003225700002103245700002203266700002303288700002203311700002403333700001903357700001503376700002603391700002203417700001803439700002003457700002103477700001703498700002203515700002003537700002103557700001903578700001903597700002303616700001603639700001803655700002003673700002103693700002203714700002503736700002203761700001803783700002003801700001803821700001803839700002303857700002803880700001803908700002403926700002103950700002003971700001903991700001604010700002104026700001704047700001704064700002204081700002004103700002704123700002004150700001904170700002004189700002304209700002004232700002204252700001904274700002304293700002004316700002804336700001904364700002704383700001904410700002404429700002204453700002804475700002004503700001804523700001904541700002104560700002404581856003604605 2010 eng d a1474-547X00aCommon genetic determinants of vitamin D insufficiency: a genome-wide association study.0 aCommon genetic determinants of vitamin D insufficiency a genomew c2010 Jul 17 a180-80 v3763 aBACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.
METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.
FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.
INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.
FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
10aCanada10aChromosomes, Human, Pair 1110aChromosomes, Human, Pair 410aCohort Studies10aDietary Supplements10aEurope10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeterozygote10aHomozygote10aHumans10aImmunoassay10aInternational Cooperation10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide10aSeasons10aUnited States10aVitamin D10aVitamin D Deficiency1 aWang, Thomas, J1 aZhang, Feng1 aRichards, Brent1 aKestenbaum, Bryan1 avan Meurs, Joyce, B1 aBerry, Diane1 aKiel, Douglas, P1 aStreeten, Elizabeth, A1 aOhlsson, Claes1 aKoller, Daniel, L1 aPeltonen, Leena1 aCooper, Jason, D1 aO'Reilly, Paul, F1 aHouston, Denise, K1 aGlazer, Nicole, L1 aVandenput, Liesbeth1 aPeacock, Munro1 aShi, Julia1 aRivadeneira, Fernando1 aMcCarthy, Mark, I1 aAnneli, Pouta1 ade Boer, Ian, H1 aMangino, Massimo1 aKato, Bernet1 aSmyth, Deborah, J1 aBooth, Sarah, L1 aJacques, Paul, F1 aBurke, Greg, L1 aGoodarzi, Mark1 aCheung, Ching-Lung1 aWolf, Myles1 aRice, Kenneth1 aGoltzman, David1 aHidiroglou, Nick1 aLadouceur, Martin1 aWareham, Nicholas, J1 aHocking, Lynne, J1 aHart, Deborah1 aArden, Nigel, K1 aCooper, Cyrus1 aMalik, Suneil1 aFraser, William, D1 aHartikainen, Anna-Liisa1 aZhai, Guangju1 aMacdonald, Helen, M1 aForouhi, Nita, G1 aLoos, Ruth, J F1 aReid, David, M1 aHakim, Alan1 aDennison, Elaine1 aLiu, Yongmei1 aPower, Chris1 aStevens, Helen, E1 aJaana, Laitinen1 aVasan, Ramachandran, S1 aSoranzo, Nicole1 aBojunga, Jörg1 aPsaty, Bruce, M1 aLorentzon, Mattias1 aForoud, Tatiana1 aHarris, Tamara, B1 aHofman, Albert1 aJansson, John-Olov1 aCauley, Jane, A1 aUitterlinden, André, G1 aGibson, Quince1 aJarvelin, Marjo-Riitta1 aKarasik, David1 aSiscovick, David, S1 aEcons, Michael, J1 aKritchevsky, Stephen, B1 aFlorez, Jose, C1 aTodd, John, A1 aDupuis, Josée1 aHyppönen, Elina1 aSpector, Timothy, D uhttps://chs-nhlbi.org/node/120404123nas a2200817 4500008004100000022001400041245007500055210006900130260001300199300001200212490000700224520182200231653001002053653000902063653004002072653001102112653003002123653001902153653001702172653002202189653003402211653001102245653001102256653000902267653001602276653001502292653003602307653003102343653001602374653005402390100002202444700002202466700001902488700002102507700002002528700001702548700001702565700002802582700002402610700002602634700002202660700002002682700002202702700001802724700002302742700002002765700002202785700001602807700002002823700002002843700002102863700002202884700001202906700001902918700002102937700001802958700001602976700001702992700002603009700001903035700002603054700002803080700001903108700002303127700002403150700002003174700003003194700002403224700002103248856003603269 2010 eng d a1533-345000aCommon genetic variants associate with serum phosphorus concentration.0 aCommon genetic variants associate with serum phosphorus concentr c2010 Jul a1223-320 v213 aPhosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.
10aAdult10aAged10aEuropean Continental Ancestry Group10aFemale10aFibroblast Growth Factors10aGene Frequency10aGenetic Loci10aGenetic Variation10aGenome-Wide Association Study10aHumans10aKidney10aMale10aMiddle Aged10aPhosphorus10aPolymorphism, Single Nucleotide10aReceptors, Calcium-Sensing10aSex Factors10aSodium-Phosphate Cotransporter Proteins, Type IIa1 aKestenbaum, Bryan1 aGlazer, Nicole, L1 aKöttgen, Anna1 aFelix, Janine, F1 aHwang, Shih-Jen1 aLiu, Yongmei1 aLohman, Kurt1 aKritchevsky, Stephen, B1 aHausman, Dorothy, B1 aPetersen, Ann-Kristin1 aGieger, Christian1 aRied, Janina, S1 aMeitinger, Thomas1 aStrom, Tim, M1 aWichmann, Erich, H1 aCampbell, Harry1 aHayward, Caroline1 aRudan, Igor1 ade Boer, Ian, H1 aPsaty, Bruce, M1 aRice, Kenneth, M1 aChen, Yii-Der Ida1 aLi, Man1 aArking, Dan, E1 aBoerwinkle, Eric1 aCoresh, Josef1 aYang, Qiong1 aLevy, Daniel1 avan Rooij, Frank, J A1 aDehghan, Abbas1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aDuijn, Cornelia, M1 aShlipak, Michael, G1 aKao, Linda, W H1 aWitteman, Jacqueline, C M1 aSiscovick, David, S1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/120605521nas a2201561 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520109100256653001201347653002101359653002301380653002601403653002401429653001701453653003401470653002801504653001101532653000901543653002101552653001901573653002201592653004001614653003601654653002001690100002201710700001801732700002501750700001801775700002901793700001901822700001501841700002101856700002201877700001901899700002101918700002501939700002201964700002601986700001902012700002302031700001702054700002202071700002602093700001802119700002002137700002202157700001202179700001902191700002602210700001902236700001902255700001802274700001802292700001902310700001802329700001802347700002702365700001902392700002402411700001902435700001702454700002002471700002702491700001702518700002602535700002202561700001702583700002302600700002202623700002402645700002402669700002002693700001902713700002502732700002002757700002302777700002802800700001902828700002402847700001702871700002102888700002402909700002202933700002002955700001702975700002202992700001903014700003003033700002103063700002003084700002303104700002203127700001903149700002003168700002103188700002803209700002903237700003003266700002603296700002303322700002103345700001903366700001603385700001703401700002603418700002403444700002203468700002203490700002903512700002003541700002003561700001803581700001603599700002003615700002103635700002603656700002403682700002003706700002403726700002303750700002203773700002203795700002003817700002603837700002203863700001903885700001903904856003603923 2010 eng d a1546-171800aCommon variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.0 aCommon variants in 22 loci are associated with QRS duration and c2010 Dec a1068-760 v423 aThe QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
10aAnimals10aAnimals, Newborn10aChromosomes, Human10aComputational Biology10aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMice10aMice, Transgenic10aModels, Animal10aMyocytes, Cardiac10aNAV1.8 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSodium Channels1 aSotoodehnia, Nona1 aIsaacs, Aaron1 ade Bakker, Paul, I W1 aDörr, Marcus1 aNewton-Cheh, Christopher1 aNolte, Ilja, M1 aHarst, Pim1 aMüller, Martina1 aEijgelsheim, Mark1 aAlonso, Alvaro1 aHicks, Andrew, A1 aPadmanabhan, Sandosh1 aHayward, Caroline1 aSmith, Albert, Vernon1 aPolasek, Ozren1 aGiovannone, Steven1 aFu, Jingyuan1 aMagnani, Jared, W1 aMarciante, Kristin, D1 aPfeufer, Arne1 aGharib, Sina, A1 aTeumer, Alexander1 aLi, Man1 aBis, Joshua, C1 aRivadeneira, Fernando1 aAspelund, Thor1 aKöttgen, Anna1 aJohnson, Toby1 aRice, Kenneth1 aSie, Mark, P S1 aWang, Ying, A1 aKlopp, Norman1 aFuchsberger, Christian1 aWild, Sarah, H1 aLeach, Irene, Mateo1 aEstrada, Karol1 aVölker, Uwe1 aWright, Alan, F1 aAsselbergs, Folkert, W1 aQu, Jiaxiang1 aChakravarti, Aravinda1 aSinner, Moritz, F1 aKors, Jan, A1 aPetersmann, Astrid1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aOostra, Ben, A1 aCupples, Adrienne, L1 aPerz, Siegfried1 ade Boer, Rudolf, A1 aUitterlinden, André, G1 aVölzke, Henry1 aSpector, Timothy, D1 aLiu, Fang-Yu1 aBoerwinkle, Eric1 aDominiczak, Anna, F1 aRotter, Jerome, I1 avan Herpen, Gé1 aLevy, Daniel1 aWichmann, H-Erich1 aGilst, Wiek, H1 aWitteman, Jacqueline, C M1 aKroemer, Heyo, K1 aKao, Linda, W H1 aHeckbert, Susan, R1 aMeitinger, Thomas1 aHofman, Albert1 aCampbell, Harry1 aFolsom, Aaron, R1 avan Veldhuisen, Dirk, J1 aSchwienbacher, Christine1 aO'Donnell, Christopher, J1 aVolpato, Claudia, Beu1 aCaulfield, Mark, J1 aConnell, John, M1 aLauner, Lenore1 aLu, Xiaowen1 aFranke, Lude1 aFehrmann, Rudolf, S N1 aMeerman, Gerard, te1 aGroen, Harry, J M1 aWeersma, Rinse, K1 avan den Berg, Leonard, H1 aWijmenga, Cisca1 aOphoff, Roel, A1 aNavis, Gerjan1 aRudan, Igor1 aSnieder, Harold1 aWilson, James, F1 aPramstaller, Peter, P1 aSiscovick, David, S1 aWang, Thomas, J1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aFelix, Stephan, B1 aFishman, Glenn, I1 aJamshidi, Yalda1 aStricker, Bruno, H Ch1 aSamani, Nilesh, J1 aKääb, Stefan1 aArking, Dan, E uhttps://chs-nhlbi.org/node/124404063nas a2201069 4500008004100000022001400041245007500055210006900130260001300199300001000212490000700222520107100229653001501300653001001315653000901325653002401334653002501358653001901383653001101402653003401413653001101447653001201458653000901470653002701479653001601506653003601522653005901558653001601617100002401633700002401657700002201681700001801703700001901721700001901740700002201759700002501781700002101806700002201827700001501849700001901864700002301883700002301906700002401929700002401953700002101977700002601998700002202024700002502046700001302071700002002084700002202104700002202126700002302148700002102171700002202192700002202214700001802236700001602254700002002270700002002290700001602310700001902326700002002345700002902365700001202394700002402406700002002430700002002450700002702470700002302497700002102520700002602541700001902567700002802586700001702614700002102631700002102652700001902673700002602692700002402718700002002742700001802762700002202780700002202802700003002824700001802854700001902872700002402891700002302915700001902938856003602957 2010 eng d a1546-171800aCommon variants in KCNN3 are associated with lone atrial fibrillation.0 aCommon variants in KCNN3 are associated with lone atrial fibrill c2010 Mar a240-40 v423 aAtrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
10aAdolescent10aAdult10aAged10aAtrial Fibrillation10aCase-Control Studies10aCohort Studies10aFemale10aGenome-Wide Association Study10aHumans10aIntrons10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aSmall-Conductance Calcium-Activated Potassium Channels10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aGlazer, Nicole, L1 aPfeufer, Arne1 aAlonso, Alvaro1 aChung, Mina, K1 aSinner, Moritz, F1 ade Bakker, Paul, I W1 aMueller, Martina1 aLubitz, Steven, A1 aFox, Ervin1 aDarbar, Dawood1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aSchnabel, Renate, B1 aSoliman, Elsayed, Z1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aBeckmann, Britt-M1 avan Noord, Charlotte1 aWang, Ke1 aEhret, Georg, B1 aRotter, Jerome, I1 aHazen, Stanley, L1 aSteinbeck, Gerhard1 aSmith, Albert, V1 aLauner, Lenore, J1 aHarris, Tamara, B1 aMakino, Seiko1 aNelis, Mari1 aMilan, David, J1 aPerz, Siegfried1 aEsko, Tõnu1 aKöttgen, Anna1 aMoebus, Susanne1 aNewton-Cheh, Christopher1 aLi, Man1 aMöhlenkamp, Stefan1 aWang, Thomas, J1 aKao, Linda, W H1 aVasan, Ramachandran, S1 aNöthen, Markus, M1 aMacRae, Calum, A1 aStricker, Bruno, H Ch1 aHofman, Albert1 aUitterlinden, André, G1 aLevy, Daniel1 aBoerwinkle, Eric1 aMetspalu, Andres1 aTopol, Eric, J1 aChakravarti, Aravinda1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aRoden, Dan, M1 aMeitinger, Thomas1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aBarnard, John1 aArking, Dan, E1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aKääb, Stefan uhttps://chs-nhlbi.org/node/117003077nas a2200529 4500008004100000022001400041245010500055210006900160260001600229300001300245490000700258520157300265653001001838653001201848653001101860653001101871653000901882653001601891653003601907653003101943100002601974700001602000700002202016700002202038700001902060700002102079700002002100700001702120700002002137700002302157700001902180700002802199700002202227700002102249700002402270700002202294700002002316700001802336700002402354700002802378700001902406700002502425700002102450700001902471710002102490856003602511 2010 eng d a1460-208300aCommon variants in the calcium-sensing receptor gene are associated with total serum calcium levels.0 aCommon variants in the calciumsensing receptor gene are associat c2010 Nov 01 a4296-3030 v193 aSerum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.
10aAdult10aCalcium10aFemale10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Calcium-Sensing1 aO'Seaghdha, Conall, M1 aYang, Qiong1 aGlazer, Nicole, L1 aLeak, Tennille, S1 aDehghan, Abbas1 aSmith, Albert, V1 aKao, Linda, W H1 aLohman, Kurt1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aHofman, Albert1 aUitterlinden, André, G1 aChen, Yii-Der Ida1 aBrown, Edward, M1 aSiscovick, David, S1 aHarris, Tamara, B1 aPsaty, Bruce, M1 aCoresh, Josef1 aGudnason, Vilmundur1 aWitteman, Jacqueline, C1 aLiu, Yong, Mei1 aKestenbaum, Bryan, R1 aFox, Caroline, S1 aKöttgen, Anna1 aGEFOS Consortium uhttps://chs-nhlbi.org/node/122403743nas a2200553 4500008004100000022001400041245013700055210006900192260001600261300001100277490000800288520220500296653002102501653001502522653001902537653002002556653002302576653001602599653002102615653002302636653002202659653001102681653001502692653001102707653001802718653002002736653001802756653000902774653001602783653001902799653001402818653002402832653002002856653001702876653001802893653001602911653001202927653001102939653001802950110004002968700002103008700003003029700001703059700001903076700002303095700001803118700001703136856003603153 2010 eng d a1474-547X00aC-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis.0 aCreactive protein concentration and risk of coronary heart disea c2010 Jan 09 a132-400 v3753 aBACKGROUND: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances.
METHODS: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1.31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels.
RESULTS: Log(e) CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors; 1.44 (1.32-1.57) and 1.27 (1.15-1.40) for ischaemic stroke; 1.71 (1.53-1.91) and 1.55 (1.37-1.76) for vascular mortality; and 1.55 (1.41-1.69) and 1.54 (1.40-1.68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07-1.42) for coronary heart disease; 1.32 (1.18-1.49) for ischaemic stroke; 1.34 (1.18-1.52) for vascular mortality; and 1.34 (1.20-1.50) for non-vascular mortality.
INTERPRETATION: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation.
FUNDING: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.
10aAlcohol Drinking10aBiomarkers10aBlood Pressure10aBody Mass Index10aC-Reactive Protein10aCholesterol10aCoronary Disease10aDatabases, Factual10aDiabetes Mellitus10aFemale10aFibrinogen10aHumans10aInterleukin-610aLeukocyte Count10aLung Diseases10aMale10aMiddle Aged10aMotor Activity10aNeoplasms10aRegression Analysis10aRisk Assessment10aRisk Factors10aSerum Albumin10aSex Factors10aSmoking10aStroke10aTriglycerides1 aEmerging Risk Factors Collaboration1 aKaptoge, Stephen1 aDi Angelantonio, Emanuele1 aLowe, Gordon1 aPepys, Mark, B1 aThompson, Simon, G1 aCollins, Rory1 aDanesh, John uhttps://chs-nhlbi.org/node/115103048nas a2200481 4500008004100000022001400041245006500055210006300120260001300183300001000196490000700206520171100213653002201924653000901946653002201955653002001977653002301997653001902020653003402039653004002073653001102113653003802124653001502162653001102177653000902188653001402197653003602211653002402247653001702271653001202288100002402300700002102324700002202345700002202367700002002389700002102409700002002430700001802450700002002468700002402488700001802512856003602530 2010 eng d a1440-184300aCRP gene variation and risk of community-acquired pneumonia.0 aCRP gene variation and risk of communityacquired pneumonia c2010 Jan a160-40 v153 aBACKGROUND AND OBJECTIVE: CRP has several potentially antibacterial effects, and variation in the CRP gene is known to influence CRP levels. Whether this variation influences risk of infection, and hence whether CRP has anti-infective activity in humans, is uncertain.
METHODS: We evaluated a series of haplotype-tagging single nucleotide polymorphisms among 5374 individuals in the Cardiovascular Health Study, a cohort of older adults from four communities, who were followed for community-acquired pneumonia for 12-13 years. Secondarily, we evaluated whether these polymorphisms varied among men in the Health Professionals Follow-up Study who self-reported pneumonia on biennial questionnaires.
RESULTS: There were 581 (507 white and 74 black) Cardiovascular Health Study participants with incident hospitalizations for pneumonia. No single nucleotide polymorphism or haplotypes were associated with risk among white Cardiovascular Health Study participants. Among black participants, the haplotype tagged by A790T was associated with lower risk of incident pneumonia (hazard ratio 0.5; 95% confidence interval: 0.3-0.9) and with higher CRP levels. In Health Professionals Follow-up Study, a separate haplotype was associated with less frequent self-reported pneumonia but not with circulating CRP levels.
CONCLUSIONS: Some genetic variants in CRP may be associated with risk of pneumonia, but haplotypes associated with risk are variably associated with baseline CRP levels. If CRP is a relevant component of innate immunity in humans, the inducibility or tissue-specificity of expression may be at least as important as chronic circulating levels.
10aAfrican Americans10aAged10aAged, 80 and over10aBody Mass Index10aC-Reactive Protein10aCohort Studies10aCommunity-Acquired Infections10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aMale10aPneumonia10aPolymorphism, Single Nucleotide10aProspective Studies10aRisk Factors10aSmoking1 aMukamal, Kenneth, J1 aPai, Jennifer, K1 aO'Meara, Ellen, S1 aTracy, Russell, P1 aPsaty, Bruce, M1 aKuller, Lewis, H1 aNewman, Anne, B1 aYende, Sachin1 aCurhan, Gary, C1 aSiscovick, David, S1 aRimm, Eric, B uhttps://chs-nhlbi.org/node/114703253nas a2200493 4500008004100000022001400041245006100055210006000116260001300176300001100189490000600200520194500206653001602151653000902167653001502176653002802191653001502219653001502234653002702249653001102276653003102287653001102318653001402329653002002343653002502363653000902388653003202397653002002429653001702449653001702466653001802483653001802501100001502519700002202534700001602556700002002572700002002592700002102612700002202633700002002655700002402675700002402699856003602723 2010 eng d a1941-770500aCystatin C and sudden cardiac death risk in the elderly.0 aCystatin C and sudden cardiac death risk in the elderly c2010 Mar a159-640 v33 aBACKGROUND: Recent studies have demonstrated an association between moderate kidney dysfunction and sudden cardiac death in people with cardiovascular disease.
METHODS AND RESULTS: The study was a longitudinal analysis among 4465 participants from the Cardiovascular Health Study without prevalent cardiovascular disease at baseline. Cystatin C and creatinine were measured from baseline sera. Sudden cardiac death (SCD) was defined as a sudden pulseless condition from a cardiac origin in a previously stable individual that occurred out of the hospital or in the emergency room. The association between cystatin C tertiles and SCD was determined with multivariate Cox proportional hazards. A similar analysis compared SCD incidence across creatinine-based estimated glomerular filtration rate (eGFR) tertiles. Over a median follow-up of 11.2 years, 91 adjudicated SCD events occurred. The annual incidence of SCD events increased across cystatin C tertiles: 10 events per 10 000 person years in tertile 1, 25 events per 10 000 person years in tertile 2, and 32 events per 10 000 person-years in the highest cystatin C tertile. These associations persisted after multivariate adjustment: hazards ratio=2.72; 95% confidence interval, 1.44 to 5.16 in tertile 2 and hazards ratio=2.67; 95% confidence interval, 1.33 to 5.35 in tertile 3. After multivariate adjustment, the rate of SCD also increased in a linear distribution across creatinine-based eGFR tertiles: 15 events per 10 000 person-years in tertile 1, 22 events per 10 000 person-years in tertile 2, and 27 events per 10 000 person-years in tertile 3. No significant associations, however, remained between creatinine-based eGFR and SCD after multivariable adjustment.
CONCLUSIONS: Impaired kidney function, as measured by cystatin C, has an independent association with SCD risk among elderly persons without clinical cardiovascular disease.
10aAge Factors10aAged10aBiomarkers10aChi-Square Distribution10aCreatinine10aCystatin C10aDeath, Sudden, Cardiac10aFemale10aGlomerular Filtration Rate10aHumans10aIncidence10aKidney Diseases10aLongitudinal Studies10aMale10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aTime Factors10aUnited States10aUp-Regulation1 aDeo, Rajat1 aSotoodehnia, Nona1 aKatz, Ronit1 aSarnak, Mark, J1 aFried, Linda, F1 aChonchol, Michel1 aKestenbaum, Bryan1 aPsaty, Bruce, M1 aSiscovick, David, S1 aShlipak, Michael, G uhttps://chs-nhlbi.org/node/117703957nas a2200517 4500008004100000022001400041245014800055210006900203260001600272300001200288490000800300520256500308653001002873653000902883653001802892653002102910653002702931653002202958653001202980653001102992653001103003653000903014653001603023653001703039653001103056110004003067700001403107700001103121700002803132700001303160700001503173700002303188700001703211700001603228700001403244700001603258700002203274700001703296700001603313700001603329700001403345700001603359700001403375700001403389856003603403 2010 eng d a1474-547X00aDiabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.0 aDiabetes mellitus fasting blood glucose concentration and risk o c2010 Jun 26 a2215-220 v3753 aBACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances.
METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease.
FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors.
INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease.
FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.
10aAdult10aAged10aBlood Glucose10aCoronary Disease10aDiabetes Complications10aDiabetes Mellitus10aFasting10aFemale10aHumans10aMale10aMiddle Aged10aRisk Factors10aStroke1 aEmerging Risk Factors Collaboration1 aSarwar, N1 aGao, P1 aSeshasai, S, R Kondapal1 aGobin, R1 aKaptoge, S1 aDi Angelantonio, E1 aIngelsson, E1 aLawlor, D A1 aSelvin, E1 aStampfer, M1 aStehouwer, C, D A1 aLewington, S1 aPennells, L1 aThompson, A1 aSattar, N1 aWhite, I, R1 aRay, K, K1 aDanesh, J uhttps://chs-nhlbi.org/node/121303170nas a2200481 4500008004100000022001400041245008500055210006900140260001600209300001200225490000800237520177400245653002202019653000902041653002402050653004002074653001102114653003402125653001102159653000902170653001602179653001702195100002302212700001902235700002302254700002202277700002202299700002202321700001802343700002402361700001702385700002202402700001502424700002202439700002302461700002402484700002002508700002402528700002402552700002302576710005302599856003602652 2010 eng d a1524-453900aEuropean ancestry as a risk factor for atrial fibrillation in African Americans.0 aEuropean ancestry as a risk factor for atrial fibrillation in Af c2010 Nov 16 a2009-150 v1223 aBACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF.
METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results.
CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.
10aAfrican Americans10aAged10aAtrial Fibrillation10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aRisk Factors1 aMarcus, Gregory, M1 aAlonso, Alvaro1 aPeralta, Carmen, A1 aLettre, Guillaume1 aVittinghoff, Eric1 aLubitz, Steven, A1 aFox, Ervin, R1 aLevitzky, Yamini, S1 aMehra, Reena1 aKerr, Kathleen, F1 aDeo, Rajat1 aSotoodehnia, Nona1 aAkylbekova, Meggie1 aEllinor, Patrick, T1 aPaltoo, Dina, N1 aSoliman, Elsayed, Z1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aCandidate-Gene Association Resource (CARe) Study uhttps://chs-nhlbi.org/node/124805209nas a2201129 4500008004100000022001400041245009100055210006900146260001600215300001300231490000600244520200900250653001502259653001002274653000902284653002202293653002802315653001002343653002102353653003202374653003202406653003102438653003102469653001902500653004002519653001102559653001702570653003402587653001102621653000902632653002702641653002102668653001602689653003602705653002002741653001602761100001802777700001702795700001702812700002302829700002502852700002002877700002002897700001902917700001802936700002402954700002702978700001703005700001703022700001903039700002803058700002603086700001903112700002703131700002303158700001503181700002003196700002603216700002203242700001903264700002203283700002003305700002303325700002403348700001903372700002203391700002203413700002003435700001603455700002203471700001803493700002603511700002103537700002203558700002403580700002003604700001703624700002203641700002303663700002803686700001703714700001903731700001603750700002703766700002103793700002303814700002203837700002203859700002103881700001903902700002403921700002403945700002803969700001803997710002804015856003604043 2010 eng d a1553-740400aFour novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.0 aFour novel Loci 19q13 6q24 12q24 and 5q14 influence the microcir c2010 Oct 28 ae10011840 v63 aThere is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aChild10aChild, Preschool10aChromosomes, Human, Pair 1210aChromosomes, Human, Pair 1910aChromosomes, Human, Pair 510aChromosomes, Human, Pair 610aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMicrocirculation10aMiddle Aged10aPolymorphism, Single Nucleotide10aRetinal Vessels10aYoung Adult1 aIkram, Kamran1 aSim, Xueling1 aXueling, Sim1 aJensen, Richard, A1 aCotch, Mary, Frances1 aHewitt, Alex, W1 aIkram, Arfan, M1 aWang, Jie, Jin1 aKlein, Ronald1 aKlein, Barbara, E K1 aBreteler, Monique, M B1 aCheung, Ning1 aLiew, Gerald1 aMitchell, Paul1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aHofman, Albert1 ade Jong, Paulus, T V M1 aDuijn, Cornelia, M1 aKao, Linda1 aCheng, Ching-Yu1 aSmith, Albert, Vernon1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aJonasson, Fridbert1 aEiriksdottir, Gudny1 aAspelund, Thor1 aHarris, Tamara, B1 aLauner, Lenore, J1 aTaylor, Kent, D1 aLi, Xiaohui1 aIyengar, Sudha, K1 aXi, Quansheng1 aSivakumaran, Theru, A1 aMackey, David, A1 aMacgregor, Stuart1 aMartin, Nicholas, G1 aYoung, Terri, L1 aBis, Josh, C1 aWiggins, Kerri, L1 aHeckbert, Susan, R1 aHammond, Christopher, J1 aAndrew, Toby1 aFahy, Samantha1 aAttia, John1 aHolliday, Elizabeth, G1 aScott, Rodney, J1 aIslam, F, M Amirul1 aRotter, Jerome, I1 aMcAuley, Annie, K1 aBoerwinkle, Eric1 aTai, Shyong, E1 aGudnason, Vilmundur1 aSiscovick, David, S1 aVingerling, Johannes, R1 aWong, Tien, Y1 aGlobal BPgen Consortium uhttps://chs-nhlbi.org/node/124303239nas a2200577 4500008004100000022001400041245008800055210006900143260001600212300001200228490000700240520165400247653001501901653001001916653000901926653001001935653002101945653001901966653001801985653001102003653002402014653003402038653001102072653000902083653001602092653003602108653001602144100002602160700002302186700002002209700002302229700001702252700002002269700001902289700002302308700001602331700002202347700001802369700001902387700001902406700001602425700002102441700001502462700002102477700002302498700001702521700002302538700002202561710004202583856003602625 2010 eng d a1460-208300aFucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.0 aFucosyltransferase 2 FUT2 nonsecretor status is associated with c2010 Sep 01 a3468-760 v193 aGenetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
10aAdolescent10aAdult10aAged10aChild10aChild, Preschool10aCohort Studies10aCrohn Disease10aFemale10aFucosyltransferases10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aYoung Adult1 aMcGovern, Dermot, P B1 aJones, Michelle, R1 aTaylor, Kent, D1 aMarciante, Kristin1 aYan, Xiaofei1 aDubinsky, Marla1 aIppoliti, Andy1 aVasiliauskas, Eric1 aBerel, Dror1 aDerkowski, Carrie1 aDutridge, Deb1 aFleshner, Phil1 aShih, David, Q1 aMelmed, Gil1 aMengesha, Emebet1 aKing, Lily1 aPressman, Sheila1 aHaritunians, Talin1 aGuo, Xiuqing1 aTargan, Stephan, R1 aRotter, Jerome, I1 aInternational IBD Genetics Consortium uhttps://chs-nhlbi.org/node/120903946nas a2200685 4500008004100000022001400041245005100055210004900106260001600155300001100171490000800182520209900190653001502289653001002304653002202314653000902336653002202345653001102367653002902378653002002407653001302427653001102440653001802451653000902469653001602478653004402494653002102538653003102559653001902590653001602609100001802625700002002643700002402663700002002687700002002707700002102727700002102748700002502769700001602794700001602810700002102826700002402847700002802871700003102899700002202930700002202952700001902974700001902993700002803012700001703040700002203057700002603079700002003105700001803125700001403143700002003157700001503177700003203192856003603224 2010 eng d a1533-440600aGenetic ancestry in lung-function predictions.0 aGenetic ancestry in lungfunction predictions c2010 Jul 22 a321-300 v3633 aBACKGROUND: Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American.
METHODS: We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations.
RESULTS: African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5% of participants.
CONCLUSIONS: Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)
10aAdolescent10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aFemale10aForced Expiratory Volume10aGenetic Markers10aGenotype10aHumans10aLinear Models10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aReference Values10aRespiratory Function Tests10aVital Capacity10aYoung Adult1 aKumar, Rajesh1 aSeibold, Max, A1 aAldrich, Melinda, C1 aWilliams, Keoki1 aReiner, Alex, P1 aColangelo, Laura1 aGalanter, Joshua1 aGignoux, Christopher1 aHu, Donglei1 aSen, Saunak1 aChoudhry, Shweta1 aPeterson, Edward, L1 aRodriguez-Santana, Jose1 aRodriguez-Cintron, William1 aNalls, Michael, A1 aLeak, Tennille, S1 aO'Meara, Ellen1 aMeibohm, Bernd1 aKritchevsky, Stephen, B1 aLi, Rongling1 aHarris, Tamara, B1 aNickerson, Deborah, A1 aFornage, Myriam1 aEnright, Paul1 aZiv, Elad1 aSmith, Lewis, J1 aLiu, Kiang1 aBurchard, Esteban González uhttps://chs-nhlbi.org/node/121803246nas a2200529 4500008004100000022001400041245006700055210006600122260001300188300001200201490000700213520174900220653001801969653001501987653001002002653001902012653001402031653002402045653001102069653001702080653003402097653001102131653003702142653000902179653003602188653001702224653003002241653005502271653001602326100002302342700002002365700002302385700002002408700002102428700001702449700001702466700001902483700001602502700002102518700002002539700002202559700002602581700002202607700002502629700002602654856003602680 2010 eng d a1536-484400aGenetic predictors of medically refractory ulcerative colitis.0 aGenetic predictors of medically refractory ulcerative colitis c2010 Nov a1830-400 v163 aBACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC.
METHODS: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls.
RESULTS: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)).
CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.
10aAcute Disease10aAdolescent10aAdult10aCohort Studies10aColectomy10aColitis, Ulcerative10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMajor Histocompatibility Complex10aMale10aPolymorphism, Single Nucleotide10aRisk Factors10aSeverity of Illness Index10aTumor Necrosis Factor Ligand Superfamily Member 1510aYoung Adult1 aHaritunians, Talin1 aTaylor, Kent, D1 aTargan, Stephan, R1 aDubinsky, Marla1 aIppoliti, Andrew1 aKwon, Soonil1 aGuo, Xiuqing1 aMelmed, Gil, Y1 aBerel, Dror1 aMengesha, Emebet1 aPsaty, Bruce, M1 aGlazer, Nicole, L1 aVasiliauskas, Eric, A1 aRotter, Jerome, I1 aFleshner, Phillip, R1 aMcGovern, Dermot, P B uhttps://chs-nhlbi.org/node/122905807nas a2201045 4500008004100000022001400041245007600055210006900131260001600200300001200216490000800228520280100236653001703037653000903054653002203063653002503085653001703110653003803127653003403165653001103199653001503210653003603225100002003261700002803281700002003309700002403329700002403353700001703377700001903394700002103413700002903434700002703463700001903490700003103509700002603540700002303566700002003589700002603609700002003635700003103655700002303686700001903709700002203728700001803750700002103768700002403789700002303813700002403836700002103860700002003881700001703901700002203918700002403940700002203964700002403986700001904010700002104029700002504050700002604075700002104101700002604122700002204148700002804170700002304198700002204221700001804243700001904261700002204280700002004302700001804322700002204340700001404362700002004376700002804396700002304424700001904447700001804466700002004484700002204504700002204526700002004548700002204568700002004590700002304610700002704633710002204660710002204682710002104704856003604725 2010 eng d a1538-359800aGenome-wide analysis of genetic loci associated with Alzheimer disease.0 aGenomewide analysis of genetic loci associated with Alzheimer di c2010 May 12 a1832-400 v3033 aCONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).
OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).
DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.
MAIN OUTCOME MEASURE: Presence of Alzheimer disease.
RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).
CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
10aAge of Onset10aAged10aAlzheimer Disease10aCase-Control Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aOdds Ratio10aPolymorphism, Single Nucleotide1 aSeshadri, Sudha1 aFitzpatrick, Annette, L1 aIkram, Arfan, M1 aDeStefano, Anita, L1 aGudnason, Vilmundur1 aBoada, Merce1 aBis, Joshua, C1 aSmith, Albert, V1 aCarassquillo, Minerva, M1 aLambert, Jean, Charles1 aHarold, Denise1 aSchrijvers, Elisabeth, M C1 aRamirez-Lorca, Reposo1 aDebette, Stephanie1 aLongstreth, W T1 aJanssens, Cecile, J W1 aPankratz, Shane1 aDartigues, Jean, François1 aHollingworth, Paul1 aAspelund, Thor1 aHernandez, Isabel1 aBeiser, Alexa1 aKuller, Lewis, H1 aKoudstaal, Peter, J1 aDickson, Dennis, W1 aTzourio, Christophe1 aAbraham, Richard1 aAntunez, Carmen1 aDu, Yangchun1 aRotter, Jerome, I1 aAulchenko, Yurii, S1 aHarris, Tamara, B1 aPetersen, Ronald, C1 aBerr, Claudine1 aOwen, Michael, J1 aLopez-Arrieta, Jesus1 aVaradarajan, Badri, N1 aBecker, James, T1 aRivadeneira, Fernando1 aNalls, Michael, A1 aGraff-Radford, Neill, R1 aCampion, Dominique1 aAuerbach, Sanford1 aRice, Kenneth1 aHofman, Albert1 aJonsson, Palmi, V1 aSchmidt, Helena1 aLathrop, Mark1 aMosley, Thomas, H1 aAu, Rhoda1 aPsaty, Bruce, M1 aUitterlinden, André, G1 aFarrer, Lindsay, A1 aLumley, Thomas1 aRuiz, Agustin1 aWilliams, Julie1 aAmouyel, Philippe1 aYounkin, Steve, G1 aWolf, Philip, A1 aLauner, Lenore, J1 aLopez, Oscar, L1 aDuijn, Cornelia, M1 aBreteler, Monique, M B1 aCHARGE Consortium1 aGERAD1 Consortium1 aEADI1 Consortium uhttps://chs-nhlbi.org/node/119905113nas a2201189 4500008004100000022001400041245009300055210006900148260001600217300001200233490000700245520181400252653001002066653000902076653001702085653001902102653001102121653001702132653001802149653003402167653001502201653001102216653000902227653001602236653003602252653000902288100002202297700002902319700002202348700002502370700002102395700002402416700002102440700001802461700001802479700001802497700001702515700002702532700001902559700001902578700001902597700002002616700001902636700002402655700001902679700002202698700002402720700002602744700002502770700002102795700002002816700001902836700002002855700001702875700002402892700002302916700001802939700001902957700001902976700002202995700002303017700002303040700001903063700002203082700002103104700001903125700002103144700002003165700002003185700001803205700001903223700002103242700001803263700001903281700002003300700002203320700001703342700003003359700002003389700002203409700002203431700001903453700002403472700002003496700002803516700002103544700002203565700002103587700002303608700002003631700002603651700002303677700002303700700002203723700002403745700001803769700002303787700002603810700002103836700003003857856003603887 2010 eng d a1460-208300aGenome-wide association analysis identifies multiple loci related to resting heart rate.0 aGenomewide association analysis identifies multiple loci related c2010 Oct 01 a3885-940 v193 aHigher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
10aAdult10aAged10aBase Pairing10aCohort Studies10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHeart Rate10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRest1 aEijgelsheim, Mark1 aNewton-Cheh, Christopher1 aSotoodehnia, Nona1 ade Bakker, Paul, I W1 aMüller, Martina1 aMorrison, Alanna, C1 aSmith, Albert, V1 aIsaacs, Aaron1 aSanna, Serena1 aDörr, Marcus1 aNavarro, Pau1 aFuchsberger, Christian1 aNolte, Ilja, M1 aGeus, Eco, J C1 aEstrada, Karol1 aHwang, Shih-Jen1 aBis, Joshua, C1 aRückert, Ina-Maria1 aAlonso, Alvaro1 aLauner, Lenore, J1 aHottenga, Jouke Jan1 aRivadeneira, Fernando1 aNoseworthy, Peter, A1 aRice, Kenneth, M1 aPerz, Siegfried1 aArking, Dan, E1 aSpector, Tim, D1 aKors, Jan, A1 aAulchenko, Yurii, S1 aTarasov, Kirill, V1 aHomuth, Georg1 aWild, Sarah, H1 aMarroni, Fabio1 aGieger, Christian1 aLicht, Carmilla, M1 aPrineas, Ronald, J1 aHofman, Albert1 aRotter, Jerome, I1 aHicks, Andrew, A1 aErnst, Florian1 aNajjar, Samer, S1 aWright, Alan, F1 aPeters, Annette1 aFox, Ervin, R1 aOostra, Ben, A1 aKroemer, Heyo, K1 aCouper, David1 aVölzke, Henry1 aCampbell, Harry1 aMeitinger, Thomas1 aUda, Manuela1 aWitteman, Jacqueline, C M1 aPsaty, Bruce, M1 aWichmann, H-Erich1 aHarris, Tamara, B1 aKääb, Stefan1 aSiscovick, David, S1 aJamshidi, Yalda1 aUitterlinden, André, G1 aFolsom, Aaron, R1 aLarson, Martin, G1 aWilson, James, F1 aPenninx, Brenda, W1 aSnieder, Harold1 aPramstaller, Peter, P1 aDuijn, Cornelia, M1 aLakatta, Edward, G1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aPfeufer, Arne1 aHeckbert, Susan, R1 aStricker, Bruno, H Ch1 aBoerwinkle, Eric1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/121703839nas a2200889 4500008004100000022001400041245008800055210006900143260001300212300001000225490000700235520129300242653002401535653003801559653003401597653001101631653002201642653002701664653003601691653001901727100002601746700001901772700002001791700002201811700001801833700002001851700002301871700001901894700002201913700001301935700001601948700002601964700002401990700002502014700001902039700001902058700002202077700002302099700002002122700002102142700002202163700002402185700001802209700002102227700002502248700002402273700002002297700002102317700002402338700002202362700002002384700002402404700001702428700001302445700002002458700002102478700002002499700002202519700002302541700002202564700002302586700001902609700001902628700002402647700002602671700002302697700001702720700002002737700002102757700002202778700002202800700001802822700001902840700002002859710003402879856003602913 2010 eng d a1546-171800aGenome-wide association identifies multiple ulcerative colitis susceptibility loci.0 aGenomewide association identifies multiple ulcerative colitis su c2010 Apr a332-70 v423 aUlcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
10aColitis, Ulcerative10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMembrane Proteins10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aReceptors, IgG1 aMcGovern, Dermot, P B1 aGardet, Agnès1 aTörkvist, Leif1 aGoyette, Philippe1 aEssers, Jonah1 aTaylor, Kent, D1 aNeale, Benjamin, M1 aOng, Rick, T H1 aLagacé, Caroline1 aLi, Chun1 aGreen, Todd1 aStevens, Christine, R1 aBeauchamp, Claudine1 aFleshner, Phillip, R1 aCarlson, Marie1 aD'Amato, Mauro1 aHalfvarson, Jonas1 aHibberd, Martin, L1 aLördal, Mikael1 aPadyukov, Leonid1 aAndriulli, Angelo1 aColombo, Elisabetta1 aLatiano, Anna1 aPalmieri, Orazio1 aBernard, Edmond-Jean1 aDeslandres, Colette1 aHommes, Daan, W1 ade Jong, Dirk, J1 aStokkers, Pieter, C1 aWeersma, Rinse, K1 aSharma, Yashoda1 aSilverberg, Mark, S1 aCho, Judy, H1 aWu, Jing1 aRoeder, Kathryn1 aBrant, Steven, R1 aSchumm, Phillip1 aDuerr, Richard, H1 aDubinsky, Marla, C1 aGlazer, Nicole, L1 aHaritunians, Talin1 aIppoliti, Andy1 aMelmed, Gil, Y1 aSiscovick, David, S1 aVasiliauskas, Eric, A1 aTargan, Stephan, R1 aAnnese, Vito1 aWijmenga, Cisca1 aPettersson, Sven1 aRotter, Jerome, I1 aXavier, Ramnik, J1 aDaly, Mark, J1 aRioux, John, D1 aSeielstad, Mark1 aNIDDK IBD Genetics Consortium uhttps://chs-nhlbi.org/node/117403424nas a2200589 4500008004100000022001400041245010200055210006900157260001600226300001100242490000800253520173500261653001901996653003402015653001302049653001102062653001502073653003602088653002102124653001302145653003002158100001702188700002402205700002002229700002102249700002002270700001402290700001902304700002802323700001602351700002302367700002402390700002802414700002102442700002202463700001602485700002002501700002402521700002102545700002702566700002502593700002202618700001602640700001802656700002102674700002102695700002002716700002002736700002402756700001802780856003602798 2010 eng d a1091-649000aGenome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.0 aGenomewide association identifies OBFC1 as a locus involved in h c2010 May 18 a9293-80 v1073 aTelomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.
10aCohort Studies10aGenome-Wide Association Study10aGenotype10aHumans10aLeukocytes10aPolymorphism, Single Nucleotide10aReceptors, CXCR410aTelomere10aTelomere-Binding Proteins1 aLevy, Daniel1 aNeuhausen, Susan, L1 aHunt, Steven, C1 aKimura, Masayuki1 aHwang, Shih-Jen1 aChen, Wei1 aBis, Joshua, C1 aFitzpatrick, Annette, L1 aSmith, Erin1 aJohnson, Andrew, D1 aGardner, Jeffrey, P1 aSrinivasan, Sathanur, R1 aSchork, Nicholas1 aRotter, Jerome, I1 aHerbig, Utz1 aPsaty, Bruce, M1 aSastrasinh, Malinee1 aMurray, Sarah, S1 aVasan, Ramachandran, S1 aProvince, Michael, A1 aGlazer, Nicole, L1 aLu, Xiaobin1 aCao, Xiaojian1 aKronmal, Richard1 aMangino, Massimo1 aSoranzo, Nicole1 aSpector, Tim, D1 aBerenson, Gerald, S1 aAviv, Abraham uhttps://chs-nhlbi.org/node/119204951nas a2201009 4500008004100000022001400041245010900055210006900164260001300233300001000246490000700256520207300263653002202336653000902358653001002367653002102377653001902398653002802417653001102445653001902456653002002475653003802495653002002533653002202553653003402575653001102609653002702620653003102647653000902678653001602687653003602703653002402739100002302763700001902786700002002805700002002825700002002845700002502865700001902890700002302909700002102932700002202953700002102975700001902996700002203015700002403037700002403061700002403085700002403109700002003133700002003153700002403173700001903197700001903216700002403235700001803259700002203277700002403299700002103323700002103344700002203365700002603387700002103413700001803434700002603452700002403478700002803502700002603530700001803556700001703574700002103591700002403612700001903636700002003655700001703675700002303692700001403715700002303729700002003752700002203772700002003794700002703814700002203841700002203863700002003885856003603905 2010 eng d a1524-462800aGenome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.0 aGenomewide association studies of MRIdefined brain infarcts meta c2010 Feb a210-70 v413 aBACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).
RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.
CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
10aAfrican Americans10aAged10aBrain10aBrain Infarction10aCohort Studies10aDNA Mutational Analysis10aFemale10aGene Frequency10aGenetic Markers10aGenetic Predisposition to Disease10aGenetic Testing10aGenetic Variation10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies1 aDebette, Stephanie1 aBis, Joshua, C1 aFornage, Myriam1 aSchmidt, Helena1 aIkram, Arfan, M1 aSigurdsson, Sigurdur1 aHeiss, Gerardo1 aStruchalin, Maksim1 aSmith, Albert, V1 avan der Lugt, Aad1 aDeCarli, Charles1 aLumley, Thomas1 aKnopman, David, S1 aEnzinger, Christian1 aEiriksdottir, Gudny1 aKoudstaal, Peter, J1 aDeStefano, Anita, L1 aPsaty, Bruce, M1 aDufouil, Carole1 aCatellier, Diane, J1 aFazekas, Franz1 aAspelund, Thor1 aAulchenko, Yurii, S1 aBeiser, Alexa1 aRotter, Jerome, I1 aTzourio, Christophe1 aShibata, Dean, K1 aTscherner, Maria1 aHarris, Tamara, B1 aRivadeneira, Fernando1 aAtwood, Larry, D1 aRice, Kenneth1 aGottesman, Rebecca, F1 avan Buchem, Mark, A1 aUitterlinden, André, G1 aKelly-Hayes, Margaret1 aCushman, Mary1 aZhu, Yicheng1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aHofman, Albert1 aRomero, Jose, R1 aLopez, Oscar1 aDuijn, Cornelia, M1 aAu, Rhoda1 aHeckbert, Susan, R1 aWolf, Philip, A1 aMosley, Thomas, H1 aSeshadri, Sudha1 aBreteler, Monique, M B1 aSchmidt, Reinhold1 aLauner, Lenore, J1 aLongstreth, W T uhttps://chs-nhlbi.org/node/115604031nas a2200733 4500008004100000022001400041245014700055210006900202260001600271490000600287520185700293653001002150653000902160653004002169653001102209653003402220653001102254653001402265653000902279653001602288653003602304653001402340653001102354100002002365700002602385700002002411700002202431700002102453700002602474700002002500700002102520700002102541700002202562700002202584700001602606700001902622700001902641700001602660700001802676700001902694700001902713700002002732700002202752700001802774700001802792700002202810700001802832700001902850700002002869700002202889700002802911700002602939700002002965700002302985700002003008700003003028700002403058700002403082700002103106700001903127710004803146710006703194856003603261 2010 eng d a1553-740400aGenome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels.0 aGenomewide association studies of serum magnesium potassium and c2010 Aug 050 v63 aMagnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.
10aAdult10aAged10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMagnesium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aPotassium10aSodium1 aMeyer, Tamra, E1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aGlazer, Nicole, L1 aSmith, Albert, V1 avan Rooij, Frank, J A1 aEhret, Georg, B1 aBoerwinkle, Eric1 aFelix, Janine, F1 aLeak, Tennille, S1 aHarris, Tamara, B1 aYang, Qiong1 aDehghan, Abbas1 aAspelund, Thor1 aKatz, Ronit1 aHomuth, Georg1 aKocher, Thomas1 aRettig, Rainer1 aRied, Janina, S1 aGieger, Christian1 aPrucha, Hanna1 aPfeufer, Arne1 aMeitinger, Thomas1 aCoresh, Josef1 aHofman, Albert1 aSarnak, Mark, J1 aChen, Yii-Der Ida1 aUitterlinden, André, G1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aKao, Linda, W H1 aWitteman, Jacqueline, C M1 aGudnason, Vilmundur1 aSiscovick, David, S1 aFox, Caroline, S1 aKöttgen, Anna1 aGenetic Factors for Osteoporosis Consortium1 aMeta Analysis of Glucose and Insulin Related Traits Consortium uhttps://chs-nhlbi.org/node/122303497nas a2200565 4500008004100000022001400041245011700055210006900172260001600241300001000257490000600267520187300273653000902146653001202155653002502167653001902192653002702211653001802238653001102256653003802267653003402305653001402339653001902353653001102372653000902383653001602392653002002408653004402428653001102472653003602483100001902519700002202538700001602560700001802576700001702594700002102611700002302632700002102655700002002676700002502696700001602721700002202737700002402759700002202783700002102805700002202826700002602848700002102874856003602895 2010 eng d a1932-620300aGenome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.0 aGenomewide association study identifies GPC5 as a novel genetic c2010 Mar 25 ae98790 v53 aBACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.
METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).
CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.
10aAged10aAlleles10aCase-Control Studies10aCohort Studies10aDeath, Sudden, Cardiac10aEthnic Groups10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlypicans10aHeart Diseases10aHumans10aMale10aMiddle Aged10aModels, Genetic10aOligonucleotide Array Sequence Analysis10aOregon10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aReinier, Kyndaron1 aPost, Wendy1 aJui, Jonathan1 aHilton, Gina1 aO'Connor, Ashley1 aPrineas, Ronald, J1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aTomaselli, Gordon, F1 aRea, Thomas1 aSotoodehnia, Nona1 aSiscovick, David, S1 aBurke, Gregory, L1 aMarbán, Eduardo1 aSpooner, Peter, M1 aChakravarti, Aravinda1 aChugh, Sumeet, S uhttps://chs-nhlbi.org/node/118204048nas a2201057 4500008004100000022001400041245005000055210004800105260001300153300001000166490000700176520109100183653000901274653002401283653001901307653002401326653001101350653001701361653003801378653003401416653002801450653001101478653000901489653002701498100001801525700002501543700002601568700001901594700002201613700002601635700002301661700002101684700002201705700002201727700002601749700001201775700002001787700001901807700001801826700001901844700002001863700001801883700002201901700002601923700001901949700001701968700002501985700002802010700002302038700002302061700001902084700002202103700002202125700002902147700002002176700002202196700002402218700001902242700001802261700002302279700002602302700002702328700001902355700002402374700002202398700002202420700002102442700002002463700002402483700001702507700002502524700002802549700002002577700002102597700002602618700002402644700002402668700002002692700002202712700002202734700001702756700002402773700002402797700001802821700001902839700003002858700001902888700002402907700002302931856003602954 2010 eng d a1546-171800aGenome-wide association study of PR interval.0 aGenomewide association study of PR interval c2010 Feb a153-90 v423 aThe electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.
10aAged10aAtrial Fibrillation10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMale10aMeta-Analysis as Topic1 aPfeufer, Arne1 avan Noord, Charlotte1 aMarciante, Kristin, D1 aArking, Dan, E1 aLarson, Martin, G1 aSmith, Albert, Vernon1 aTarasov, Kirill, V1 aMüller, Martina1 aSotoodehnia, Nona1 aSinner, Moritz, F1 aVerwoert, Germaine, C1 aLi, Man1 aKao, Linda, W H1 aKöttgen, Anna1 aCoresh, Josef1 aBis, Joshua, C1 aPsaty, Bruce, M1 aRice, Kenneth1 aRotter, Jerome, I1 aRivadeneira, Fernando1 aHofman, Albert1 aKors, Jan, A1 aStricker, Bruno, H C1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aBeckmann, Britt, M1 aSauter, Wiebke1 aGieger, Christian1 aLubitz, Steven, A1 aNewton-Cheh, Christopher1 aWang, Thomas, J1 aMagnani, Jared, W1 aSchnabel, Renate, B1 aChung, Mina, K1 aBarnard, John1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aVasan, Ramachandran, S1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLauner, Lenore, J1 aNajjar, Samer, S1 aLakatta, Edward1 aSchlessinger, David1 aUda, Manuela1 aAbecasis, Goncalo, R1 aMüller-Myhsok, Bertram1 aEhret, Georg, B1 aBoerwinkle, Eric1 aChakravarti, Aravinda1 aSoliman, Elsayed, Z1 aLunetta, Kathryn, L1 aPerz, Siegfried1 aWichmann, H-Erich1 aMeitinger, Thomas1 aLevy, Daniel1 aGudnason, Vilmundur1 aEllinor, Patrick, T1 aSanna, Serena1 aKääb, Stefan1 aWitteman, Jacqueline, C M1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/115904709nas a2201405 4500008004100000022001400041245010700055210006900162260001300231300001200244490000700256520077800263653002601041653001801067653002001085653001701105653003801122653002201160653001801182653003401200653001101234653003101245100001801276700002601294700002401320700001401344700002901358700001701387700002101404700002101425700001501446700002101461700002201482700001901504700002301523700002201546700002401568700002001592700001601612700002301628700001801651700001801669700002701687700002501714700002501739700002501764700002201789700001901811700002001830700001901850700002001869700002001889700002001909700002601929700002001955700002501975700001902000700002102019700001802040700002902058700001902087700002002106700001602126700002002142700001902162700002002181700002102201700001602222700002302238700002002261700001802281700002202299700002402321700002202345700002302367700002302390700001702413700001902430700001802449700001702467700001702484700002202501700001902523700001702542700002002559700002002579700001902599700002402618700002102642700002102663700002002684700002202704700001702726700001902743700002302762700002602785700002002811700002402831700001802855700002002873700002302893700002102916700001902937700001902956700002202975700002202997700002303019700002303042700002303065700002203088700002403110700001903134700002203153700001703175700001703192700002203209700001803231700001803249856003603267 2010 eng d a1546-171800aGenome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.0 aGenomewide metaanalysis increases to 71 the number of confirmed c2010 Dec a1118-250 v423 aWe undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
10aComputational Biology10aCrohn Disease10aGenetic Linkage10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aReproducibility of Results1 aFranke, Andre1 aMcGovern, Dermot, P B1 aBarrett, Jeffrey, C1 aWang, Kai1 aRadford-Smith, Graham, L1 aAhmad, Tariq1 aLees, Charlie, W1 aBalschun, Tobias1 aLee, James1 aRoberts, Rebecca1 aAnderson, Carl, A1 aBis, Joshua, C1 aBumpstead, Suzanne1 aEllinghaus, David1 aFesten, Eleonora, M1 aGeorges, Michel1 aGreen, Todd1 aHaritunians, Talin1 aJostins, Luke1 aLatiano, Anna1 aMathew, Christopher, G1 aMontgomery, Grant, W1 aPrescott, Natalie, J1 aRaychaudhuri, Soumya1 aRotter, Jerome, I1 aSchumm, Philip1 aSharma, Yashoda1 aSimms, Lisa, A1 aTaylor, Kent, D1 aWhiteman, David1 aWijmenga, Cisca1 aBaldassano, Robert, N1 aBarclay, Murray1 aBayless, Theodore, M1 aBrand, Stephan1 aBüning, Carsten1 aCohen, Albert1 aColombel, Jean-Frederick1 aCottone, Mario1 aStronati, Laura1 aDenson, Ted1 aDe Vos, Martine1 aD'Inca, Renata1 aDubinsky, Marla1 aEdwards, Cathryn1 aFlorin, Tim1 aFranchimont, Denis1 aGearry, Richard1 aGlas, Jürgen1 aVan Gossum, Andre1 aGuthery, Stephen, L1 aHalfvarson, Jonas1 aVerspaget, Hein, W1 aHugot, Jean-Pierre1 aKarban, Amir1 aLaukens, Debby1 aLawrance, Ian1 aLemann, Marc1 aLevine, Arie1 aLibioulle, Cecile1 aLouis, Edouard1 aMowat, Craig1 aNewman, William1 aPanés, Julián1 aPhillips, Anne1 aProctor, Deborah, D1 aRegueiro, Miguel1 aRussell, Richard1 aRutgeerts, Paul1 aSanderson, Jeremy1 aSans, Miquel1 aSeibold, Frank1 aSteinhart, Hillary1 aStokkers, Pieter, C F1 aTörkvist, Leif1 aKullak-Ublick, Gerd1 aWilson, David1 aWalters, Thomas1 aTargan, Stephan, R1 aBrant, Steven, R1 aRioux, John, D1 aD'Amato, Mauro1 aWeersma, Rinse, K1 aKugathasan, Subra1 aGriffiths, Anne, M1 aMansfield, John, C1 aVermeire, Severine1 aDuerr, Richard, H1 aSilverberg, Mark, S1 aSatsangi, Jack1 aSchreiber, Stefan1 aCho, Judy, H1 aAnnese, Vito1 aHakonarson, Hakon1 aDaly, Mark, J1 aParkes, Miles uhttps://chs-nhlbi.org/node/124904080nas a2200757 4500008004100000022001400041245019100055210006900246260001300315300001100328490000600339520181900345653002202164653000902186653002202195653001502217653001902232653004002251653001102291653003402302653001302336653001802349653001102367653001202378653000902390653003802399653002202437653001602459653003602475653001702511100002402528700002102552700002502573700002202598700002002620700001902640700002302659700001902682700002302701700002402724700001802748700002302766700002102789700002602810700002402836700001902860700001802879700002302897700003002920700002102950700002302971700001902994700001703013700002203030700001803052700002803070700002003098700002003118700002403138700002303162700002103185700003003206700002703236700002303263856003603286 2010 eng d a1942-326800aGenomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium.0 aGenomic variation associated with mortality among adults of Euro c2010 Jun a248-550 v33 aBACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.
CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.
10aAfrican Americans10aAged10aAged, 80 and over10aChemokines10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Failure10aHumans10aIntrons10aMale10aMARVEL Domain-Containing Proteins10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aMorrison, Alanna, C1 aFelix, Janine, F1 aCupples, Adrienne, L1 aGlazer, Nicole, L1 aLoehr, Laura, R1 aDehghan, Abbas1 aDemissie, Serkalem1 aBis, Joshua, C1 aRosamond, Wayne, D1 aAulchenko, Yurii, S1 aWang, Ying, A1 aHaritunians, Talin1 aFolsom, Aaron, R1 aRivadeneira, Fernando1 aBenjamin, Emelia, J1 aLumley, Thomas1 aCouper, David1 aStricker, Bruno, H1 aO'Donnell, Christopher, J1 aRice, Kenneth, M1 aChang, Patricia, P1 aHofman, Albert1 aLevy, Daniel1 aRotter, Jerome, I1 aFox, Ervin, R1 aUitterlinden, André, G1 aWang, Thomas, J1 aPsaty, Bruce, M1 aWillerson, James, T1 aDuijn, Cornelia, M1 aBoerwinkle, Eric1 aWitteman, Jacqueline, C M1 aVasan, Ramachandran, S1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/118702286nas a2200337 4500008004100000022001400041245008400055210006900139260001300208300001000221490000700231520139500238653000901633653001101642653001801653653001801671653001101689653001401700653000901714653001701723653001801740100001901758700002101777700002001798700002101818700001501839700001501854700002201869700002101891856003601912 2010 eng d a1522-964500aHip fractures and heart failure: findings from the Cardiovascular Health Study.0 aHip fractures and heart failure findings from the Cardiovascular c2010 Jan a77-840 v313 aAIMS: The aim of the study was to find the epidemiology of hip fractures in heart failure. The increasing survival rate for patients with heart failure places them at risk for other diseases of ageing, including osteoporosis.
METHODS AND RESULTS: We included 5613 persons from the Cardiovascular Health Study (CHS) with an average of 11.5 year follow-up. We determined incidence rates and hazard ratios (HRs) in persons with heart failure compared with persons without heart failure and mortality hazards following these fractures. Annualized incidence rates for hip fractures were 14 per 1000 person-years in heart failure and 6.8 per 1000 person-years without heart failure. Unadjusted and multivariable adjusted HRs for hip fracture associated with heart failure in men were 1.87 (95% CI 1.2-2.93) and 1.59 (95% CI 0.93-2.72), respectively. Respective HRs for women were 1.75 (95% CI 1.27-2.4) and 1.41 (95% CI 0.98-2.03). Mortality hazard was approximately 2-fold greater in patients with heart failure and hip fracture compared with those having heart failure alone.
CONCLUSION: Persons with heart failure are at high risk for hip fractures. However, much of the association between hip fractures and heart failure is explained by shared risk factors. Hip fractures are a substantial contributor to mortality in men and women with heart failure.
10aAged10aFemale10aHeart Failure10aHip Fractures10aHumans10aIncidence10aMale10aRisk Factors10aUnited States1 aCarbone, Laura1 aBůzková, Petra1 aFink, Howard, A1 aLee, Jennifer, S1 aChen, Zhao1 aAhmed, Ali1 aParashar, Susmita1 aRobbins, John, R uhttps://chs-nhlbi.org/node/114312698nas a2203781 4500008004100000022001400041245009600055210006900151260001600220300001000236490000800246520210000254653001602354653003102370653001702401653003802418653001802456653003402474653001102508653003602519653003102555653001402586653003602600100002302636700001902659700002202678700002102700700002302721700002602744700002302770700002102793700002202814700002502836700002102861700002002882700002202902700002302924700002802947700002102975700002002996700001803016700001503034700002503049700002603074700002303100700001103123700002603134700001803160700001903178700001803197700001803215700001803233700002503251700002303276700002403299700001703323700002003340700003103360700002403391700001903415700002503434700002103459700001603480700001803496700002003514700001703534700002103551700002103572700001803593700001803611700001903629700002203648700002203670700002403692700002103716700002303737700002103760700001903781700001903800700002003819700002103839700002303860700003203883700002303915700002403938700002103962700001703983700001904000700002004019700002004039700001904059700002104078700001704099700002404116700002704140700001604167700001904183700002104202700002304223700002304246700002004269700001804289700002304307700001904330700001904349700002004368700001204388700002104400700001904421700002304440700002004463700001504483700002404498700002504522700002304547700002204570700002204592700002104614700002204635700001904657700002004676700001904696700001704715700001804732700001704750700001604767700002204783700002404805700002404829700002604853700002204879700002204901700002104923700001904944700002604963700002004989700002105009700002605030700002105056700001605077700001805093700002005111700002305131700002305154700001905177700002105196700001805217700002805235700002205263700002105285700001605306700001605322700001805338700001605356700001905372700002805391700002105419700001805440700002005458700001805478700002005496700001705516700002305533700001705556700002005573700002205593700002105615700002105636700002005657700001905677700002305696700001905719700002705738700001805765700002605783700002205809700002605831700002105857700002905878700001905907700001705926700002605943700001905969700002105988700001906009700002306028700001806051700001606069700001906085700002006104700002006124700002206144700001606166700002506182700002006207700002606227700001906253700002306272700002506295700002006320700002406340700001906364700002406383700001806407700002406425700002406449700002106473700002206494700002006516700002306536700002206559700002006581700001906601700002206620700002406642700001906666700002206685700002206707700001906729700001906748700002006767700002406787700003006811700001906841700001606860700002006876700002006896700002006916700001906936700001906955700001906974700002406993700002307017700002407040700002207064700001807086700002307104700002407127700001907151700002107170700002407191700002507215700002507240700002007265700002107285700002107306700002107327700002407348700002007372700002207392700002207414700001407436700002607450700002807476700002207504700002107526700002007547700002207567700001707589700002107606700002007627700002907647700001907676700001907695700002107714700002307735700002307758700002507781700002207806700002107828700002407849700002007873700002207893700002207915700002707937700002007964700002407984700002408008700002308032700002608055700002408081700001608105700002208121700002408143700001908167700001808186700002108204700001908225700002308244700001708267700002208284700002108306700001908327700002408346700002508370700002108395700002608416700002308442700002208465700002308487700002308510700002008533700002808553700002008581700002808601700002308629700002508652700002008677700002108697700002208718700002008740700002508760700002508785700002108810700002508831700002408856856003608880 2010 eng d a1476-468700aHundreds of variants clustered in genomic loci and biological pathways affect human height.0 aHundreds of variants clustered in genomic loci and biological pa c2010 Oct 14 a832-80 v4673 aMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
10aBody Height10aChromosomes, Human, Pair 310aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMetabolic Networks and Pathways10aMultifactorial Inheritance10aPhenotype10aPolymorphism, Single Nucleotide1 aAllen, Hana, Lango1 aEstrada, Karol1 aLettre, Guillaume1 aBerndt, Sonja, I1 aWeedon, Michael, N1 aRivadeneira, Fernando1 aWiller, Cristen, J1 aJackson, Anne, U1 aVedantam, Sailaja1 aRaychaudhuri, Soumya1 aFerreira, Teresa1 aWood, Andrew, R1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aSpeliotes, Elizabeth, K1 aWheeler, Eleanor1 aSoranzo, Nicole1 aPark, Ju-Hyun1 aYang, Jian1 aGudbjartsson, Daniel1 aHeard-Costa, Nancy, L1 aRandall, Joshua, C1 aQi, Lu1 aSmith, Albert, Vernon1 aMägi, Reedik1 aPastinen, Tomi1 aLiang, Liming1 aHeid, Iris, M1 aLuan, Jian'an1 aThorleifsson, Gudmar1 aWinkler, Thomas, W1 aGoddard, Michael, E1 aLo, Ken, Sin1 aPalmer, Cameron1 aWorkalemahu, Tsegaselassie1 aAulchenko, Yurii, S1 aJohansson, Asa1 aZillikens, Carola, M1 aFeitosa, Mary, F1 aEsko, Tõnu1 aJohnson, Toby1 aKetkar, Shamika1 aKraft, Peter1 aMangino, Massimo1 aProkopenko, Inga1 aAbsher, Devin1 aAlbrecht, Eva1 aErnst, Florian1 aGlazer, Nicole, L1 aHayward, Caroline1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aKnowles, Joshua, W1 aKutalik, Zoltán1 aMonda, Keri, L1 aPolasek, Ozren1 aPreuss, Michael1 aRayner, Nigel, W1 aRobertson, Neil, R1 aSteinthorsdottir, Valgerdur1 aTyrer, Jonathan, P1 aVoight, Benjamin, F1 aWiklund, Fredrik1 aXu, Jianfeng1 aZhao, Jing Hua1 aNyholt, Dale, R1 aPellikka, Niina1 aPerola, Markus1 aPerry, John, R B1 aSurakka, Ida1 aTammesoo, Mari-Liis1 aAltmaier, Elizabeth, L1 aAmin, Najaf1 aAspelund, Thor1 aBhangale, Tushar1 aBoucher, Gabrielle1 aChasman, Daniel, I1 aChen, Constance1 aCoin, Lachlan1 aCooper, Matthew, N1 aDixon, Anna, L1 aGibson, Quince1 aGrundberg, Elin1 aHao, Ke1 aJunttila, Juhani1 aKaplan, Lee, M1 aKettunen, Johannes1 aKönig, Inke, R1 aKwan, Tony1 aLawrence, Robert, W1 aLevinson, Douglas, F1 aLorentzon, Mattias1 aMcKnight, Barbara1 aMorris, Andrew, P1 aMüller, Martina1 aNgwa, Julius, Suh1 aPurcell, Shaun1 aRafelt, Suzanne1 aSalem, Rany, M1 aSalvi, Erika1 aSanna, Serena1 aShi, Jianxin1 aSovio, Ulla1 aThompson, John, R1 aTurchin, Michael, C1 aVandenput, Liesbeth1 aVerlaan, Dominique, J1 aVitart, Veronique1 aWhite, Charles, C1 aZiegler, Andreas1 aAlmgren, Peter1 aBalmforth, Anthony, J1 aCampbell, Harry1 aCitterio, Lorena1 aDe Grandi, Alessandro1 aDominiczak, Anna1 aDuan, Jubao1 aElliott, Paul1 aElosua, Roberto1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aGeus, Eco, J C1 aGlorioso, Nicola1 aHaiqing, Shen1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aIllig, Thomas1 aJula, Antti1 aKajantie, Eero1 aKilpeläinen, Tuomas, O1 aKoiranen, Markku1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aLaitinen, Jaana1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aMarusic, Ana1 aMaschio, Andrea1 aMeitinger, Thomas1 aMulas, Antonella1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPetersmann, Astrid1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPouta, Anneli1 aRidderstråle, Martin1 aRotter, Jerome, I1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSchmidt, Carsten, Oliver1 aSinisalo, Juha1 aSmit, Jan, H1 aStringham, Heather, M1 aWalters, Bragi1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aZagato, Laura1 aZgaga, Lina1 aZitting, Paavo1 aAlavere, Helene1 aFarrall, Martin1 aMcArdle, Wendy, L1 aNelis, Mari1 aPeters, Marjolein, J1 aRipatti, Samuli1 avan Meurs, Joyce, B J1 aAben, Katja, K1 aArdlie, Kristin, G1 aBeckmann, Jacques, S1 aBeilby, John, P1 aBergman, Richard, N1 aBergmann, Sven1 aCollins, Francis, S1 aCusi, Daniele1 aHeijer, Martin, den1 aEiriksdottir, Gudny1 aGejman, Pablo, V1 aHall, Alistair, S1 aHamsten, Anders1 aHuikuri, Heikki, V1 aIribarren, Carlos1 aKähönen, Mika1 aKaprio, Jaakko1 aKathiresan, Sekar1 aKiemeney, Lambertus1 aKocher, Thomas1 aLauner, Lenore, J1 aLehtimäki, Terho1 aMelander, Olle1 aMosley, Tom, H1 aMusk, Arthur, W1 aNieminen, Markku, S1 aO'Donnell, Christopher, J1 aOhlsson, Claes1 aOostra, Ben1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aRioux, John, D1 aRissanen, Aila1 aRivolta, Carlo1 aSchunkert, Heribert1 aShuldiner, Alan, R1 aSiscovick, David, S1 aStumvoll, Michael1 aTönjes, Anke1 aTuomilehto, Jaakko1 avan Ommen, Gert-Jan1 aViikari, Jorma1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aProvince, Michael, A1 aKayser, Manfred1 aArnold, Alice, M1 aAtwood, Larry, D1 aBoerwinkle, Eric1 aChanock, Stephen, J1 aDeloukas, Panos1 aGieger, Christian1 aGrönberg, Henrik1 aHall, Per1 aHattersley, Andrew, T1 aHengstenberg, Christian1 aHoffman, Wolfgang1 aLathrop, Mark, G1 aSalomaa, Veikko1 aSchreiber, Stefan1 aUda, Manuela1 aWaterworth, Dawn1 aWright, Alan, F1 aAssimes, Themistocles, L1 aBarroso, Inês1 aHofman, Albert1 aMohlke, Karen, L1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCupples, Adrienne, L1 aErdmann, Jeanette1 aFox, Caroline, S1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHarris, Tamara, B1 aHayes, Richard, B1 aJarvelin, Marjo-Riitta1 aMooser, Vincent1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aRudan, Igor1 aSamani, Nilesh, J1 aSpector, Timothy, D1 aVölzke, Henry1 aWatkins, Hugh1 aWilson, James, F1 aGroop, Leif, C1 aHaritunians, Talin1 aHu, Frank, B1 aKaplan, Robert, C1 aMetspalu, Andres1 aNorth, Kari, E1 aSchlessinger, David1 aWareham, Nicholas, J1 aHunter, David, J1 aO'Connell, Jeffrey, R1 aStrachan, David, P1 aWichmann, H-Erich1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aSchadt, Eric, E1 aThorsteinsdottir, Unnur1 aPeltonen, Leena1 aUitterlinden, André, G1 aVisscher, Peter, M1 aChatterjee, Nilanjan1 aLoos, Ruth, J F1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aIngelsson, Erik1 aLindgren, Cecilia, M1 aAbecasis, Goncalo, R1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N uhttps://chs-nhlbi.org/node/123402681nas a2200385 4500008004100000022001400041245007400055210006900129260001300198300001000211490000700221520162500228653001601853653000901869653002201878653002401900653001901924653002801943653001101971653002201982653003102004653001102035653002002046653002602066653000902092100001502101700001602116700002202132700001702154700002002171700002002191700002402211700002402235856003602259 2010 eng d a1532-841400aImpaired kidney function and atrial fibrillation in elderly subjects.0 aImpaired kidney function and atrial fibrillation in elderly subj c2010 Jan a55-600 v163 aBACKGROUND: Impaired kidney function is associated with increased risk for cardiovascular events. We evaluated whether kidney function is associated with atrial fibrillation (AF) risk in elderly persons.
METHODS AND RESULTS: Subjects were participants in the Cardiovascular Health Study (CHS), a population-based cohort of ambulatory elderly. Measures of kidney function were cystatin C and creatinine-based estimated glomerular filtration rate (eGFR). Among the 4663 participants, 342 (7%) had AF at baseline and 579 (13%) developed incident AF during follow-up (mean 7.4 years). In unadjusted analyses, cystatin C quartiles were strongly associated with prevalent AF with a nearly 3-fold odds in the highest quartile compared with the lowest (HR=1.19, 95% CI [0.80-1.76] in quartile 2; HR=2.00, 95% CI [1.38-2.88] in quartile 3; and HR=2.87, 95% CI [2.03-4.07] in quartile 4). This increased risk for prevalent AF remained significant after multivariate adjustment. The risk for incident AF increased across cystatin C quartiles in the unadjusted analysis (HR=1.37, 95% CI [1.07-1.75] in quartile 2; HR=1.43, 95% CI [1.11-1.84] in quartile 3; and HR=1.88, 95% CI [1.47-2.41] in quartile 4); however, after multivariate adjustment, these findings were no longer significant. An estimated GFR <60 mL.min.1.73m(2) was associated with prevalent and incident AF in unadjusted, but not multivariate analyses.
CONCLUSIONS: Impaired kidney function, as measured by cystatin C, is an independent marker of prevalent AF; however, neither cystatin C nor eGFR are predictors of incident AF.
10aAge Factors10aAged10aAged, 80 and over10aAtrial Fibrillation10aCohort Studies10aCross-Sectional Studies10aFemale10aFollow-Up Studies10aGlomerular Filtration Rate10aHumans10aKidney Diseases10aKidney Function Tests10aMale1 aDeo, Rajat1 aKatz, Ronit1 aKestenbaum, Bryan1 aFried, Linda1 aSarnak, Mark, J1 aPsaty, Bruce, M1 aSiscovick, David, S1 aShlipak, Michael, G uhttps://chs-nhlbi.org/node/116603706nas a2200685 4500008004100000022001400041245008300055210006900138260001600207300001100223490000800234520175600242653000901998653002202007653002402029653002302053653003102076653004002107653001102147653002002158653003802178653001502216653001102231653000902242653001602251653003602267653001702303100002202320700002202342700002402364700001802388700001802406700002002424700002502444700001802469700001902487700002202506700001902528700002002547700002402567700002002591700002102611700002002632700002502652700002002677700002502697700002102722700002502743700002502768700002302793700001902816700002302835700002402858700002102882700001902903700001902922700001902941700002402960856003602984 2010 eng d a1524-453900aIndependent susceptibility markers for atrial fibrillation on chromosome 4q25.0 aIndependent susceptibility markers for atrial fibrillation on ch c2010 Sep 07 a976-840 v1223 aBACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.
METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.
CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aLubitz, Steven, A1 aSinner, Moritz, F1 aLunetta, Kathryn, L1 aMakino, Seiko1 aPfeufer, Arne1 aRahman, Rosanna1 aVeltman, Caroline, E1 aBarnard, John1 aBis, Joshua, C1 aDanik, Stephan, P1 aSonni, Akshata1 aShea, Marisa, A1 aDel Monte, Federica1 aPerz, Siegfried1 aMüller, Martina1 aPeters, Annette1 aGreenberg, Steven, M1 aFurie, Karen, L1 avan Noord, Charlotte1 aBoerwinkle, Eric1 aStricker, Bruno, H C1 aWitteman, Jacqueline1 aSmith, Jonathan, D1 aChung, Mina, K1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aRosand, Jonathan1 aArking, Dan, E1 aAlonso, Alvaro1 aKääb, Stefan1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/122605042nas a2201093 4500008004100000022001400041245017600055210006900231260001300300300001200313490000700325520188300332653001002215653000902225653001802234653001702252653004002269653001202309653001102321653001702332653003402349653001302383653001102396653001202407653000902419653001602428653003602444100002702480700002302507700002202530700002402552700002502576700001702601700002602618700002102644700002402665700001402689700001702703700002002720700002602740700002002766700001802786700002102804700002902825700002502854700002502879700002502904700002302929700002302952700002102975700002002996700002103016700002703037700002103064700001903085700001903104700002303123700001703146700002403163700002803187700002403215700001903239700001703258700001803275700001903293700002503312700002003337700001803357700001703375700002103392700002203413700002003435700002503455700001703480700001803497700003103515700002803546700002503574700002103599700002103620700002303641700002003664700003003684700001903714700002503733700002103758700002003779700002503799700002403824700002003848700002003868710002403888856003603912 2010 eng d a1935-554800aInteractions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.0 aInteractions of dietary wholegrain intake with fasting glucose a c2010 Dec a2684-910 v333 aOBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.
RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.
RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.
CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
10aAdult10aAged10aBlood Glucose10aEdible Grain10aEuropean Continental Ancestry Group10aFasting10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aNettleton, Jennifer, A1 aMcKeown, Nicola, M1 aKanoni, Stavroula1 aLemaitre, Rozenn, N1 aHivert, Marie-France1 aNgwa, Julius1 avan Rooij, Frank, J A1 aSonestedt, Emily1 aWojczynski, Mary, K1 aYe, Zheng1 aTanaka, Tosh1 aGarcia, Melissa1 aAnderson, Jennifer, S1 aFollis, Jack, L1 aDjoussé, Luc1 aMukamal, Kenneth1 aPapoutsakis, Constantina1 aMozaffarian, Dariush1 aZillikens, Carola, M1 aBandinelli, Stefania1 aBennett, Amanda, J1 aBorecki, Ingrid, B1 aFeitosa, Mary, F1 aFerrucci, Luigi1 aForouhi, Nita, G1 aGroves, Christopher, J1 aHallmans, Göran1 aHarris, Tamara1 aHofman, Albert1 aHouston, Denise, K1 aHu, Frank, B1 aJohansson, Ingegerd1 aKritchevsky, Stephen, B1 aLangenberg, Claudia1 aLauner, Lenore1 aLiu, Yongmei1 aLoos, Ruth, J1 aNalls, Michael1 aOrho-Melander, Marju1 aRenstrom, Frida1 aRice, Kenneth1 aRiserus, Ulf1 aRolandsson, Olov1 aRotter, Jerome, I1 aSaylor, Georgia1 aSijbrands, Eric, J G1 aSjogren, Per1 aSmith, Albert1 aSteingrímsdóttir, Laufey1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aProkopenko, Inga1 aPankow, James, S1 aDuijn, Cornelia, M1 aFlorez, Jose, C1 aWitteman, Jacqueline, C M1 aDupuis, Josée1 aDedoussis, George, V1 aOrdovas, Jose, M1 aIngelsson, Erik1 aCupples, Adrienne, L1 aSiscovick, David, S1 aFranks, Paul, W1 aMeigs, James, B1 aMAGIC investigators uhttps://chs-nhlbi.org/node/122202582nas a2200337 4500008004100000022001400041245007200055210006900127260001300196300001100209490000700220520164100227653002201868653001101890653002401901653001101925653002501936653000901961653001301970653004201983653001102025653003302036653002202069653001802091100002002109700001602129700002502145700001802170700002002188856003602208 2010 eng d a1532-817100aIntravenous tissue plasminogen activator and stroke in the elderly.0 aIntravenous tissue plasminogen activator and stroke in the elder c2010 Mar a359-630 v283 aOBJECTIVE: Since publication in 1995 of the National Institute of Neurological Disorders and Stroke (NINDS) trial of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke, the benefit and frequency of use of IV tPA in the elderly have remained uncertain.
METHODS: We obtained data from the NINDS trial to summarize outcomes for randomized subjects older than 80 years. We used data from the Cardiovascular Health Study, a cohort study of 5888 elderly participants from 4 US communities followed longitudinally for stroke since 1989 to estimate the use of and hospital outcome after IV tPA in older adults following publication of the trial in 1995.
RESULTS: In the NINDS trial, 44 subjects older than 80 years were randomized, and their 3-month functional outcomes were not significantly improved with IV tPA. Of 25 randomized to IV tPA, 4 experienced symptomatic intracranial hemorrhages within 36 hours of treatment. Compared with younger patients, older patients were 2.87 times more likely to experience a symptomatic intracranial hemorrhage within 36 hours of IV tPA (95% confidence interval, 1.04-7.93). Of 227 Cardiovascular Health Study participants hospitalized for ischemic stroke between 1995 and 2002, seven, whose mean age was 84 years, were treated with IV tPA (3.1%; 95% confidence interval 1.2-6.2). Two had symptomatic intracranial hemorrhages, 3 failed to improve, and 2 of the 7 had good outcomes.
CONCLUSIONS: These data highlight the need to clarify the risk-benefit profile of IV tPA in ischemic stroke victims who are older than 80 years.
10aAged, 80 and over10aFemale10aFibrinolytic Agents10aHumans10aLongitudinal Studies10aMale10aPlacebos10aRandomized Controlled Trials as Topic10aStroke10aTissue Plasminogen Activator10aTreatment Outcome10aUnited States1 aLongstreth, W T1 aKatz, Ronit1 aTirschwell, David, L1 aCushman, Mary1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/117303243nas a2200625 4500008004100000022001400041245009400055210006900149260001600218300001200234490000700246520141500253653002701668653002001695653003801715653004001753653001701793653003401810653001101844653003801855653001501893100001901908700001901927700001901946700001901965700002201984700002402006700001702030700002102047700002302068700002002091700001302111700002202124700001802146700001702164700002002181700001802201700002202219700002702241700002202268700002202290700002802312700002302340700001702363700002302380700002002403700002102423700001902444700002102463700002002484700002802504700002502532700002402557856003602581 2010 eng d a1460-208300aLarge-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels.0 aLargescale genomic studies reveal central role of ABO in sPselec c2010 May 01 a1863-720 v193 aP-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.
10aABO Blood-Group System10aBlood Platelets10aEnzyme-Linked Immunosorbent Assay10aEuropean Continental Ancestry Group10aFluorescence10aGenome-Wide Association Study10aHumans10aIntercellular Adhesion Molecule-110aP-Selectin1 aBarbalic, Maja1 aDupuis, Josée1 aDehghan, Abbas1 aBis, Joshua, C1 aHoogeveen, Ron, C1 aSchnabel, Renate, B1 aNambi, Vijay1 aBretler, Monique1 aSmith, Nicholas, L1 aPeters, Annette1 aLu, Chen1 aTracy, Russell, P1 aAleksic, Nena1 aHeeriga, Jan1 aKeaney, John, F1 aRice, Kenneth1 aLip, Gregory, Y H1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aLarson, Martin, G1 aUitterlinden, André, G1 aYamamoto, Jennifer1 aDurda, Peter1 aHaritunians, Talin1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aHofman, Albert1 aKoenig, Wolfgang1 aJenny, Nancy, S1 aWitteman, Jacqueline, C1 aBallantyne, Christie1 aBenjamin, Emelia, J uhttps://chs-nhlbi.org/node/116903615nas a2200493 4500008004100000022001400041245014900055210006900204260001600273300001200289490000800301520218300309653005102492653001902543653002102562653001102583653001102594653001802605653001102623653000902634653001602643653002402659653002002683653001702703653001102720653001202731110003602743700002402779700001302803700001502816700001802831700003002849700002102879700002502900700002702925700002002952700001802972700001902990700001903009700002303028700001803051700001703069856003503086 2010 eng d a1474-547X00aLipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies.0 aLipoproteinassociated phospholipase A2 and risk of coronary dise c2010 May 01 a1536-440 v3753 aBACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances.
METHODS: With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease.
FINDINGS: Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure.
INTERPRETATION: Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids.
FUNDING: UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aBlood Pressure10aCoronary Disease10aFemale10aHumans10aLinear Models10aLipids10aMale10aMiddle Aged10aProspective Studies10aRisk Assessment10aRisk Factors10aStroke10aSystole1 aLp-PLA(2) Studies Collaboration1 aThompson, Alexander1 aGao, Pei1 aOrfei, Lia1 aWatson, Sarah1 aDi Angelantonio, Emanuele1 aKaptoge, Stephen1 aBallantyne, Christie1 aCannon, Christopher, P1 aCriqui, Michael1 aCushman, Mary1 aHofman, Albert1 aPackard, Chris1 aThompson, Simon, G1 aCollins, Rory1 aDanesh, John uhttps://chs-nhlbi.org/node/58302752nas a2200349 4500008004100000022001400041245015600055210006900211260001300280300001100293490000800304520167600312653005101988653000902039653002302048653002802071653001102099653001102110653002602121653002802147653002402175653000902199653001102208100002502219700001702244700001802261700002202279700002402301700002002325700002102345856003602366 2010 eng d a1879-148400aLipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and risk of cardiovascular disease in older adults: results from the Cardiovascular Health Study.0 aLipoproteinassociated phospholipase A2 LpPLA2 and risk of cardio c2010 Apr a528-320 v2093 aOBJECTIVE: To examine associations between lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) antigen level (mass) and enzymatic activity (activity) and cardiovascular disease (CVD) in older adults.
METHODS: We examined associations of Lp-PLA(2) mass and activity with incident myocardial infarction (MI; n=508), stroke (n=565) and CVD death (n=665) using Cox regressions adjusted for age, sex, ethnicity and CVD risk factors in 3949 older adults, aged > or =65 years at baseline, from the Cardiovascular Health Study (CHS).
RESULTS: Lp-PLA(2) was associated with incident CVD events in these older adults. Hazard ratios (95% confidence intervals) for highest versus lowest tertiles of Lp-PLA(2) mass were 1.49 (1.19-1.85) for MI, 1.21 (0.98-1.49) for stroke and 1.11 (0.92-1.33) for CVD death. The highest tertile of Lp-PLA(2) activity was associated with MI (1.36; 1.09-1.70) and CVD death (1.23; 1.02-1.50). Combined Lp-PLA(2) tertile 3 and CRP>3mg/l, compared to Lp-PLA(2) tertile 1 and CRP<1mg/l, was associated with MI (2.29; 1.49-3.52) for Lp-PLA(2) mass and MI (1.66; 1.10-2.51) and CVD death (1.57; 1.08-2.26) for activity. For MI, both mass and activity added excess risk to elevated CRP alone ( approximately 20% excess risk) and activity added excess risk for CVD death ( approximately 12%).
CONCLUSION: Lp-PLA(2) mass and activity were associated with incident CVD events in older adults in CHS. Lp-PLA(2) and CRP were independent and additive in prediction of events. While associations were modest, these results support further exploration of Lp-PLA(2) to identify older individuals at risk for CVD.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aC-Reactive Protein10aCardiovascular Diseases10aFemale10aHumans10aMyocardial Infarction10aPopulation Surveillance10aProspective Studies10aRisk10aStroke1 aJenny, Nancy, Swords1 aSolomon, Cam1 aCushman, Mary1 aTracy, Russell, P1 aNelson, Jeanenne, J1 aPsaty, Bruce, M1 aFurberg, Curt, D uhttps://chs-nhlbi.org/node/113302822nas a2200637 4500008004100000022001400041245011200055210006900167260001300236300001000249490000700259520095900266653002301225653001101248653002901259653003801288653001801326653003401344653001101378653000901389653001801398653000901416653002701425653003601452653001501488653001901503100002101522700002201543700001901565700002001584700002001604700002601624700002301650700003001673700001901703700001701722700002501739700002101764700002201785700002001807700002301827700002201850700002801872700001901900700002301919700002601942700002401968700002101992700001902013700002302032700001902055700002502074700002402099700002502123856003602148 2010 eng d a1546-171800aMeta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.0 aMetaanalyses of genomewide association studies identify multiple c2010 Jan a45-520 v423 aSpirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.
10aDatabases, Genetic10aFemale10aForced Expiratory Volume10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLung10aLung Diseases10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aSpirometry10aVital Capacity1 aHancock, Dana, B1 aEijgelsheim, Mark1 aWilk, Jemma, B1 aGharib, Sina, A1 aLoehr, Laura, R1 aMarciante, Kristin, D1 aFranceschini, Nora1 avan Durme, Yannick, M T A1 aChen, Ting-Hsu1 aBarr, Graham1 aSchabath, Matthew, B1 aCouper, David, J1 aBrusselle, Guy, G1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aRotter, Jerome, I1 aUitterlinden, André, G1 aHofman, Albert1 aPunjabi, Naresh, M1 aRivadeneira, Fernando1 aMorrison, Alanna, C1 aEnright, Paul, L1 aNorth, Kari, E1 aHeckbert, Susan, R1 aLumley, Thomas1 aStricker, Bruno, H C1 aO'Connor, George, T1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/115011930nas a2203889 4500008004100000022001400041245014500055210006900200260001300269300001100282490000700293520104400300653001901344653001601363653002301379653001101402653001801413653003401431653001101465653000901476653002701485653003601512653002401548653002001572100001801592700002101610700002301631700002301654700001101677700003201688700002501720700002501745700002801770700001801798700003101816700002201847700002501869700002201894700002101916700002001937700002301957700002301980700001802003700002202021700001602043700002802059700002102087700001602108700001902124700001902143700002702162700001902189700001802208700001902226700002302245700001902268700002202287700002002309700002402329700002102353700002102374700002302395700002202418700002102440700002002461700001902481700002402500700002202524700002102546700002002567700001902587700002602606700002302632700001502655700002502670700001802695700002402713700001802737700001602755700001902771700001802790700002202808700002202830700002602852700002402878700001902902700001802921700002102939700001702960700002002977700002302997700001703020700001903037700002003056700002603076700002203102700002203124700001603146700002103162700002503183700001903208700002103227700002103248700002003269700002603289700002303315700001803338700001603356700001703372700002203389700002603411700002203437700001903459700003503478700002103513700001603534700002403550700002103574700001903595700002203614700002003636700002003656700001703676700002403693700002403717700002803741700002503769700001603794700002303810700002303833700002303856700002303879700002403902700002003926700001903946700002403965700002003989700001904009700002104028700002304049700001904072700002504091700002504116700002404141700002004165700001804185700001704203700001804220700001804238700002204256700002304278700002304301700001204324700001804336700001904354700002304373700002104396700002304417700002704440700002204467700002804489700002204517700002204539700002304561700002104584700001604605700001604621700002204637700001604659700001904675700002004694700001804714700002004732700001804752700002104770700002204791700002204813700001904835700002004854700002204874700002104896700002304917700002104940700002004961700002204981700001905003700002105022700001605043700002105059700002105080700002005101700001905121700001905140700002705159700002205186700001805208700002605226700002205252700002005274700001905294700001705313700002505330700002605355700001805381700002405399700001905423700002005442700002605462700002405488700001905512700002405531700002505555700002205580700002105602700001905623700002305642700002105665700001605686700001905702700002005721700001905741700002005760700002205780700002405802700001905826700002005845700002005865700002005885700002205905700001805927700001905945700002105964700002105985700002406006700001906030700002406049700001806073700002206091700001906113700002806132700002006160700001506180700002306195700001906218700001806237700001906255700002206274700001806296700002206314700002106336700002406357700001906381700002006400700002406420700002206444700002306466700001906489700002506508700002106533700002506554700001906579700002106598700002306619700002306642700002406665700002406689700002406713700002006737700002006757700002606777700001906803700001706822700001806839700002206857700002706879700002006906700001906926700002206945700002406967700001606991700002307007700002607030700002007056700002407076700001907100700001607119700002307135700002007158700002407178700002807202700001707230700002407247700001907271700002407290700002107314700002807335700002007363700002507383700002107408700002307429700002007452700002507472700001907497700002307516700002107539700002207560700001907582700002607601700002007627700002407647700002307671700002407694700002907718700002207747700002807769700002307797700002107820700002507841700002007866700001907886700002207905700002107927700002107948700002507969710001007994856003608004 2010 eng d a1546-171800aMeta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.0 aMetaanalysis identifies 13 new loci associated with waisthip rat c2010 Nov a949-600 v423 aWaist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
10aAdipose Tissue10aAge Factors10aChromosome Mapping10aFemale10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist-Hip Ratio1 aHeid, Iris, M1 aJackson, Anne, U1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aQi, Lu1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aZillikens, Carola, M1 aSpeliotes, Elizabeth, K1 aMägi, Reedik1 aWorkalemahu, Tsegaselassie1 aWhite, Charles, C1 aBouatia-Naji, Nabila1 aHarris, Tamara, B1 aBerndt, Sonja, I1 aIngelsson, Erik1 aWiller, Cristen, J1 aWeedon, Michael, N1 aLuan, Jian'an1 aVedantam, Sailaja1 aEsko, Tõnu1 aKilpeläinen, Tuomas, O1 aKutalik, Zoltán1 aLi, Shengxu1 aMonda, Keri, L1 aDixon, Anna, L1 aHolmes, Christopher, C1 aKaplan, Lee, M1 aLiang, Liming1 aMin, Josine, L1 aMoffatt, Miriam, F1 aMolony, Cliona1 aNicholson, George1 aSchadt, Eric, E1 aZondervan, Krina, T1 aFeitosa, Mary, F1 aFerreira, Teresa1 aAllen, Hana, Lango1 aWeyant, Robert, J1 aWheeler, Eleanor1 aWood, Andrew, R1 aEstrada, Karol1 aGoddard, Michael, E1 aLettre, Guillaume1 aMangino, Massimo1 aNyholt, Dale, R1 aPurcell, Shaun1 aSmith, Albert, Vernon1 aVisscher, Peter, M1 aYang, Jian1 aMcCarroll, Steven, A1 aNemesh, James1 aVoight, Benjamin, F1 aAbsher, Devin1 aAmin, Najaf1 aAspelund, Thor1 aCoin, Lachlan1 aGlazer, Nicole, L1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKapur, Karen1 aKetkar, Shamika1 aKnowles, Joshua, W1 aKraft, Peter1 aKraja, Aldi, T1 aLamina, Claudia1 aLeitzmann, Michael, F1 aMcKnight, Barbara1 aMorris, Andrew, P1 aOng, Ken, K1 aPerry, John, R B1 aPeters, Marjolein, J1 aPolasek, Ozren1 aProkopenko, Inga1 aRayner, Nigel, W1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRobertson, Neil, R1 aSanna, Serena1 aSovio, Ulla1 aSurakka, Ida1 aTeumer, Alexander1 avan Wingerden, Sophie1 aVitart, Veronique1 aZhao, Jing Hua1 aCavalcanti-Proença, Christine1 aChines, Peter, S1 aFisher, Eva1 aKulzer, Jennifer, R1 aLecoeur, Cécile1 aNarisu, Narisu1 aSandholt, Camilla1 aScott, Laura, J1 aSilander, Kaisa1 aStark, Klaus1 aTammesoo, Mari-Liis1 aTeslovich, Tanya, M1 aTimpson, Nicholas, John1 aWatanabe, Richard, M1 aWelch, Ryan1 aChasman, Daniel, I1 aCooper, Matthew, N1 aJansson, John-Olov1 aKettunen, Johannes1 aLawrence, Robert, W1 aPellikka, Niina1 aPerola, Markus1 aVandenput, Liesbeth1 aAlavere, Helene1 aAlmgren, Peter1 aAtwood, Larry, D1 aBennett, Amanda, J1 aBiffar, Reiner1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBuchanan, Thomas, A1 aCampbell, Harry1 aDay, Ian, N M1 aDei, Mariano1 aDörr, Marcus1 aElliott, Paul1 aErdos, Michael, R1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGeus, Eco, J C1 aGjesing, Anette, P1 aGrallert, Harald1 aGrässler, Jürgen1 aGroves, Christopher, J1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHavulinna, Aki, S1 aHerzig, Karl-Heinz1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aJousilahti, Pekka1 aJula, Antti1 aKajantie, Eero1 aKinnunen, Leena1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aKroemer, Heyo, K1 aKrzelj, Vjekoslav1 aKuusisto, Johanna1 aKvaloy, Kirsti1 aLaitinen, Jaana1 aLantieri, Olivier1 aLathrop, Mark, G1 aLokki, Marja-Liisa1 aLuben, Robert, N1 aLudwig, Barbara1 aMcArdle, Wendy, L1 aMcCarthy, Anne1 aMorken, Mario, A1 aNelis, Mari1 aNeville, Matt, J1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPlatou, Carl, G P1 aPouta, Anneli1 aRidderstråle, Martin1 aSamani, Nilesh, J1 aSaramies, Jouko1 aSinisalo, Juha1 aSmit, Jan, H1 aStrawbridge, Rona, J1 aStringham, Heather, M1 aSwift, Amy, J1 aTeder-Laving, Maris1 aThomson, Brian1 aUsala, Gianluca1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aVolpato, Claudia, B1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aZgaga, Lina1 aZitting, Paavo1 aBeilby, John, P1 aJames, Alan, L1 aKähönen, Mika1 aLehtimäki, Terho1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aStumvoll, Michael1 aTönjes, Anke1 aViikari, Jorma1 aBalkau, Beverley1 aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBoeing, Heiner1 aSmith, George Davey1 aEbrahim, Shah1 aFroguel, Philippe1 aHansen, Torben1 aHengstenberg, Christian1 aHveem, Kristian1 aIsomaa, Bo1 aJørgensen, Torben1 aKarpe, Fredrik1 aKhaw, Kay-Tee1 aLaakso, Markku1 aLawlor, Debbie, A1 aMarre, Michel1 aMeitinger, Thomas1 aMetspalu, Andres1 aMidthjell, Kristian1 aPedersen, Oluf1 aSalomaa, Veikko1 aSchwarz, Peter, E H1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aValle, Timo, T1 aWareham, Nicholas, J1 aArnold, Alice, M1 aBeckmann, Jacques, S1 aBergmann, Sven1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCollins, Francis, S1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHattersley, Andrew, T1 aHofman, Albert1 aHu, Frank, B1 aIllig, Thomas1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aKao, Linda, W H1 aKaprio, Jaakko1 aLauner, Lenore, J1 aMunroe, Patricia, B1 aOostra, Ben1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRissanen, Aila1 aRudan, Igor1 aShuldiner, Alan, R1 aSoranzo, Nicole1 aSpector, Timothy, D1 aSyvänen, Ann-Christine1 aUda, Manuela1 aUitterlinden, Andre1 aVölzke, Henry1 aVollenweider, Peter1 aWilson, James, F1 aWitteman, Jacqueline, C1 aWright, Alan, F1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFrayling, Timothy, M1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aHirschhorn, Joel, N1 aAssimes, Themistocles, L1 aWichmann, H-Erich1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aStefansson, Kari1 aCupples, Adrienne, L1 aLoos, Ruth, J F1 aBarroso, Inês1 aMcCarthy, Mark, I1 aFox, Caroline, S1 aMohlke, Karen, L1 aLindgren, Cecilia, M1 aMAGIC uhttps://chs-nhlbi.org/node/123604122nas a2200841 4500008004100000022001400041245017500055210006900230260001300299300001100312490000700323520169700330653001002027653001602037653000902053653002202062653001202084653001902096653002502115653001102140653003402151653001302185653001102198653001402209653000902223653001602232653001502248653003602263100002002299700001902319700002402338700002302362700002002385700002302405700002102428700001902449700002402468700002402492700002302516700002502539700002802564700002302592700002202615700002402637700001902661700001902680700001902699700002602718700002102744700002202765700002602787700002302813700001902836700002202855700002002877700002002897700002602917700001902943700002002962700002102982700002003003700002203023700001603045700002803061700002103089700002003110700002603130700002203156700001903178700002303197700002403220856003603244 2010 eng d a1758-535X00aA meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.0 ametaanalysis of four genomewide association studies of survival c2010 May a478-870 v653 aBACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.
METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.
RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.
CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.
10aAdult10aAge Factors10aAged10aAged, 80 and over10aAlleles10aCohort Studies10aConfidence Intervals10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aLongevity10aMale10aMiddle Aged10aOdds Ratio10aPolymorphism, Single Nucleotide1 aNewman, Anne, B1 aWalter, Stefan1 aLunetta, Kathryn, L1 aGarcia, Melissa, E1 aSlagboom, Eline1 aChristensen, Kaare1 aArnold, Alice, M1 aAspelund, Thor1 aAulchenko, Yurii, S1 aBenjamin, Emelia, J1 aChristiansen, Lene1 aD'Agostino, Ralph, B1 aFitzpatrick, Annette, L1 aFranceschini, Nora1 aGlazer, Nicole, L1 aGudnason, Vilmundur1 aHofman, Albert1 aKaplan, Robert1 aKarasik, David1 aKelly-Hayes, Margaret1 aKiel, Douglas, P1 aLauner, Lenore, J1 aMarciante, Kristin, D1 aMassaro, Joseph, M1 aMiljkovic, Iva1 aNalls, Michael, A1 aHernandez, Dena1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome1 aSeshadri, Sudha1 aSmith, Albert, V1 aTaylor, Kent, D1 aTiemeier, Henning1 aUh, Hae-Won1 aUitterlinden, André, G1 aVaupel, James, W1 aWalston, Jeremy1 aWestendorp, Rudi, G J1 aHarris, Tamara, B1 aLumley, Thomas1 aDuijn, Cornelia, M1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/117903867nas a2200745 4500008004100000022001400041245012900055210006900184260001300253300001100266490000600277520177500283653002802058653002102086653001102107653001702118653003402135653000902169653001102178653000902189653001702198653001402215100001602229700001902245700001902264700002102283700002202304700002002326700002302346700001902369700002402388700002202412700001902434700001902453700002002472700001902492700002102511700002002532700001202552700002002564700002102584700002302605700001202628700001902640700002002659700002102679700002002700700002202720700003002742700002102772700002302793700001902816700002602835700002002861700002802881700002102909700002002930700002002950700002402970700002402994700002803018700002103046700001803067856003603085 2010 eng d a1942-326800aMultiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.0 aMultiple genetic loci influence serum urate levels and their rel c2010 Dec a523-300 v33 aBACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).
METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.
CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
10aCardiovascular Diseases10aCoronary Disease10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGout10aHumans10aMale10aRisk Factors10aUric Acid1 aYang, Qiong1 aKöttgen, Anna1 aDehghan, Abbas1 aSmith, Albert, V1 aGlazer, Nicole, L1 aChen, Ming-Huei1 aChasman, Daniel, I1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLauner, Lenore1 aNalls, Michael1 aHernandez, Dena1 aArking, Dan, E1 aBoerwinkle, Eric1 aGrove, Megan, L1 aLi, Man1 aKao, W, H Linda1 aChonchol, Michel1 aHaritunians, Talin1 aLi, Guo1 aLumley, Thomas1 aPsaty, Bruce, M1 aShlipak, Michael1 aHwang, Shih-Jen1 aLarson, Martin, G1 aO'Donnell, Christopher, J1 aUpadhyay, Ashish1 aDuijn, Cornelia, M1 aHofman, Albert1 aRivadeneira, Fernando1 aStricker, Bruno1 aUitterlinden, André, G1 aParé, Guillaume1 aParker, Alex, N1 aRidker, Paul, M1 aSiscovick, David, S1 aGudnason, Vilmundur1 aWitteman, Jacqueline, C1 aFox, Caroline, S1 aCoresh, Josef uhttps://chs-nhlbi.org/node/123512636nas a2204069 4500008004100000022001400041245010500055210006900160260001300229300001100242490000700253520123400260653001501494653001001509653001201519653001801531653001001549653002301559653003001582653003101612653001201643653003101655653001701686653003801703653003401741653001601775653001101791653002701802653003601829653002801865653003401893653003101927100001901958700002401977700002102001700001802022700002002040700002102060700002102081700002202102700002502124700001902149700002502168700001802193700002202211700002002233700001802253700001802271700001702289700002502306700003202331700002002363700002102383700001902404700002402423700002902447700001702476700001802493700001502511700002102526700002302547700001902570700001802589700002002607700001602627700002402643700002602667700001202693700002202705700001902727700003502746700001802781700001102799700002502810700002202835700001902857700002402876700002002900700001302920700002302933700001802956700002002974700002502994700002003019700002703039700002203066700002403088700002003112700002003132700002103152700001903173700002003192700002103212700002303233700002303256700001903279700002103298700002103319700002303340700002503363700002403388700002203412700001803434700002703452700002703479700002203506700001803528700001903546700002303565700002303588700002203611700001903633700002003652700001803672700001903690700002303709700002003732700002203752700002303774700002803797700002103825700002103846700001703867700002703884700001703911700002203928700002303950700002703973700001804000700002004018700002004038700001804058700002104076700001904097700001604116700002804132700002204160700002204182700002004204700002004224700002204244700002104266700002204287700002404309700001904333700001604352700001404368700001504382700002304397700002304420700001604443700002104459700001904480700002504499700001904524700002104543700002004564700001804584700002304602700002104625700002204646700002404668700002104692700001204713700002304725700001904748700002104767700002204788700003604810700002304846700002404869700002004893700002304913700001804936700001704954700002504971700002104996700002205017700001905039700001905058700002405077700001905101700001705120700001605137700002305153700002305176700002205199700002005221700001905241700002305260700001905283700002705302700001905329700001905348700002305367700002105390700001805411700002505429700002005454700002305474700002105497700001805518700002005536700002605556700001905582700002105601700002205622700002205644700001805666700002205684700001705706700002005723700001705743700002205760700002205782700002505804700002505829700002105854700001905875700002205894700002305916700001605939700001505955700001905970700002805989700002006017700002106037700001706058700001806075700002206093700002806115700002106143700001606164700001806180700002706198700002206225700002306247700002006270700002106290700001906311700002206330700001706352700001806369700002306387700001906410700002306429700002906452700002306481700002406504700002006528700002206548700001806570700001906588700002506607700002306632700002006655700002006675700002706695700002106722700002406743700002606767700002006793700002006813700002406833700002506857700001906882700002206901700001906923700002306942700001806965700002506983700002607008700002207034700001507056700002007071700001707091700002007108700001807128700002007146700002007166700002107186700002407207700002207231700001907253700001907272700001907291700002807310700002307338700001807361700001607379700002007395700002207415700002007437700002107457700002407478700002407502700002407526700002107550700002307571700001907594700002107613700002207634700002407656700002707680700002307707700002007730700002407750700002507774700002007799700002007819700002807839700002107867700002307888700002407911700001707935700002007952700002407972700001707996700001908013700002708032700002408059700002408083700002008107700002008127700002508147700002508172700001908197700002208216700002508238700002008263700001608283700002108299700002208320700002008342700001908362710002308381710002108404710002808425710005308453710002408506856003608530 2010 eng d a1546-171800aNew genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.0 aNew genetic loci implicated in fasting glucose homeostasis and t c2010 Feb a105-160 v423 aLevels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
10aAdolescent10aAdult10aAlleles10aBlood Glucose10aChild10aDatabases, Genetic10aDiabetes Mellitus, Type 210aDNA Copy Number Variations10aFasting10aGene Expression Regulation10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeostasis10aHumans10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aReproducibility of Results1 aDupuis, Josée1 aLangenberg, Claudia1 aProkopenko, Inga1 aSaxena, Richa1 aSoranzo, Nicole1 aJackson, Anne, U1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aGloyn, Anna, L1 aLindgren, Cecilia, M1 aMägi, Reedik1 aMorris, Andrew, P1 aRandall, Joshua1 aJohnson, Toby1 aElliott, Paul1 aRybin, Denis1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aHenneman, Peter1 aGrallert, Harald1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aFranklin, Christopher, S1 aNavarro, Pau1 aSong, Kijoung1 aGoel, Anuj1 aPerry, John, R B1 aEgan, Josephine, M1 aLajunen, Taina1 aGrarup, Niels1 aSparsø, Thomas1 aDoney, Alex1 aVoight, Benjamin, F1 aStringham, Heather, M1 aLi, Man1 aKanoni, Stavroula1 aShrader, Peter1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aQi, Lu1 aTimpson, Nicholas, J1 aGieger, Christian1 aZabena, Carina1 aRocheleau, Ghislain1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aPayne, Felicity1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aArdlie, Kristin1 aAriyurek, Yavuz1 aBalkau, Beverley1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBonnefond, Amélie1 aBonnycastle, Lori, L1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aCharpentier, Guillaume1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCornelis, Marilyn1 aCrawford, Gabe1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aDina, Christian1 aErdos, Michael, R1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFox, Caroline, S1 aFrants, Rune1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGroves, Christopher, J1 aGrundy, Scott1 aGwilliam, Rhian1 aGyllensten, Ulf1 aHadjadj, Samy1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHerder, Christian1 aHicks, Andrew, A1 aHillman, David, R1 aHingorani, Aroon, D1 aHofman, Albert1 aHui, Jennie1 aHung, Joe1 aIsomaa, Bo1 aJohnson, Paul, R V1 aJørgensen, Torben1 aJula, Antti1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aLyssenko, Valeriya1 aMahley, Robert1 aMangino, Massimo1 aManning, Alisa, K1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcCulloch, Laura, J1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, Braxton, D1 aMorken, Mario, A1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNarisu, Narisu1 aNeville, Matthew, J1 aOostra, Ben, A1 aOrrù, Marco1 aPakyz, Ruth1 aPalmer, Colin, N A1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPerola, Markus1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRathmann, Wolfgang1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRoden, Michael1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aScott, Laura, J1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurethsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTanaka, Toshiko1 aThorand, Barbara1 aTichet, Jean1 aTönjes, Anke1 aTuomi, Tiinamaija1 aUitterlinden, André, G1 aDijk, Ko Willems1 aHoek, Mandy1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWalters, Bragi, G1 aWard, Kim, L1 aWatkins, Hugh1 aWeedon, Michael, N1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZeggini, Eleftheria1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aLoos, Ruth, J F1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aHattersley, Andrew, T1 aSilander, Kaisa1 aSalomaa, Veikko1 aSmith, George Davey1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aDedoussis, George, V1 aSerrano-Ríos, Manuel1 aMorris, Andrew, D1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPankow, James, S1 aSampson, Michael, J1 aKuusisto, Johanna1 aLaakso, Markku1 aHansen, Torben1 aPedersen, Oluf1 aPramstaller, Peter Paul1 aWichmann, Erich, H1 aIllig, Thomas1 aRudan, Igor1 aWright, Alan, F1 aStumvoll, Michael1 aCampbell, Harry1 aWilson, James, F1 aBergman, Richard, N1 aBuchanan, Thomas, A1 aCollins, Francis, S1 aMohlke, Karen, L1 aTuomilehto, Jaakko1 aValle, Timo, T1 aAltshuler, David1 aRotter, Jerome, I1 aSiscovick, David, S1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aDeloukas, Panos1 aSpector, Timothy, D1 aFrayling, Timothy, M1 aFerrucci, Luigi1 aKong, Augustine1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAulchenko, Yurii, S1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aWaterworth, Dawn, M1 aVollenweider, Peter1 aPeltonen, Leena1 aMooser, Vincent1 aAbecasis, Goncalo, R1 aWareham, Nicholas, J1 aSladek, Robert1 aFroguel, Philippe1 aWatanabe, Richard, M1 aMeigs, James, B1 aGroop, Leif1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aFlorez, Jose, C1 aBarroso, Inês1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal BPgen Consortium1 aAnders Hamsten on behalf of Procardis Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/116006326nas a2201873 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2010 eng d a1546-171800aNew loci associated with kidney function and chronic kidney disease.0 aNew loci associated with kidney function and chronic kidney dise c2010 May a376-840 v423 aChronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
10aCohort Studies10aCreatinine10aCystatin C10aDiet10aEurope10aGenetic Markers10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aModels, Genetic10aRisk Factors1 aKöttgen, Anna1 aPattaro, Cristian1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aGlazer, Nicole, L1 aParsa, Afshin1 aGao, Xiaoyi1 aYang, Qiong1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aLi, Man1 aSchmidt, Helena1 aTanaka, Toshiko1 aIsaacs, Aaron1 aKetkar, Shamika1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aDehghan, Abbas1 aTeumer, Alexander1 aParé, Guillaume1 aAtkinson, Elizabeth, J1 aZeller, Tanja1 aLohman, Kurt1 aCornelis, Marilyn, C1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aTönjes, Anke1 aHayward, Caroline1 aAspelund, Thor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aRampersaud, Evadnie1 aMitchell, Braxton, D1 aArking, Dan, E1 aBoerwinkle, Eric1 aStruchalin, Maksim1 aCavalieri, Margherita1 aSingleton, Andrew1 aGiallauria, Francesco1 aMetter, Jeffrey1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSiscovick, David1 aPsaty, Bruce, M1 aZillikens, Carola, M1 aOostra, Ben, A1 aFeitosa, Mary1 aProvince, Michael1 ade Andrade, Mariza1 aTurner, Stephen, T1 aSchillert, Arne1 aZiegler, Andreas1 aWild, Philipp, S1 aSchnabel, Renate, B1 aWilde, Sandra1 aMunzel, Thomas, F1 aLeak, Tennille, S1 aIllig, Thomas1 aKlopp, Norman1 aMeisinger, Christa1 aWichmann, H-Erich1 aKoenig, Wolfgang1 aZgaga, Lina1 aZemunik, Tatijana1 aKolcic, Ivana1 aMinelli, Cosetta1 aHu, Frank, B1 aJohansson, Asa1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aSchreiber, Stefan1 aAulchenko, Yurii, S1 aFelix, Janine, F1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aImboden, Medea1 aNitsch, Dorothea1 aBrandstätter, Anita1 aKollerits, Barbara1 aKedenko, Lyudmyla1 aMägi, Reedik1 aStumvoll, Michael1 aKovacs, Peter1 aBoban, Mladen1 aCampbell, Susan1 aEndlich, Karlhans1 aVölzke, Henry1 aKroemer, Heyo, K1 aNauck, Matthias1 aVölker, Uwe1 aPolasek, Ozren1 aVitart, Veronique1 aBadola, Sunita1 aParker, Alexander, N1 aRidker, Paul, M1 aKardia, Sharon, L R1 aBlankenberg, Stefan1 aLiu, Yongmei1 aCurhan, Gary, C1 aFranke, Andre1 aRochat, Thierry1 aPaulweber, Bernhard1 aProkopenko, Inga1 aWang, Wei1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aShlipak, Michael, G1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKrämer, Bernhard, K1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aWitteman, Jacqueline, C1 aPramstaller, Peter, P1 aRettig, Rainer1 aHastie, Nick1 aChasman, Daniel, I1 aKao, W H1 aHeid, Iris, M1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/118302243nas a2200361 4500008004100000022001400041245014200055210006900197260001300266300001100279490000700290520121600297653001601513653000901529653001501538653002001553653001901573653001101592653001101603653000901614653001601623653003001639653001701669653001401686653002601700653001201726653002401738100001701762700002301779700002301802700002001825856003601845 2010 eng d a0161-810500aA novel approach to prediction of mild obstructive sleep disordered breathing in a population-based sample: the Sleep Heart Health Study.0 anovel approach to prediction of mild obstructive sleep disordere c2010 Dec a1641-80 v333 aThis manuscript considers a data-mining approach for the prediction of mild obstructive sleep disordered breathing, defined as an elevated respiratory disturbance index (RDI), in 5,530 participants in a community-based study, the Sleep Heart Health Study. The prediction algorithm was built using modern ensemble learning algorithms, boosting in specific, which allowed for assessing potential high-dimensional interactions between predictor variables or classifiers. To evaluate the performance of the algorithm, the data were split into training and validation sets for varying thresholds for predicting the probability of a high RDI (≥7 events per hour in the given results). Based on a moderate classification threshold from the boosting algorithm, the estimated post-test odds of a high RDI were 2.20 times higher than the pre-test odds given a positive test, while the corresponding post-test odds were decreased by 52% given a negative test (sensitivity and specificity of 0.66 and 0.70, respectively). In rank order, the following variables had the largest impact on prediction performance: neck circumference, body mass index, age, snoring frequency, waist circumference, and snoring loudness.
10aAge Factors10aAged10aAlgorithms10aBody Mass Index10aCohort Studies10aFemale10aHumans10aMale10aMiddle Aged10aPredictive Value of Tests10aRisk Factors10aROC Curve10aSleep Apnea Syndromes10aSnoring10aWaist Circumference1 aCaffo, Brian1 aDiener-West, Marie1 aPunjabi, Naresh, M1 aSamet, Jonathan uhttps://chs-nhlbi.org/node/125204638nas a2200901 4500008004100000022001400041245020700055210006900262260001600331300001200347490000800359520199800367653001002365653001502375653001602390653001102406653003402417653001502451653001102466653000902477653001602486653001402502653003602516653001502552653002602567100002302593700002002616700001902636700002302655700001702678700002002695700002202715700001602737700002502753700001902778700002502797700001602822700001902838700001602857700002702873700002202900700002002922700002302942700002202965700002302987700002203010700002103032700002303053700002103076700002203097700002803119700001803147700002003165700002003185700002103205700001803226700002203244700002203266700002103288700001903309700002103328700002403349700001903373700002003392700001903412700002103431700002203452700002403474700002003498700002103518700002003539700001903559700003003578700001803608700003003626710004403656856003603700 2010 eng d a1524-453900aNovel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.0 aNovel associations of multiple genetic loci with plasma levels o c2010 Mar 30 a1382-920 v1213 aBACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.
METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.
CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.
10aAdult10aFactor VII10aFactor VIII10aFemale10aGenome-Wide Association Study10aHemostasis10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aThrombosis10avon Willebrand Factor1 aSmith, Nicholas, L1 aChen, Ming-Huei1 aDehghan, Abbas1 aStrachan, David, P1 aBasu, Saonli1 aSoranzo, Nicole1 aHayward, Caroline1 aRudan, Igor1 aSabater-Lleal, Maria1 aBis, Joshua, C1 ade Maat, Moniek, P M1 aRumley, Ann1 aKong, Xiaoxiao1 aYang, Qiong1 aWilliams, Frances, M K1 aVitart, Veronique1 aCampbell, Harry1 aMälarstig, Anders1 aWiggins, Kerri, L1 aDuijn, Cornelia, M1 aMcArdle, Wendy, L1 aPankow, James, S1 aJohnson, Andrew, D1 aSilveira, Angela1 aMcKnight, Barbara1 aUitterlinden, André, G1 aAleksic, Nena1 aMeigs, James, B1 aPeters, Annette1 aKoenig, Wolfgang1 aCushman, Mary1 aKathiresan, Sekar1 aRotter, Jerome, I1 aBovill, Edwin, G1 aHofman, Albert1 aBoerwinkle, Eric1 aTofler, Geoffrey, H1 aPeden, John, F1 aPsaty, Bruce, M1 aLeebeek, Frank1 aFolsom, Aaron, R1 aLarson, Martin, G1 aSpector, Timothy, D1 aWright, Alan, F1 aWilson, James, F1 aHamsten, Anders1 aLumley, Thomas1 aWitteman, Jacqueline, C M1 aTang, Weihong1 aO'Donnell, Christopher, J1 aWellcome Trust Case Control Consortium; uhttps://chs-nhlbi.org/node/117602992nas a2200445 4500008004100000022001400041245008800055210006900143260001600212300001100228490000800239520174000247653000901987653001101996653001102007653002502018653000902043653001602052653002002068653003202088653002402120653003002144653001602174653002902190653001102219100001902230700002102249700002402270700001702294700002402311700002402335700002302359700002102382700002002403700002502423700001702448700002202465700002302487856003602510 2010 eng d a1535-497000aObstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study.0 aObstructive sleep apneahypopnea and incident stroke the sleep he c2010 Jul 15 a269-770 v1823 aRATIONALE: Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population.
OBJECTIVES: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea.
METHODS: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke.
MEASUREMENTS AND MAIN RESULTS: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25.
CONCLUSIONS: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.
10aAged10aFemale10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aPolysomnography10aProportional Hazards Models10aProspective Studies10aSeverity of Illness Index10aSex Factors10aSleep Apnea, Obstructive10aStroke1 aRedline, Susan1 aYenokyan, Gayane1 aGottlieb, Daniel, J1 aShahar, Eyal1 aO'Connor, George, T1 aResnick, Helaine, E1 aDiener-West, Marie1 aSanders, Mark, H1 aWolf, Philip, A1 aGeraghty, Estella, M1 aAli, Tauqeer1 aLebowitz, Michael1 aPunjabi, Naresh, M uhttps://chs-nhlbi.org/node/118102166nas a2200409 4500008004100000022001400041245011100055210006900166260001300235300001100248490000700259520100900266653003101275653001601306653000901322653002201331653002801353653001901381653001301400653001101413653002001424653001801444653001101462653002301473653001501496653000901511653003201520653001601552100002201568700001701590700002001607700002401627700002101651700002501672700002301697856003601720 2010 eng d a1063-865200aPhysical activity and years of healthy life in older adults: results from the cardiovascular health study.0 aPhysical activity and years of healthy life in older adults resu c2010 Jul a313-340 v183 aLittle is known about how many years of life and disability-free years seniors can gain through exercise. Using data from the Cardiovascular Health Study, the authors estimated the extra years of life and self-reported healthy life (over 11 years) and years without impairment in activities of daily living (over 6 years) associated with quintiles of physical activity (PA) in older adults from different age groups. They estimated PA from the Minnesota Leisure Time Activities Questionnaire. Multivariable linear regression adjusted for health-related covariates. The relative gains in survival and years of healthy life (YHL) generally were proportionate to the amount of PA, greater among those 75+, and higher in men. Compared with being sedentary, the most active men 75+ had 1.49 more YHL (95% CI: 0.79, 2.19), and the most active women 75+ had 1.06 more YHL (95% CI: 0.44, 1.68). Seniors over age 74 experience the largest relative gains in survival and healthy life from physical activity.
10aActivities of Daily Living10aAge Factors10aAged10aAged, 80 and over10aCardiovascular Diseases10aCohort Studies10aExercise10aFemale10aHealth Behavior10aHealth Status10aHumans10aLeisure Activities10aLife Style10aMale10aQuality-Adjusted Life Years10aSex Factors1 aHirsch, Calvin, H1 aDiehr, Paula1 aNewman, Anne, B1 aGerrior, Shirley, A1 aPratt, Charlotte1 aLebowitz, Michael, D1 aJackson, Sharon, A uhttps://chs-nhlbi.org/node/121902972nas a2200433 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520171800293653001002011653000902021653002102030653001102051653001802062653001102080653002502091653000902116653001602125653002002141653003202161653002402193653002902217653002202246100002402268700002102292700002002313700002402333700002302357700002002380700001902400700002402419700001902443700002302462700001702485856003602502 2010 eng d a1524-453900aProspective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study.0 aProspective study of obstructive sleep apnea and incident corona c2010 Jul 27 a352-600 v1223 aBACKGROUND: Clinic-based observational studies in men have reported that obstructive sleep apnea is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of obstructive sleep apnea to incident coronary heart disease and heart failure in a general community sample of adult men and women.
METHODS AND RESULTS: A total of 1927 men and 2495 women > or =40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study. After adjustment for multiple risk factors, obstructive sleep apnea was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men < or =70 years of age (adjusted hazard ratio 1.10 [95% confidence interval 1.00 to 1.21] per 10-unit increase in apnea-hypopnea index [AHI]) but not in older men or in women of any age. Among men 40 to 70 years old, those with AHI > or =30 were 68% more likely to develop coronary heart disease than those with AHI <5. Obstructive sleep apnea predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% confidence interval 1.02 to 1.26] per 10-unit increase in AHI). Men with AHI > or =30 were 58% more likely to develop heart failure than those with AHI <5.
CONCLUSIONS: Obstructive sleep apnea is associated with an increased risk of incident heart failure in community-dwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal.
10aAdult10aAged10aCoronary Disease10aFemale10aHeart Failure10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aPolysomnography10aProportional Hazards Models10aProspective Studies10aSleep Apnea, Obstructive10aSurvival Analysis1 aGottlieb, Daniel, J1 aYenokyan, Gayane1 aNewman, Anne, B1 aO'Connor, George, T1 aPunjabi, Naresh, M1 aQuan, Stuart, F1 aRedline, Susan1 aResnick, Helaine, E1 aTong, Elisa, K1 aDiener-West, Marie1 aShahar, Eyal uhttps://chs-nhlbi.org/node/121502828nas a2200349 4500008004100000022001400041245010500055210006900160260001600229300001300245490000800258520184300266653000902109653003802118653001102156653001102167653000902178653001602187653002002203653002002223653001002243653002602253653001502279100002102294700002202315700002202337700001602359700002002375700002302395700002402418856003602442 2010 eng d a1535-497000aSleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing.0 aSleepiness quality of life and sleep maintenance in REM versus n c2010 May 01 a997-10020 v1813 aRATIONALE: The impact of REM-predominant sleep-disordered breathing (SDB) on sleepiness, quality of life (QOL), and sleep maintenance is uncertain.
OBJECTIVE: To evaluate the association of SDB during REM sleep with daytime sleepiness, health-related QOL, and difficulty maintaining sleep, in comparison to their association with SDB during non-REM sleep in a community-based cohort.
METHODS: Cross-sectional analysis of 5,649 Sleep Heart Health Study participants (mean age 62.5 [SD = 10.9], 52.6% women, 22.6% ethnic minorities). SDB during REM and non-REM sleep was quantified using polysomnographically derived apnea-hypopnea index in REM (AHI(REM)) and non-REM (AHI(NREM)) sleep. Sleepiness, sleep maintenance, and QOL were respectively quantified using the Epworth Sleepiness Scale (ESS), the Sleep Heart Health Study Sleep Habit Questionnaire, and the physical and mental composites scales of the Medical Outcomes Study Short Form (SF)-36.
MEASUREMENTS AND MAIN RESULTS: AHI(REM) was not associated with the ESS scores or the physical and mental components scales scores of the SF-36 after adjusting for demographics, body mass index, and AHI(NREM) x AHI(REM) was not associated with frequent difficulty maintaining sleep or early awakening from sleep. AHI(NREM) was associated with the ESS score (beta = 0.25; 95% confidence interval [CI], 0.16 to 0.34) and the physical (beta = -0.12; 95% CI, -0.42 to -0.01) and mental (beta = -0.20; 95% CI, -0.20 to -0.01) components scores of the SF-36 adjusting for demographics, body mass index, and AHI(REM).
CONCLUSIONS: In a community-based sample of middle-aged and older adults, REM-predominant SDB is not independently associated with daytime sleepiness, impaired health-related QOL, or self-reported sleep disruption.
10aAged10aDisorders of Excessive Somnolence10aFemale10aHumans10aMale10aMiddle Aged10aPolysomnography10aQuality of Life10aSleep10aSleep Apnea Syndromes10aSleep, REM1 aChami, Hassan, A1 aBaldwin, Carol, M1 aSilverman, Angela1 aZhang, Ying1 aRapoport, David1 aPunjabi, Naresh, M1 aGottlieb, Daniel, J uhttps://chs-nhlbi.org/node/116100951nas a2200337 4500008004100000022001400041245009000055210006900145260001300214300001000227490000600237653001000243653002200253653001200275653001100287653001100298653001800309653000900327653001600336653003600352653002900388100002000417700002100437700001800458700002200476700002000498700002000518700002000538700001900558856003600577 2010 eng d a1752-806200aStudy of the relationship between the interleukin-6 gene and obstructive sleep apnea.0 aStudy of the relationship between the interleukin6 gene and obst c2010 Dec a337-90 v310aAdult10aAfrican Americans10aAlleles10aFemale10aHumans10aInterleukin-610aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSleep Apnea, Obstructive1 aLarkin, Emma, K1 aPatel, Sanjay, R1 aZhu, Xiaofeng1 aTracy, Russell, P1 aJenny, Nancy, S1 aReiner, Alex, P1 aWalston, Jeremy1 aRedline, Susan uhttps://chs-nhlbi.org/node/126003091nas a2200361 4500008004100000022001400041245007000055210006900125260001300194300001100207490000700218520213900225653001602364653000902380653001202389653002002401653001902421653001102440653001102451653000902462653001602471653002002487653003002507653001702537653001602554653001702570653002502587100001902612700001702631700002202648700002302670856003602693 2010 eng d a0161-810500aUtility of sleep stage transitions in assessing sleep continuity.0 aUtility of sleep stage transitions in assessing sleep continuity c2010 Dec a1681-60 v333 aSTUDY OBJECTIVES: Sleep continuity is commonly assessed with polysomnographic measures such as sleep efficiency, sleep stage percentages, and the arousal index. The aim of this study was to examine whether the transition rate between different sleep stages could be used as an index of sleep continuity to predict self-reported sleep quality independent of other commonly used metrics.
DESIGN AND SETTING: Analysis of the Sleep Heart Health Study polysomnographic data.
PARTICIPANTS: A community cohort.
MEASUREMENTS AND RESULTS: Sleep recordings on 5,684 participants were deemed to be of sufficient quality to allow visual scoring of NREM and REM sleep. For each participant, we tabulated the frequency of transitions between wake, NREM sleep, and REM sleep. An overall transition rate was determined as the number of all transitions per hour sleep. Stage-specific transition rates between wake, NREM sleep, and REM sleep were also determined. A 5-point Likert scale was used to assess the subjective experience of restless and light sleep the morning after the sleep study. Multivariable regression models showed that a high overall sleep stage transition rate was associated with restless and light sleep independent of several covariates including total sleep time, percentages of sleep stages, wake time after sleep onset, and the arousal index. Compared to the lowest quartile of the overall transition rate (<7.76 events/h), the odds ratios for restless sleep were 1.27, 1.42, and 1.38, for the second (7.77-10.10 events/h), third (10.11-13.34 events/h), and fourth (≥13.35 events/h) quartiles, respectively. Analysis of stage-specific transition rates showed that transitions between wake and NREM sleep were also independently associated with restless and light sleep.
CONCLUSIONS: Assessing overall and stage-specific transition rates provides a complementary approach for assessing sleep continuity. Incorporating such measures, along with conventional metrics, could yield useful insights into the significance of sleep continuity for clinical outcomes.
10aAge Factors10aAged10aArousal10aBody Mass Index10aCohort Studies10aFemale10aHumans10aMale10aMiddle Aged10aPolysomnography10aPredictive Value of Tests10aRisk Factors10aSex Factors10aSleep Stages10aSleep Wake Disorders1 aLaffan, Alison1 aCaffo, Brian1 aSwihart, Bruce, J1 aPunjabi, Naresh, M uhttps://chs-nhlbi.org/node/125303858nas a2200685 4500008004100000022001400041245008900055210006900144260001600213300001200229490000800241520195200249653003902201653001602240653000902256653002202265653001502287653002402302653001902326653002002345653001902365653002402384653001102408653004002419653001102459653002202470653001802492653001102510653001702521653001402538653002602552653000902578653001602587653003202603653001702635653001602652653001202668653001802680100002402698700001902722700001202741700002202753700002402775700002202799700002402821700002502845700001702870700002302887700002002910700002402930700002002954700002202974700002202996700002703018700002003045700002403065700002403089700002303113856003603136 2010 eng d a1538-367900aValidation of an atrial fibrillation risk algorithm in whites and African Americans.0 aValidation of an atrial fibrillation risk algorithm in whites an c2010 Nov 22 a1909-170 v1703 aBACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.
METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.
RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.
CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.
10aAfrican Continental Ancestry Group10aAge Factors10aAged10aAged, 80 and over10aAlgorithms10aAtrial Fibrillation10aBlood Pressure10aBody Mass Index10aCohort Studies10aElectrocardiography10aEurope10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHeart Failure10aHumans10aHypertension10aIncidence10aKaplan-Meier Estimate10aMale10aMiddle Aged10aProportional Hazards Models10aRisk Factors10aSex Factors10aSystole10aUnited States1 aSchnabel, Renate, B1 aAspelund, Thor1 aLi, Guo1 aSullivan, Lisa, M1 aSuchy-Dicey, Astrid1 aHarris, Tamara, B1 aPencina, Michael, J1 aD'Agostino, Ralph, B1 aLevy, Daniel1 aKannel, William, B1 aWang, Thomas, J1 aKronmal, Richard, A1 aWolf, Philip, A1 aBurke, Gregory, L1 aLauner, Lenore, J1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/124703318nas a2200517 4500008004100000022001400041245013000055210006900185260001300254300001200267490000600279520179800285653002102083653000902104653002202113653001902135653001902154653002502173653002402198653003002222653001102252653001802263653001102281653001402292653000902306653002402315653003002339653001402369653003002383653002102413653002202434653001802456100002802474700002002502700002702522700002802549700002102577700002302598700002802621700002302649700002002672700002202692700001802714710003202732856003602764 2010 eng d a1941-329700aValidation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study.0 aValidation of the health ABC heart failure model for incident he c2010 Jul a495-5020 v33 aBACKGROUND: The recently developed and internally validated Health ABC HF model uses 9 routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model.
METHODS AND RESULTS: Observed 5-year incidence of heart failure, defined as first hospitalization for new-onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5%) participants developed heart failure over 5 years versus 364 (6.8%) predicted by the Health ABC HF model (predicted-to-observed ratio, 0.90). Observed versus predicted 5-year heart failure probabilities were 3.2% versus 2.8%, 9.0% versus 7.0%, 15.9% versus 13.7%, and 24.6% versus 30.8% for the <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk categories, respectively. The Hosmer-Lemeshow chi(2) was 14.72 (degrees of freedom, 10; P=0.14), and the C index was 0.74 (95% CI, 0.72 to 0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however, risk was underestimated in white men, especially in the 5% to 10% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results.
CONCLUSIONS: The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to whom to target heart failure prevention efforts.
10aAge Distribution10aAged10aAged, 80 and over10aCause of Death10aCohort Studies10aConfidence Intervals10aDisease Progression10aEchocardiography, Doppler10aFemale10aHeart Failure10aHumans10aIncidence10aMale10aModels, Statistical10aPredictive Value of Tests10aPrognosis10aSeverity of Illness Index10aSex Distribution10aSurvival Analysis10aUnited States1 aKalogeropoulos, Andreas1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aGeorgiopoulou, Vasiliki1 aSmith, Andrew, L1 aSmith, Nicholas, L1 aKritchevsky, Stephen, B1 aWilson, Peter, W F1 aNewman, Anne, B1 aHarris, Tamara, B1 aButler, Javed1 aCardiovascular Health Study uhttps://chs-nhlbi.org/node/119402817nas a2200385 4500008004100000022001400041245012300055210006900178260000900247300001500256490000600271520169500277653000901972653002801981653001502009653003702024653001102061653003102072653001102103653001702114653001102131653002502142653000902167653002402176100002302200700001802223700002602241700002502267700002302292700001602315700002002331700002002351700002402371856003602395 2011 eng d a1557-467900aAntihypertensive medication use and change in kidney function in elderly adults: a marginal structural model analysis.0 aAntihypertensive medication use and change in kidney function in c2011 aArticle 340 v73 aBACKGROUND: The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.
METHODS: Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989-1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.
RESULTS: The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m(2). In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m(2) per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (-0.13, 4.59) ml/min/1.73 m(2) per year slower decline in eGFR.
CONCLUSION: In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.
10aAged10aAntihypertensive Agents10aCystatin C10aData Interpretation, Statistical10aFemale10aGlomerular Filtration Rate10aHumans10aHypertension10aKidney10aLongitudinal Studies10aMale10aModels, Statistical1 aOdden, Michelle, C1 aTager, Ira, B1 avan der Laan, Mark, J1 aDelaney, Joseph, A C1 aPeralta, Carmen, A1 aKatz, Ronit1 aSarnak, Mark, J1 aPsaty, Bruce, M1 aShlipak, Michael, G uhttps://chs-nhlbi.org/node/134803845nas a2200817 4500008004100000022001400041245008400055210006900139260001300208300001300221490000600234520156700240653004101807653001001848653000901858653002001867653001501887653004001902653001101942653002201953653003201975653001102007653002002018653002802038653000902066653001602075653003602091653003802127653001502165100002302180700002002203700001202223700002502235700001902260700001602279700002202295700001602317700002602333700002102359700002202380700001702402700001402419700002002433700001802453700002302471700001702494700002402511700001902535700001202554700002402566700001502590700002002605700001902625700002602644700002402670700001902694700002502713700002502738700002502763700002102788700002102809700001902830700002402849700002202873700002202895700001802917700002102935700001302956710002202969856003602991 2011 eng d a1553-740400aAssociation of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.0 aAssociation of eGFRRelated Loci Identified by GWAS with Incident c2011 Sep ae10022920 v73 aFamily studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
10aAdaptor Proteins, Signal Transducing10aAdult10aAged10aChronic Disease10aCreatinine10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGenetic Association Studies10aHumans10aKidney Diseases10aKidney Failure, Chronic10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptor, Epidermal Growth Factor10aUromodulin1 aBöger, Carsten, A1 aGorski, Mathias1 aLi, Man1 aHoffmann, Michael, M1 aHuang, Chunmei1 aYang, Qiong1 aTeumer, Alexander1 aKrane, Vera1 aO'Seaghdha, Conall, M1 aKutalik, Zoltán1 aWichmann, H-Erich1 aHaak, Thomas1 aBoes, Eva1 aCoassin, Stefan1 aCoresh, Josef1 aKollerits, Barbara1 aHaun, Margot1 aPaulweber, Bernhard1 aKöttgen, Anna1 aLi, Guo1 aShlipak, Michael, G1 aPowe, Neil1 aHwang, Shih-Jen1 aDehghan, Abbas1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aHofman, Albert1 aBeckmann, Jacques, S1 aKrämer, Bernhard, K1 aWitteman, Jacqueline1 aBochud, Murielle1 aSiscovick, David1 aRettig, Rainer1 aKronenberg, Florian1 aWanner, Christoph1 aThadhani, Ravi, I1 aHeid, Iris, M1 aFox, Caroline, S1 aKao, W H1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/133603263nas a2200553 4500008004100000022001400041245011200055210006900167260001300236300001100249490000600260520171300266653000901979653002201988653003402010653002102044653001102065653003402076653001102110653000902121653001602130653003602146653002402182100002302206700001602229700002102245700002002266700001902286700001202305700002102317700002302338700002102361700002102382700001602403700001902419700001802438700002302456700001902479700002202498700001702520700001902537700001902556700002102575700001702596700002402613700001702637700001902654856003602673 2011 eng d a1942-326800aAssociation of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.0 aAssociation of genetic variants and incident coronary heart dise c2011 Dec a661-720 v43 aBACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.
METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.
CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.
10aAged10aAged, 80 and over10aContinental Population Groups10aCoronary Disease10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies1 aFranceschini, Nora1 aCarty, Cara1 aBůzková, Petra1 aReiner, Alex, P1 aGarrett, Tiana1 aLin, Yi1 aVöckler, Jens-S1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBoerwinkle, Eric1 aLin, Dan-Yu1 aBookman, Ebony1 aBest, Lyle, G1 aBella, Jonathan, N1 aEaton, Charles1 aGreenland, Philip1 aJenny, Nancy1 aNorth, Kari, E1 aTaverna, Darin1 aYoung, Alicia, M1 aDeelman, Ewa1 aKooperberg, Charles1 aPsaty, Bruce1 aHeiss, Gerardo uhttps://chs-nhlbi.org/node/134704248nas a2200877 4500008004100000022001400041245015200055210006900207260001600276300001200292490000700304520170700311653001002018653002202028653000902050653001902059653001902078653001302097653004002110653001102150653001702161653003402178653001302212653001102225653001702236653000902253653001602262653001402278653003602292653001202328100001802340700002102358700001302379700002502392700002402417700002302441700001502464700002402479700001902503700002102522700002702543700002002570700002402590700002102614700002302635700001902658700002302677700002302700700001602723700002102739700002002760700001902780700002202799700002502821700002102846700002202867700002202889700001902911700001702930700002302947700002302970700002302993700001603016700002003032700002203052700002403074700002203098700002303120700002003143700001803163700002603181700001803207700001703225710009203242856003603334 2011 eng d a1460-208300aAssociation of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.0 aAssociation of genetic variation with systolic and diastolic blo c2011 Jun 01 a2273-840 v203 aThe prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
10aAdult10aAfrican Americans10aAged10aBlood Pressure10aCohort Studies10aDiastole10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aHypertension10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aYoung, Hunter, J1 aLi, Yali1 aDreisbach, Albert, W1 aKeating, Brendan, J1 aMusani, Solomon, K1 aLiu, Kiang1 aMorrison, Alanna, C1 aGanesh, Santhi1 aKutlar, Abdullah1 aRamachandran, Vasan, S1 aPolak, Josef, F1 aFabsitz, Richard, R1 aDries, Daniel, L1 aFarlow, Deborah, N1 aRedline, Susan1 aAdeyemo, Adebowale1 aHirschorn, Joel, N1 aSun, Yan, V1 aWyatt, Sharon, B1 aPenman, Alan, D1 aPalmas, Walter1 aRotter, Jerome, I1 aTownsend, Raymond, R1 aDoumatey, Ayo, P1 aTayo, Bamidele, O1 aMosley, Thomas, H1 aLyon, Helen, N1 aKang, Sun, J1 aRotimi, Charles, N1 aCooper, Richard, S1 aFranceschini, Nora1 aCurb, David1 aMartin, Lisa, W1 aEaton, Charles, B1 aKardia, Sharon, L R1 aTaylor, Herman, A1 aCaulfield, Mark, J1 aEhret, Georg, B1 aJohnson, Toby1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aLevy, Daniel1 aInternational Consortium for Blood Pressure Genome-wide Association Studies (ICBP-GWAS) uhttps://chs-nhlbi.org/node/127303311nas a2200601 4500008004100000022001400041245020900055210006900264260001600333300001100349490000800360520151200368653001001880653002201890653000901912653002801921653001901949653004001968653001102008653001502019653003802034653001502072653001102087653000902098653001602107653001402123653003602137653001702173100002502190700002102215700002402236700002002260700002302280700002002303700001902323700002302342700002002365700001202385700001602397700002302413700001802436700002102454700001902475700002202494700002102516700002202537700002102559700002102580700001702601700003002618700002502648856003602673 2011 eng d a1528-002000aAssociation of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe).0 aAssociation of genomic loci from a cardiovascular gene SNP array c2011 Jan 06 a268-750 v1173 aSeveral common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.
10aAdult10aAfrican Americans10aAged10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors1 aWassel, Christina, L1 aLange, Leslie, A1 aKeating, Brendan, J1 aTaylor, Kira, C1 aJohnson, Andrew, D1 aPalmer, Cameron1 aHo, Lindsey, A1 aSmith, Nicholas, L1 aLange, Ethan, M1 aLi, Yun1 aYang, Qiong1 aDelaney, Joseph, A1 aTang, Weihong1 aTofler, Geoffrey1 aRedline, Susan1 aTaylor, Herman, A1 aWilson, James, G1 aTracy, Russell, P1 aJacobs, David, R1 aFolsom, Aaron, R1 aGreen, David1 aO'Donnell, Christopher, J1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/156203513nas a2200541 4500008004100000022001400041245011000055210006900165260001300234300001100247490000700258520187400265653001202139653002002151653002802171653001902199653001102218653003802229653001302267653001102280653001702291653000902308653002102317653003602338653003402374100002302408700002902431700002302460700002002483700001802503700001602521700001802537700002602555700002202581700002402603700002202627700002602649700002002675700002002695700002302715700002002738700002402758700001702782710007602799710002802875710003202903856003602935 2011 eng d a1524-456300aAssociation of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals.0 aAssociation of hypertension drug target genes with blood pressur c2011 May a903-100 v573 aWe previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29,136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34,433) and the Women's Genome Health Study (n=23,019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10(-10)), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10(-10)), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10(-4)). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10(-6)), as well as diastolic blood pressure (P=5.0×10(-8)) and hypertension (P=3.7×10(-7)). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10(-5)). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.
10aAlleles10aAngiotensinogen10aAntihypertensive Agents10aBlood Pressure10aFemale10aGenetic Predisposition to Disease10aGenotype10aHumans10aHypertension10aMale10aPharmacogenetics10aPolymorphism, Single Nucleotide10aReceptors, Adrenergic, beta-11 aJohnson, Andrew, D1 aNewton-Cheh, Christopher1 aChasman, Daniel, I1 aEhret, Georg, B1 aJohnson, Toby1 aRose, Lynda1 aRice, Kenneth1 aVerwoert, Germaine, C1 aLauner, Lenore, J1 aGudnason, Vilmundur1 aLarson, Martin, G1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aCaulfield, Mark1 aDuijn, Cornelia, M1 aRidker, Paul, M1 aMunroe, Patricia, B1 aLevy, Daniel1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium1 aGlobal BPgen Consortium1 aWomen's Genome Health Study uhttps://chs-nhlbi.org/node/128203582nas a2200661 4500008004100000022001400041245009700055210006900152260001600221300001100237490000700248520163600255653001001891653000901901653003101910653002301941653003801964653003802002653003402040653001302074653002902087653001102116653001602127653001602143653003102159653003602190653003002226653002602256100002302282700002202305700002402327700002602351700001602377700002002393700002202413700002102435700002002456700002302476700002302499700001602522700002102538700001702559700002002576700002302596700002802619700002202647700002202669700002002691700001902711700002502730700002202755700002002777700002002797700002502817700002202842700002002864856003602884 2011 eng d a1552-578300aAssociation of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.0 aAssociation of polymorphisms in the hepatocyte growth factor gen c2011 Oct 31 a8514-90 v523 aPURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.
METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.
RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).
CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.
10aAdult10aAged10aChromosomes, Human, Pair 710aCorneal Topography10aEnzyme-Linked Immunosorbent Assay10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHepatocyte Growth Factor10aHumans10aKeratoconus10aMiddle Aged10aNucleic Acid Hybridization10aPolymorphism, Single Nucleotide10aPromoter Regions, Genetic10aSequence Tagged Sites1 aBurdon, Kathryn, P1 aMacgregor, Stuart1 aBykhovskaya, Yelena1 aJavadiyan, Sharhbanou1 aLi, Xiaohui1 aLaurie, Kate, J1 aMuszynska, Dorota1 aLindsay, Richard1 aLechner, Judith1 aHaritunians, Talin1 aHenders, Anjali, K1 aDash, Durga1 aSiscovick, David1 aAnand, Seema1 aAldave, Anthony1 aCoster, Douglas, J1 aSzczotka-Flynn, Loretta1 aMills, Richard, A1 aIyengar, Sudha, K1 aTaylor, Kent, D1 aPhillips, Tony1 aMontgomery, Grant, W1 aRotter, Jerome, I1 aHewitt, Alex, W1 aSharma, Shiwani1 aRabinowitz, Yaron, S1 aWilloughby, Colin1 aCraig, Jamie, E uhttps://chs-nhlbi.org/node/134003940nas a2200757 4500008004100000022001400041245008100055210006900136260001300205300001200218490000700230520182400237653001002061653000902071653001102080653003802091653003402129653001302163653001102176653000902187653002702196653002302223653001602246653001402262653003602276100001902312700002202331700002102353700002202374700002902396700002302425700001602448700002302464700001602487700002302503700001802526700001202544700001902556700002102575700002202596700002302618700002802641700002302669700001902692700002202711700001602733700001602749700002202765700002202787700002102809700002102830700002602851700002002877700002102897700002502918700002102943700002402964700001902988700002703007700002103034700002403055700002203079700002203101700002303123856003603146 2011 eng d a1939-327X00aA bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium.0 abivariate genomewide approach to metabolic syndrome STAMPEED con c2011 Apr a1329-390 v603 aOBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
10aAdult10aAged10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMeta-Analysis as Topic10aMetabolic Syndrome10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide1 aKraja, Aldi, T1 aVaidya, Dhananjay1 aPankow, James, S1 aGoodarzi, Mark, O1 aAssimes, Themistocles, L1 aKullo, Iftikhar, J1 aSovio, Ulla1 aMathias, Rasika, A1 aSun, Yan, V1 aFranceschini, Nora1 aAbsher, Devin1 aLi, Guo1 aZhang, Qunyuan1 aFeitosa, Mary, F1 aGlazer, Nicole, L1 aHaritunians, Talin1 aHartikainen, Anna-Liisa1 aKnowles, Joshua, W1 aNorth, Kari, E1 aIribarren, Carlos1 aKral, Brian1 aYanek, Lisa1 aO'Reilly, Paul, F1 aMcCarthy, Mark, I1 aJaquish, Cashell1 aCouper, David, J1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aBecker, Lewis, C1 aProvince, Michael, A1 aBoerwinkle, Eric1 aQuertermous, Thomas1 aPalotie, Leena1 aJarvelin, Marjo-Riitta1 aBecker, Diane, M1 aKardia, Sharon, L R1 aRotter, Jerome, I1 aChen, Yii-Der Ida1 aBorecki, Ingrid, B uhttps://chs-nhlbi.org/node/127404125nas a2200745 4500008004100000022001400041245014300055210006900198260001600267300001300283490000700296520189000303653002802193653003002221653002702251653002502278653003802303653003402341653001302375653001102388653001602399653001502415653001502430653003602445653001702481100001802498700001602516700001702532700002302549700001902572700001902591700001902610700001902629700002002648700001602668700002002684700002202704700002002726700002402746700002402770700002102794700002402815700002102839700002202860700002102882700002302903700001902926700002202945700002102967700001702988700001903005700002203024700001903046700001403065700002203079700002203101700002403123700002503147700001803172700001803190700001803208710007203226710004503298856003603343 2011 eng d a1552-578300aCandidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe).0 aCandidate gene association study for diabetic retinopathy in per c2011 Sep 29 a7593-6020 v523 aPURPOSE: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).
METHODS: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥ 14 and ≥ 30. The χ² analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.
RESULTS: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.
CONCLUSIONS: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.
10aCardiovascular Diseases10aDiabetes Mellitus, Type 210aDiabetic Nephropathies10aDiabetic Retinopathy10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aIduronidase10aOdds Ratio10aP-Selectin10aPolymorphism, Single Nucleotide10aRisk Factors1 aSobrin, Lucia1 aGreen, Todd1 aSim, Xueling1 aJensen, Richard, A1 aTai, Shyong, E1 aTay, Wan, Ting1 aWang, Jie, Jin1 aMitchell, Paul1 aSandholm, Niina1 aLiu, Yiyuan1 aHietala, Kustaa1 aIyengar, Sudha, K1 aBrooks, Matthew1 aBuraczynska, Monika1 aVan Zuydam, Natalie1 aSmith, Albert, V1 aGudnason, Vilmundur1 aDoney, Alex, S F1 aMorris, Andrew, D1 aLeese, Graham, P1 aPalmer, Colin, N A1 aSwaroop, Anand1 aTaylor, Herman, A1 aWilson, James, G1 aPenman, Alan1 aChen, Ching, J1 aGroop, Per-Henrik1 aSaw, Seang-Mei1 aAung, Tin1 aKlein, Barbara, E1 aRotter, Jerome, I1 aSiscovick, David, S1 aCotch, Mary, Frances1 aKlein, Ronald1 aDaly, Mark, J1 aWong, Tien, Y1 aFamily Investigation of Nephropathy and Diabetes-Eye Research Group1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/156702927nas a2200349 4500008004100000022001400041245013000055210006900185260001300254300001100267490000700278520189700285653003502182653002402217653001902241653002402260653001102284653002202295653001102317653003402328653001402362653000902376653001602385653002402401653001702425100002102442700002102463700002002484700001702504700002002521856003602541 2011 eng d a1524-462800aCarotid intima-media thickness, electrocardiographic left ventricular hypertrophy, and incidence of intracerebral hemorrhage.0 aCarotid intimamedia thickness electrocardiographic left ventricu c2011 Nov a3075-90 v423 aBACKGROUND AND PURPOSE: Carotid intima-media thickness and electrocardiographic left ventricular hypertrophy are 2 subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased intima-media thickness and electrocardiographic left ventricular hypertrophy also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid intima-media thickness and the presence of electrocardiographic left ventricular hypertrophy would be independently associated with increased ICH incidence.
METHODS: Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid intima-media thickness, carotid plaque, and electrocardiographic left ventricular hypertrophy. Over a median of 18 years of follow-up, 162 incident ICH events occurred.
RESULTS: After adjustment for other ICH risk factors, carotid intima-media thickness was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific Quartile 1, elevated 1.6- to 2.6-fold in Quartiles 2 to 3, and elevated 2.5 to 3.7-fold in Quartile 4 (P<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95% CI, 1.1-3.4) greater ICH risk than having no plaque, but only 1.2-fold (95% CI, 0.76-2.0) greater ICH risk in ARIC. Electrocardiographic left ventricular hypertrophy carried a hazard ratio of ICH of 1.7 (95% CI, 0.77-3.7) in CHS and 2.8 (95% CI, 1.2-6.4) in ARIC.
CONCLUSIONS: Our data suggest that people with carotid atherosclerosis and possibly left ventricular hypertrophy are at increased risk not only of ischemic stroke, but also of ICH.
10aCarotid Intima-Media Thickness10aCerebral Hemorrhage10aCohort Studies10aElectrocardiography10aFemale10aFollow-Up Studies10aHumans10aHypertrophy, Left Ventricular10aIncidence10aMale10aMiddle Aged10aProspective Studies10aRisk Factors1 aFolsom, Aaron, R1 aYatsuya, Hiroshi1 aPsaty, Bruce, M1 aShahar, Eyal1 aLongstreth, W T uhttps://chs-nhlbi.org/node/133103692nas a2200637 4500008004100000022001400041245006800055210006500123260001300188300001000201490000700211520184500218653001002063653000902073653002202082653003402104653002502138653002802163653001102191653002202202653003402224653002802258653001102286653005102297653000902348653001602357653003102373653003602404653001402440653001902454653000902473653004702482653006302529100002602592700001802618700002302636700001902659700001402678700002202692700002002714700001702734700002202751700002202773700002202795700001902817700002202836700001202858700002202870700002002892700002202912700002402934700001802958700002202976700002002998856003603018 2011 eng d a1744-688000aCerivastatin, genetic variants, and the risk of rhabdomyolysis.0 aCerivastatin genetic variants and the risk of rhabdomyolysis c2011 May a280-80 v213 aOBJECTIVE: The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.
METHODS: This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.
RESULTS: Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63).
CONCLUSION: We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.
10aAdult10aAged10aAged, 80 and over10aAryl Hydrocarbon Hydroxylases10aCase-Control Studies10aCytochrome P-450 CYP2C810aFemale10aGenetic Variation10aGenome-Wide Association Study10aGlucuronosyltransferase10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aOrganic Anion Transporters10aPolymorphism, Single Nucleotide10aPyridines10aRhabdomyolysis10aRisk10aRyanodine Receptor Calcium Release Channel10aSolute Carrier Organic Anion Transporter Family Member 1b11 aMarciante, Kristin, D1 aDurda, Jon, P1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Ken1 aMcKnight, Barbara1 aTotah, Rheem, A1 aTamraz, Bani1 aKroetz, Deanna, L1 aFukushima, Hisayo1 aKaspera, Rüdiger1 aBis, Joshua, C1 aGlazer, Nicole, L1 aLi, Guo1 aAustin, Thomas, R1 aTaylor, Kent, D1 aRotter, Jerome, I1 aJaquish, Cashell, E1 aKwok, Pui-Yan1 aTracy, Russell, P1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/127503282nas a2200301 4500008004100000022001400041245018500055210006900240260001600309300001200325490000800337520234400345653000902689653001102698653002802709653001102737653000902748653001502757653001702772653002002789653003402809100001602843700002402859700002002883700001902903700002202922856003602944 2011 eng d a1879-191300aComparison of characteristics and outcomes of asymptomatic versus symptomatic left ventricular dysfunction in subjects 65 years old or older (from the Cardiovascular Health Study).0 aComparison of characteristics and outcomes of asymptomatic versu c2011 Jun 01 a1667-740 v1073 aAlthough asymptomatic left ventricular (LV) systolic dysfunction (ALVSD) is common, its phenotype and prognosis for incident heart failure (HF) and mortality are insufficiently understood. Echocardiography was done in 5,649 participants in the Cardiovascular Health Study (age 73.0 ± 5.6 years, 57.6% women). The clinical characteristics and cardiovascular risk factors of the participants with ALVSD were compared to those with normal LV function (ejection fraction ≥55%) and with symptomatic LV systolic dysfunction (SLVSD; ejection fraction <55% and a history of HF). Cox proportional hazards models were used to estimate the risk of incident HF and mortality in those with ALVSD. Also, comparisons were made among the LV ejection fraction subgroups using previously validated cutoff values (<45% and 45% to 55%), adjusting for the demographic and cardiovascular disease risk factors. Those with ALVSD (7.3%) were more likely to have cardiovascular risk factors than those in the reference group (without LV dysfunction or symptomatic HF) but less likely than those with SLVSD. The HF rate was 24 occurrences per 1,000 person-years in the reference group and 57 occurrences per 1,000 person-years in those with ALVSD. The HF rate was 45 occurrences per 1,000 person-years for those with ALVSD and mildly impaired LV dysfunction and 93 occurrences per 1,000 person-years for those with ALVSD and moderate to severe LV dysfunction. The mortality rate was 51 deaths per 1,000 person-years in the reference group, 90 deaths per 1,000 person-years in the ALVSD group, and 156 deaths per 1,000 person-years in the SLVSD group. Adjusting for covariates, compared to the reference group, ALVSD was associated with an increased risk of incident HF (hazard ratio 1.60, 95% confidence interval 1.35 to 1.91), cardiovascular mortality (hazard ratio 2.13, 95% confidence interval 1.81 to 2.51), and all-cause mortality (hazard ratio 1.46, 95% confidence interval 1.29 to 1.64). In conclusion, subjects with ALVSD are characterized by a greater prevalence of cardiovascular risk factors and co-morbidities than those with normal LV function and without HF. However, the prevalence is lower than in those with SLVSD. Patients with ALVSD are at an increased risk of HF and mortality, particularly those with greater severity of LV impairment.
10aAged10aFemale10aHeart Failure, Systolic10aHumans10aMale10aPrevalence10aRisk Factors10aUltrasonography10aVentricular Dysfunction, Left1 aPandhi, Jay1 aGottdiener, John, S1 aBartz, Traci, M1 aKop, Willem, J1 aMehra, Mandeep, R uhttps://chs-nhlbi.org/node/129003024nas a2200421 4500008004100000022001400041245014900055210006900204260001600273300000700289490000700296520175700303653003902060653000902099653002202108653002302130653002502153653004002178653001102218653002202229653002202251653001102273653001202284653000902296653002602305653003002331653002402361653001702385100001802402700002202420700002402442700001902466700001802485700002202503700002102525700002002546856003602566 2011 eng d a1471-226100aThe contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study.0 acontribution of a 9p213 variant a KIF6 variant and Creactive pro c2011 Mar 15 a100 v113 aBACKGROUND: Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older.
METHODS: Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI).
RESULTS: Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24).
CONCLUSIONS: While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.
10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aC-Reactive Protein10aCase-Control Studies10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGenetic Variation10aHumans10aKinesin10aMale10aMyocardial Infarction10aPredictive Value of Tests10aProspective Studies10aRisk Factors1 aShiffman, Dov1 aO'Meara, Ellen, S1 aRowland, Charles, M1 aLouie, Judy, Z1 aCushman, Mary1 aTracy, Russell, P1 aDevlin, James, J1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/128005938nas a2201621 4500008004100000022001400041245004200055210004100097260001300138300001100151490000700162520145500169653003901624653001601663653004001679653001701719653003801736653001101774653002301785653002801808100002301836700002001859700001801879700002001897700001901917700002001936700002701956700002601983700002202009700002202031700001802053700002202071700001202093700002602105700002002131700002302151700002102174700001802195700001902213700002002232700002202252700001802274700001502292700002102307700001702328700002302345700002202368700002302390700001802413700001902431700002002450700002402470700002202494700002202516700002302538700002502561700001902586700002302605700002102628700002002649700002002669700002102689700002502710700001902735700002402754700002002778700002202798700002302820700001902843700002402862700002002886700002002906700002102926700002302947700002002970700002002990700001703010700002303027700002703050700002203077700001903099700001903118700002803137700001803165700001803183700002103201700002503222700002103247700002603268700002103294700002503315700002203340700002403362700002003386700002203406700002103428700001903449700002003468700001903488700002203507700001803529700002003547700002203567700002403589700002403613700002403637700001703661700001903678700001703697700002403714700002103738700001603759700001903775700001803794700001803812700001803830700002003848700001803868700002403886700002103910700002603931700002203957700002503979700002004004700002204024700002604046700002504072700002504097700001604122700001804138700001904156700002504175700002104200700002104221700001604242710002204258856003604280 2011 eng d a1533-345000aCUBN is a gene locus for albuminuria.0 aCUBN is a gene locus for albuminuria c2011 Mar a555-700 v223 aIdentification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
10aAfrican Continental Ancestry Group10aAlbuminuria10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aHumans10aMutation, Missense10aReceptors, Cell Surface1 aBöger, Carsten, A1 aChen, Ming-Huei1 aTin, Adrienne1 aOlden, Matthias1 aKöttgen, Anna1 ade Boer, Ian, H1 aFuchsberger, Christian1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 aTeumer, Alexander1 aLiu, Ching-Ti1 aGlazer, Nicole, L1 aLi, Man1 aO'Connell, Jeffrey, R1 aTanaka, Toshiko1 aPeralta, Carmen, A1 aKutalik, Zoltán1 aLuan, Jian'an1 aZhao, Jing Hua1 aHwang, Shih-Jen1 aAkylbekova, Ermeg1 aKramer, Holly1 aHarst, Pim1 aSmith, Albert, V1 aLohman, Kurt1 ade Andrade, Mariza1 aHayward, Caroline1 aKollerits, Barbara1 aTönjes, Anke1 aAspelund, Thor1 aIngelsson, Erik1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aShuldiner, Alan, R1 aMitchell, Braxton, D1 aArking, Dan, E1 aFranceschini, Nora1 aBoerwinkle, Eric1 aEgan, Josephine1 aHernandez, Dena1 aReilly, Muredach1 aTownsend, Raymond, R1 aLumley, Thomas1 aSiscovick, David, S1 aPsaty, Bruce, M1 aKestenbaum, Bryan1 aHaritunians, Talin1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aMooser, Vincent1 aWaterworth, Dawn1 aJohnson, Andrew, D1 aFlorez, Jose, C1 aMeigs, James, B1 aLu, Xiaoning1 aTurner, Stephen, T1 aAtkinson, Elizabeth, J1 aLeak, Tennille, S1 aAasarød, Knut1 aSkorpen, Frank1 aSyvänen, Ann-Christine1 aIllig, Thomas1 aBaumert, Jens1 aKoenig, Wolfgang1 aKrämer, Bernhard, K1 aDevuyst, Olivier1 aMychaleckyj, Josyf, C1 aMinelli, Cosetta1 aBakker, Stephan, J L1 aKedenko, Lyudmyla1 aPaulweber, Bernhard1 aCoassin, Stefan1 aEndlich, Karlhans1 aKroemer, Heyo, K1 aBiffar, Reiner1 aStracke, Sylvia1 aVölzke, Henry1 aStumvoll, Michael1 aMägi, Reedik1 aCampbell, Harry1 aVitart, Veronique1 aHastie, Nicholas, D1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPolasek, Ozren1 aCurhan, Gary1 aKronenberg, Florian1 aProkopenko, Inga1 aRudan, Igor1 aArnlöv, Johan1 aHallan, Stein1 aNavis, Gerjan1 aParsa, Afshin1 aFerrucci, Luigi1 aCoresh, Josef1 aShlipak, Michael, G1 aBull, Shelley, B1 aPaterson, Nicholas, J1 aWichmann, H-Erich1 aWareham, Nicholas, J1 aLoos, Ruth, J F1 aRotter, Jerome, I1 aPramstaller, Peter, P1 aCupples, Adrienne, L1 aBeckmann, Jacques, S1 aYang, Qiong1 aHeid, Iris, M1 aRettig, Rainer1 aDreisbach, Albert, W1 aBochud, Murielle1 aFox, Caroline, S1 aKao, W, H L1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/127102955nas a2200481 4500008004100000022001400041245009200055210006900147260001300216300001100229490000700240520162800247653000901875653002201884653001501906653002801921653002001949653001501969653001501984653002401999653001102023653003102034653001802065653001102083653002002094653002802114653000902142653001602151653003002167653002602197653001702223100002302240700001602263700002002279700001602299700002002315700001702335700001902352700002102371700002102392700002402413856003602437 2011 eng d a1533-345000aCystatin C identifies chronic kidney disease patients at higher risk for complications.0 aCystatin C identifies chronic kidney disease patients at higher c2011 Jan a147-550 v223 aAlthough cystatin C is a stronger predictor of clinical outcomes associated with CKD than creatinine, the clinical role for cystatin C is unclear. We included 11,909 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) and assessed risks for death, cardiovascular events, heart failure, and ESRD among persons categorized into mutually exclusive groups on the basis of the biomarkers that supported a diagnosis of CKD (eGFR <60 ml/min per 1.73 m(2)): creatinine only, cystatin C only, both, or neither. We used CKD-EPI equations to estimate GFR from these biomarkers. In MESA, 9% had CKD by the creatinine-based equation only, 2% had CKD by the cystatin C-based equation only, and 4% had CKD by both equations; in CHS, these percentages were 12, 4, and 13%, respectively. Compared with those without CKD, the adjusted hazard ratios (HR) for mortality in MESA were: 0.80 (95% CI 0.50 to 1.26) for CKD by creatinine only; 3.23 (95% CI 1.84 to 5.67) for CKD by cystatin C only; and 1.93 (95% CI 1.27 to 2.92) for CKD by both; in CHS, the adjusted HR were 1.09 (95% CI 0.98 to 1.21), 1.78 (95% CI 1.53 to 2.08), and 1.74 (95% CI 1.58 to 1.93), respectively. The pattern was similar for cardiovascular disease (CVD), heart failure, and kidney failure outcomes. In conclusion, among adults diagnosed with CKD using the creatinine-based CKD-EPI equation, the adverse prognosis is limited to the subset who also have CKD according to the cystatin C-based equation. Cystatin C may have a role in identifying persons with CKD who have the highest risk for complications.
10aAged10aAged, 80 and over10aBiomarkers10aCardiovascular Diseases10aChronic Disease10aCreatinine10aCystatin C10aDisease Progression10aFemale10aGlomerular Filtration Rate10aHeart Failure10aHumans10aKidney Diseases10aKidney Failure, Chronic10aMale10aMiddle Aged10aPredictive Value of Tests10aRetrospective Studies10aRisk Factors1 aPeralta, Carmen, A1 aKatz, Ronit1 aSarnak, Mark, J1 aIx, Joachim1 aFried, Linda, F1 ade Boer, Ian1 aPalmas, Walter1 aSiscovick, David1 aLevey, Andrew, S1 aShlipak, Michael, G uhttps://chs-nhlbi.org/node/125603004nas a2200337 4500008004100000022001400041245013200055210006900187260001300256300001000269490000700279520201500286653000902301653002202310653002802332653001502360653002602375653001102401653001102412653000902423653001902432653003702451653001802488100001502506700001802521700002402539700002402563700001902587700002402606856003602630 2011 eng d a1468-201X00aDepressive symptoms, physical inactivity and risk of cardiovascular mortality in older adults: the Cardiovascular Health Study.0 aDepressive symptoms physical inactivity and risk of cardiovascul c2011 Mar a500-50 v973 aBACKGROUND: Depressed older individuals have a higher mortality than older persons without depression. Depression is associated with physical inactivity, and low levels of physical activity have been shown in some cohorts to be a partial mediator of the relationship between depression and cardiovascular events and mortality.
METHODS: A cohort of 5888 individuals (mean 72.8 ± 5.6 years, 58% female, 16% African-American) from four US communities was followed for an average of 10.3 years. Self-reported depressive symptoms (10-item Center for Epidemiological Studies Depression Scale) were assessed annually and self-reported physical activity was assessed at baseline and at 3 and 7 years. To estimate how much of the increased risk of cardiovascular mortality associated with depressive symptoms was due to physical inactivity, Cox regression with time-varying covariates was used to determine the percentage change in the log HR of depressive symptoms for cardiovascular mortality after adding physical activity variables.
RESULTS: At baseline, 20% of participants scored above the cut-off for depressive symptoms. There were 2915 deaths (49.8%), of which 1176 (20.1%) were from cardiovascular causes. Depressive symptoms and physical inactivity each independently increased the risk of cardiovascular mortality and were strongly associated with each other (all p < 0.001). Individuals with both depressive symptoms and physical inactivity had greater cardiovascular mortality than those with either individually (p < 0.001, log rank test). Physical inactivity reduced the log HR of depressive symptoms for cardiovascular mortality by 26% after adjustment. This was similar for persons with (25%) and without (23%) established coronary heart disease.
CONCLUSIONS: Physical inactivity accounted for a significant proportion of the risk of cardiovascular mortality due to depressive symptoms in older adults, regardless of coronary heart disease status.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aDepression10aEpidemiologic Methods10aFemale10aHumans10aMale10aMotor Activity10aPsychiatric Status Rating Scales10aUnited States1 aWin, Sithu1 aParakh, Kapil1 aEze-Nliam, Chete, M1 aGottdiener, John, S1 aKop, Willem, J1 aZiegelstein, Roy, C uhttps://chs-nhlbi.org/node/127003900nas a2200529 4500008004100000022001400041245013500055210006900190260001300259300001300272490000700285520240400292653001002696653000902706653002202715653002002737653003402757653002102791653002702812653002402839653001802863653001102881653001502892653001102907653001702918653000902935653001602944653003002960653001402990653003203004653002003036653001703056653001703073653001803090100002403108700002303132700001803155700002103173700002003194700001603214700002203230700001903252700002103271700002003292700002203312856003603334 2011 eng d a1468-201X00aElectrocardiographic and clinical predictors separating atherosclerotic sudden cardiac death from incident coronary heart disease.0 aElectrocardiographic and clinical predictors separating atherosc c2011 Oct a1597-6010 v973 aOBJECTIVE: To identify specific ECG and clinical predictors that separate atherosclerotic sudden cardiac death (SCD) from incident coronary heart disease (CHD) (non-fatal events and non-sudden death) in the combined cohorts of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study.
METHODS: This analysis included 18,497 participants (58% females, 24% black individuals, mean age 58 years) who were initially free of clinical CHD. A competing risk analysis was conducted to examine the prognostic significance of baseline clinical characteristics and an extensive electronic database of ECG measurements for prediction of 229 cases of SCD as a first event versus 2297 incident CHD cases (2122 non-fatal events and 175 non-sudden death) that occurred during a median follow-up time of 13 years in the Cardiovascular Health Study and 14 years in the Atherosclerosis Risk in Communities study.
RESULTS: After adjusting for common CHD risk factors, a number of clinical characteristics and ECG measurements were independently predictive of SCD and CHD. However, the risk of SCD versus incident CHD was significantly different for race/ethnicity, hypertension, body mass index (BMI), heart rate, QTc, abnormally inverted T wave in any ECG lead group and level of ST elevation in V2. Black race/ethnicity (compared to non-black) was predictive of high SCD risk but less risk of incident CHD (p value for differences in the risk (HR) for SCD versus CHD <0.0001). Hypertension, increased heart rate, prolongation of QTc and abnormally inverted T wave were stronger predictors of high SCD risk compared to CHD (p value=0.0460, 0.0398, 0.0158 and 0.0265, respectively). BMI was not predictive of incident CHD but was predictive of high SCD risk in a quadratic fashion (p value=0.0220). On the other hand, elevated ST height as measured at the J point and that measured at 60 ms after the J point in V2 were not predictive of SCD but were predictive of high incident CHD risk (p value=0.0251 and 0.0155, respectively).
CONCLUSIONS: SCD and CHD have many risk factors in common. Hypertension, race/ethnicity, BMI, heart rate, QTc, abnormally inverted T wave in any ECG lead group and level of ST elevation in V2 have the potential to separate between the risks of SCD and CHD. These results need to be validated in another cohort.
10aAdult10aAged10aAged, 80 and over10aBody Mass Index10aContinental Population Groups10aCoronary Disease10aDeath, Sudden, Cardiac10aElectrocardiography10aEthnic Groups10aFemale10aHeart Rate10aHumans10aHypertension10aMale10aMiddle Aged10aPredictive Value of Tests10aPrognosis10aProportional Hazards Models10aRisk Adjustment10aRisk Factors10aTime Factors10aUnited States1 aSoliman, Elsayed, Z1 aPrineas, Ronald, J1 aCase, Douglas1 aRussell, Gregory1 aRosamond, Wayne1 aRea, Thomas1 aSotoodehnia, Nona1 aPost, Wendy, S1 aSiscovick, David1 aPsaty, Bruce, M1 aBurke, Gregory, L uhttps://chs-nhlbi.org/node/130604476nas a2200937 4500008004100000022001400041245014100055210006900196260001300265300001300278490000600291520177500297653002202072653001502094653002102109653002302130653002102153653003002174653001102204653001902215653002202234653002502256653001802281653003402299653001302333653001102346653002702357653000902384653001502393653001402408653003602422653003302458653004702491653001302538100002102551700001802572700002202590700001802612700001702630700002002647700002002667700002002687700002402707700001802731700001702749700002102766700002502787700001602812700002502828700002302853700001902876700002102895700001602916700002802932700002402960700002802984700002003012700002203032700001503054700002003069700002303089700002103112700002203133700001903155700002203174700002403196700002203220700002803242700002303270700001903293700002003312700002403332700002403356700001703380700002703397700001703424700002003441700002103461700002003482856003603502 2011 eng d a1553-740400aEnhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium.0 aEnhanced statistical tests for GWAS in admixed populations asses c2011 Apr ae10013710 v73 aWhile genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.
10aAfrican Americans10aAlgorithms10aBreast Neoplasms10aChromosome Mapping10aCoronary Disease10aDiabetes Mellitus, Type 210aFemale10aGene Frequency10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLinkage Disequilibrium10aMale10aOdds Ratio10aPhenotype10aPolymorphism, Single Nucleotide10aPrincipal Component Analysis10aReceptor, Fibroblast Growth Factor, Type 210aSoftware1 aPasaniuc, Bogdan1 aZaitlen, Noah1 aLettre, Guillaume1 aChen, Gary, K1 aTandon, Arti1 aKao, Linda, W H1 aRuczinski, Ingo1 aFornage, Myriam1 aSiscovick, David, S1 aZhu, Xiaofeng1 aLarkin, Emma1 aLange, Leslie, A1 aCupples, Adrienne, L1 aYang, Qiong1 aAkylbekova, Ermeg, L1 aMusani, Solomon, K1 aDivers, Jasmin1 aMychaleckyj, Joe1 aLi, Mingyao1 aPapanicolaou, George, J1 aMillikan, Robert, C1 aAmbrosone, Christine, B1 aJohn, Esther, M1 aBernstein, Leslie1 aZheng, Wei1 aHu, Jennifer, J1 aZiegler, Regina, G1 aNyante, Sarah, J1 aBandera, Elisa, V1 aIngles, Sue, A1 aPress, Michael, F1 aChanock, Stephen, J1 aDeming, Sandra, L1 aRodriguez-Gil, Jorge, L1 aPalmer, Cameron, D1 aBuxbaum, Sarah1 aEkunwe, Lynette1 aHirschhorn, Joel, N1 aHenderson, Brian, E1 aMyers, Simon1 aHaiman, Christopher, A1 aReich, David1 aPatterson, Nick1 aWilson, James, G1 aPrice, Alkes, L uhttps://chs-nhlbi.org/node/128802783nas a2200457 4500008004100000022001400041245011000055210006900165260001300234300001200247490000700259520152800266653000901794653002201803653001801825653002001843653001901863653001201882653001101894653001101905653001401916653002301930653000901953653000901962653001101971100002101982700002002003700002202023700002302045700002002068700002402088700002002112700002002132700002102152700002702173700002002200700002202220700002302242700002402265856003602289 2011 eng d a1524-462800aFasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults.0 aFasting and postglucose load measures of insulin resistance and c2011 Dec a3347-510 v423 aBACKGROUND AND PURPOSE: Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in nondiabetic, older adults.
METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and from fasting and 2-hour postload insulin and glucose; a lower Gutt index indicates higher insulin resistance.
RESULTS: Analyses included 3442 participants (42% men) with a mean age of 73 years. Incidence of ischemic stroke was 9.8 strokes per 1000 person-years. The relative risk (RR) for lowest quartile versus highest quartile of Gutt index was 1.64 (95% CI, 1.24-2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile versus lowest quartile of 2-hour glucose was 1.84 (95% CI, 1.39-2.42). In contrast, the adjusted RR for highest quartile versus lowest quartile of fasting insulin was 1.10 (95% CI, 0.84-1.46).
CONCLUSIONS: In nondiabetic, older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not by fasting insulin, was associated with risk of incident ischemic stroke.
10aAged10aAged, 80 and over10aBlood Glucose10aBody Mass Index10aBrain Ischemia10aFasting10aFemale10aHumans10aIncidence10aInsulin Resistance10aMale10aRisk10aStroke1 aThacker, Evan, L1 aPsaty, Bruce, M1 aMcKnight, Barbara1 aHeckbert, Susan, R1 aLongstreth, W T1 aMukamal, Kenneth, J1 aMeigs, James, B1 ade Boer, Ian, H1 aBoyko, Edward, J1 aCarnethon, Mercedes, R1 aKizer, Jorge, R1 aTracy, Russell, P1 aSmith, Nicholas, L1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/133903089nas a2200481 4500008004100000022001400041245004500055210004400100260001600144300000900160490000800169520183600177653000902013653001902022653001102041653000902052653002502061653001102086653002002097653000902117653002202126653001802148100002502166700002102191700001902212700002102231700002302252700002002275700002002295700002002315700001902335700003102354700002002385700002202405700002502427700002402452700001902476700002002495700001702515700002002532700001902552856003602571 2011 eng d a1538-359800aGait speed and survival in older adults.0 aGait speed and survival in older adults c2011 Jan 05 a50-80 v3053 aCONTEXT: Survival estimates help individualize goals of care for geriatric patients, but life tables fail to account for the great variability in survival. Physical performance measures, such as gait speed, might help account for variability, allowing clinicians to make more individualized estimates.
OBJECTIVE: To evaluate the relationship between gait speed and survival.
DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 9 cohort studies (collected between 1986 and 2000), using individual data from 34,485 community-dwelling older adults aged 65 years or older with baseline gait speed data, followed up for 6 to 21 years. Participants were a mean (SD) age of 73.5 (5.9) years; 59.6%, women; and 79.8%, white; and had a mean (SD) gait speed of 0.92 (0.27) m/s.
MAIN OUTCOME MEASURES: Survival rates and life expectancy.
RESULTS: There were 17,528 deaths; the overall 5-year survival rate was 84.8% (confidence interval [CI], 79.6%-88.8%) and 10-year survival rate was 59.7% (95% CI, 46.5%-70.6%). Gait speed was associated with survival in all studies (pooled hazard ratio per 0.1 m/s, 0.88; 95% CI, 0.87-0.90; P < .001). Survival increased across the full range of gait speeds, with significant increments per 0.1 m/s. At age 75, predicted 10-year survival across the range of gait speeds ranged from 19% to 87% in men and from 35% to 91% in women. Predicted survival based on age, sex, and gait speed was as accurate as predicted based on age, sex, use of mobility aids, and self-reported function or as age, sex, chronic conditions, smoking history, blood pressure, body mass index, and hospitalization.
CONCLUSION: In this pooled analysis of individual data from 9 selected cohorts, gait speed was associated with survival in older adults.
10aAged10aCohort Studies10aFemale10aGait10aGeriatric Assessment10aHumans10aLife Expectancy10aMale10aSurvival Analysis10aUnited States1 aStudenski, Stephanie1 aPerera, Subashan1 aPatel, Kushang1 aRosano, Caterina1 aFaulkner, Kimberly1 aInzitari, Marco1 aBrach, Jennifer1 aChandler, Julie1 aCawthon, Peggy1 aConnor, Elizabeth, Barrett1 aNevitt, Michael1 aVisser, Marjolein1 aKritchevsky, Stephen1 aBadinelli, Stefania1 aHarris, Tamara1 aNewman, Anne, B1 aCauley, Jane1 aFerrucci, Luigi1 aGuralnik, Jack uhttps://chs-nhlbi.org/node/125902600nas a2200397 4500008004100000022001400041245016200055210006900217260001600286300001500302490000800317520140500325653000901730653002101739653002401760653001101784653001101795653001401806653000901820653003001829653001401859653003201873653002401905653002001929653001701949653001601966653001801982100002002000700002302020700001502043700002002058700001902078700002202097710004702119856003602166 2011 eng d a1879-191300aGender differences between the Minnesota code and Novacode electrocardiographic prognostication of coronary heart disease in the cardiovascular health study.0 aGender differences between the Minnesota code and Novacode elect c2011 Mar 15 a817-820.e10 v1073 aThe Minnesota Code (MC) and Novacode (Nova) are the most widely used electrocardiographic (ECG) classification systems. The comparative strengths of their classifications for Q- and ST-T-wave abnormalities in predicting coronary heart disease (CHD) events and total mortality have not been evaluated separately by gender. We studied standard 12-lead electrocardiograms at rest from 4,988 participants in the Cardiovascular Health Study. Average age at baseline was 73 years, 60% of participants were women 85% were white, and 22% had a history of cardiovascular disease or presence of ECG myocardial infarction by MC or Nova. Starting in 1989 with an average 17-year follow-up, 65% of participants died and 33% had incident CHD in a cohort free of cardiovascular disease at baseline. Of these, electrocardiograms with major Q-wave or major ST-T abnormalities by MC or Nova predicted increased risk for CHD events and total mortality with no significant differences in predictability between men and women. The study also found that women had fewer major Q-wave changes but more major ST-T abnormalities than men. However, there were no gender differences in predicting CHD events and total mortality. In conclusion, ECG classification systems for myocardial infarction/ischemia abnormalities by MC or Nova are valuable and useful for men and women in clinical trials and epidemiologic studies.
10aAged10aCoronary Disease10aElectrocardiography10aFemale10aHumans10aIncidence10aMale10aPredictive Value of Tests10aPrognosis10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aSex Factors10aUnited States1 aZhang, Zhu-Ming1 aPrineas, Ronald, J1 aCase, Doug1 aPsaty, Bruce, M1 aSuzuki, Takeki1 aBurke, Gregory, L1 aCardiovascular Health Study Research Group uhttps://chs-nhlbi.org/node/126204453nas a2200889 4500008004100000022001400041245011700055210006900172260001300241300001300254490000600267520190600273653004202179653001002221653003902231653000902270653001202279653001102291653003002302653003202332653001702364653003402381653003102415653001102446653002802457653001102485653002802496653000902524653001602533653002202549653001402571653003602585653001402621100001802635700002202653700001802675700001902693700002302712700002302735700002002758700001702778700002402795700002002819700001902839700002002858700001802878700002102896700002902917700002102946700002202967700001802989700001603007700002303023700001203046700002403058700002503082700002303107700002303130700002303153700002303176700002203199700002203221700002303243700001703266700002403283700002203307700002403329700001803353700002503371700002503396700002303421700002503444700001503469700002103484710002203505856003603527 2011 eng d a1553-740400aGenetic association for renal traits among participants of African ancestry reveals new loci for renal function.0 aGenetic association for renal traits among participants of Afric c2011 Sep ae10022640 v73 aChronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
10aAdaptor Proteins, Vesicular Transport10aAdult10aAfrican Continental Ancestry Group10aAged10aAnimals10aFemale10aGene Knockdown Techniques10aGenetic Association Studies10aGenetic Loci10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKCNQ1 Potassium Channel10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aNeoplasm Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aZebrafish1 aLiu, Ching-Ti1 aGarnaas, Maija, K1 aTin, Adrienne1 aKöttgen, Anna1 aFranceschini, Nora1 aPeralta, Carmen, A1 ade Boer, Ian, H1 aLu, Xiaoning1 aAtkinson, Elizabeth1 aDing, Jingzhong1 aNalls, Michael1 aShriner, Daniel1 aCoresh, Josef1 aKutlar, Abdullah1 aBibbins-Domingo, Kirsten1 aSiscovick, David1 aAkylbekova, Ermeg1 aWyatt, Sharon1 aAstor, Brad1 aMychaleckjy, Josef1 aLi, Man1 aReilly, Muredach, P1 aTownsend, Raymond, R1 aAdeyemo, Adebowale1 aZonderman, Alan, B1 ade Andrade, Mariza1 aTurner, Stephen, T1 aMosley, Thomas, H1 aHarris, Tamara, B1 aRotimi, Charles, N1 aLiu, Yongmei1 aKardia, Sharon, L R1 aEvans, Michele, K1 aShlipak, Michael, G1 aKramer, Holly1 aFlessner, Michael, F1 aDreisbach, Albert, W1 aGoessling, Wolfram1 aCupples, Adrienne, L1 aKao, Linda1 aFox, Caroline, S1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/132704377nas a2200829 4500008004100000022001400041245014300055210006900198260001300267300001300280490000600293520197700299653001502276653001002291653000902301653002202310653003402332653001102366653001902377653002502396653003402421653001102455653002702466653002102493653002202514653002202536653000902558653001602567653002702583653003602610653002802646653001702674653001802691653001602709100002202725700001902747700001702766700002802783700002302811700002102834700002102855700001802876700002602894700002102920700002802941700002102969700002102990700002503011700001703036700002203053700002003075700002303095700001903118700002303137700002203160700001903182700002503201700001803226700002203244700002103266700002603287700002103313700002103334700002203355700002703377700002303404700001903427700002403446700001903470700002203489856003603511 2011 eng d a1553-740400aGenetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.0 aGenetic determinants of lipid traits in diverse populations from c2011 Jun ae10021380 v73 aFor the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aContinental Population Groups10aFemale10aGene Frequency10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aLipid Metabolism10aLipoproteins, HDL10aLipoproteins, LDL10aMale10aMiddle Aged10aMolecular Epidemiology10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors10aTriglycerides10aYoung Adult1 aDumitrescu, Logan1 aCarty, Cara, L1 aTaylor, Kira1 aSchumacher, Fredrick, R1 aHindorff, Lucia, A1 aAmbite, José, L1 aAnderson, Garnet1 aBest, Lyle, G1 aBrown-Gentry, Kristin1 aBůzková, Petra1 aCarlson, Christopher, S1 aCochran, Barbara1 aCole, Shelley, A1 aDevereux, Richard, B1 aDuggan, Dave1 aEaton, Charles, B1 aFornage, Myriam1 aFranceschini, Nora1 aHaessler, Jeff1 aHoward, Barbara, V1 aJohnson, Karen, C1 aLaston, Sandra1 aKolonel, Laurence, N1 aLee, Elisa, T1 aMacCluer, Jean, W1 aManolio, Teri, A1 aPendergrass, Sarah, A1 aQuibrera, Miguel1 aShohet, Ralph, V1 aWilkens, Lynne, R1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aBuyske, Steven1 aKooperberg, Charles1 aNorth, Kari, E1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/130303576nas a2200673 4500008004100000022001400041245014900055210006900204260001300273300001300286490000600299520159100305653001201896653003401908653002501942653001101967653001701978653003401995653001102029653000902040653003602049653003602085100002402121700002002145700001802165700002102183700001902204700002502223700002702248700001902275700001802294700002602312700002502338700001902363700002102382700002102403700002302424700002202447700001802469700001702487700001802504700002102522700001902543700002302562700002002585700002102605700002502626700001802651700001802669700002402687700002802711700002102739700002002760700002002780700002102800700002502821700002002846856003602866 2011 eng d a1553-740400aGenetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.0 aGenetic loci associated with plasma phospholipid n3 fatty acids c2011 Jul ae10021930 v73 aLong-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻⁶⁴) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻⁵⁸) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹⁵⁴). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻⁴³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹⁵). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻⁸). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.
10aAlleles10aContinental Population Groups10aFatty Acids, Omega-310aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide1 aLemaitre, Rozenn, N1 aTanaka, Toshiko1 aTang, Weihong1 aManichaikul, Ani1 aFoy, Millennia1 aKabagambe, Edmond, K1 aNettleton, Jennifer, A1 aKing, Irena, B1 aWeng, Lu-Chen1 aBhattacharya, Sayanti1 aBandinelli, Stefania1 aBis, Joshua, C1 aRich, Stephen, S1 aJacobs, David, R1 aCherubini, Antonio1 aMcKnight, Barbara1 aLiang, Shuang1 aGu, Xiangjun1 aRice, Kenneth1 aLaurie, Cathy, C1 aLumley, Thomas1 aBrowning, Brian, L1 aPsaty, Bruce, M1 aChen, Yii-der, I1 aFriedlander, Yechiel1 aDjoussé, Luc1 aH Y Wu, Jason1 aSiscovick, David, S1 aUitterlinden, André, G1 aArnett, Donna, K1 aFerrucci, Luigi1 aFornage, Myriam1 aTsai, Michael, Y1 aMozaffarian, Dariush1 aSteffen, Lyn, M uhttps://chs-nhlbi.org/node/131104787nas a2201105 4500008004100000022001400041245006700055210006500122260001600187300001200203490000800215520177000223653001001993653000902003653002202012653004002034653001302074653001102087653004302098653001502141653002002156653003402176653001102210653000902221653001602230653002102246653001902267100002302286700002502309700002302334700001502357700001902372700002002391700002002411700001802431700001802449700002202467700001902489700001902508700001602527700001602543700002802559700002002587700001702607700002202624700002102646700001902667700002202686700002002708700002402728700002002752700002402772700002102796700002002817700002002837700001902857700002502876700002202901700002202923700002002945700001402965700001702979700002202996700002303018700001703041700001903058700001903077700001803096700002003114700002303134700002003157700001803177700001603195700002103211700002003232700002203252700002103274700001903295700002603314700001903340700002003359700001903379700002403398700002003422700002103442700002203463700003003485700003003515700001903545700001803564700002003582700002103602700002203623856003603645 2011 eng d a1524-453900aGenetic predictors of fibrin D-dimer levels in healthy adults.0 aGenetic predictors of fibrin Ddimer levels in healthy adults c2011 May 03 a1864-720 v1233 aBACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.
METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.
CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
10aAdult10aAged10aBlood Coagulation10aEuropean Continental Ancestry Group10aFactor V10aFemale10aFibrin Fibrinogen Degradation Products10aFibrinogen10aGenetic Testing10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aReference Values10aThromboplastin1 aSmith, Nicholas, L1 aHuffman, Jennifer, E1 aStrachan, David, P1 aHuang, Jie1 aDehghan, Abbas1 aTrompet, Stella1 aLopez, Lorna, M1 aShin, So-Youn1 aBaumert, Jens1 aVitart, Veronique1 aBis, Joshua, C1 aWild, Sarah, H1 aRumley, Ann1 aYang, Qiong1 aUitterlinden, André, G1 aStott, David, J1 aDavies, Gail1 aCarter, Angela, M1 aThorand, Barbara1 aPolasek, Ozren1 aMcKnight, Barbara1 aCampbell, Harry1 aRudnicka, Alicja, R1 aChen, Ming-Huei1 aBuckley, Brendan, M1 aHarris, Sarah, E1 aPeters, Annette1 aPulanic, Drazen1 aLumley, Thomas1 ade Craen, Anton, J M1 aLiewald, David, C1 aGieger, Christian1 aCampbell, Susan1 aFord, Ian1 aGow, Alan, J1 aLuciano, Michelle1 aPorteous, David, J1 aGuo, Xiuqing1 aSattar, Naveed1 aTenesa, Albert1 aCushman, Mary1 aSlagboom, Eline1 aVisscher, Peter, M1 aSpector, Tim, D1 aIllig, Thomas1 aRudan, Igor1 aBovill, Edwin, G1 aWright, Alan, F1 aMcArdle, Wendy, L1 aTofler, Geoffrey1 aHofman, Albert1 aWestendorp, Rudi, G J1 aStarr, John, M1 aGrant, Peter, J1 aKarakas, Mahir1 aHastie, Nicholas, D1 aPsaty, Bruce, M1 aWilson, James, F1 aLowe, Gordon, D O1 aO'Donnell, Christopher, J1 aWitteman, Jacqueline, C M1 aJukema, Wouter1 aDeary, Ian, J1 aSoranzo, Nicole1 aKoenig, Wolfgang1 aHayward, Caroline uhttps://chs-nhlbi.org/node/128413785nas a2204513 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2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium uhttps://chs-nhlbi.org/node/132504780nas a2200553 4500008004100000022001400041245014300055210006900198260001300267300001200280490000800292520317000300653000903470653002203479653001203501653001003513653003503523653001003558653001103568653002203579653003203601653001303633653001103646653001703657653003103674653000903705653001603714653001403730653003003744653002403774653002103798653002103819100002003840700002103860700001903881700002403900700002003924700002603944700001803970700002403988700002004012700002304032700002204055700002304077700002204100700002204122710004604144856003604190 2011 eng d a1460-215600aGenetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.0 aGenetic variants of the NOTCH3 gene in the elderly and magnetic c2011 Nov a3384-970 v1343 aCerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.
10aAged10aAged, 80 and over10aAlleles10aBrain10aCerebral Small Vessel Diseases10aExons10aFemale10aFollow-Up Studies10aGenetic Association Studies10aGenotype10aHumans10aHypertension10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPhenotype10aPromoter Regions, Genetic10aProspective Studies10aReceptor, Notch310aReceptors, Notch1 aSchmidt, Helena1 aZeginigg, Marion1 aWiltgen, Marco1 aFreudenberger, Paul1 aPetrovic, Katja1 aCavalieri, Margherita1 aGider, Pierre1 aEnzinger, Christian1 aFornage, Myriam1 aDebette, Stephanie1 aRotter, Jerome, I1 aIkram, Mohammad, A1 aLauner, Lenore, J1 aSchmidt, Reinhold1 aCHARGE consortium Neurology working group uhttps://chs-nhlbi.org/node/134306039nas a2201765 4500008004100000022001400041245010100055210006900156260001600225300001100241490000700252520104700259653001601306653001401322653001201336653002601348653002001374653001601394653001101410653002201421653003401443653001101477653004001488653005001528653000901578653002201587653002701609653001501636653001201651653003601663653002101699100002801720700002501748700002501773700002501798700002001823700002401843700001801867700002501885700001801910700002401928700002601952700001701978700002601995700001902021700001602040700002202056700001802078700002302096700001202119700002102131700001802152700002702170700001902197700002102216700002202237700001302259700002102272700002402293700001902317700002002336700002502356700002202381700002002403700002402423700001902447700003502466700002002501700002202521700002202543700002202565700001902587700002402606700001502630700002202645700001602667700001902683700002402702700001802726700001902744700001902763700001802782700002102800700002202821700001702843700002102860700002302881700002102904700002202925700002002947700002502967700002002992700002503012700002103037700002603058700001803084700002003102700001803122700001903140700002003159700002003179700002103199700002203220700002603242700002303268700002103291700002403312700002803336700002403364700002503388700002803413700002803441700002303469700002403492700001903516700002003535700002203555700001703577700002103594700001603615700002003631700002303651700002303674700002003697700002303717700002203740700002403762700002203786700001603808700002103824700002603845700001703871700001903888700002403907700002003931700002203951700002203973700002003995700002404015700002104039700002204060700001904082700002304101700002504124700002804149700002104177700001904198700002004217856003604237 2011 eng d a1546-171800aGenetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.0 aGenetic variation near IRS1 associates with reduced adiposity an c2011 Jun 26 a753-600 v433 aGenome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
10aAdiponectin10aAdiposity10aAlleles10aBody Fat Distribution10aBody Mass Index10aBody Weight10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aInsulin Receptor Substrate Proteins10aIntracellular Signaling Peptides and Proteins10aMale10aMembrane Proteins10aMeta-Analysis as Topic10aMetabolome10aObesity10aPolymorphism, Single Nucleotide10aSubcutaneous Fat1 aKilpeläinen, Tuomas, O1 aZillikens, Carola, M1 aStančáková, Alena1 aFinucane, Francis, M1 aRied, Janina, S1 aLangenberg, Claudia1 aZhang, Weihua1 aBeckmann, Jacques, S1 aLuan, Jian'an1 aVandenput, Liesbeth1 aStyrkarsdottir, Unnur1 aZhou, Yanhua1 aSmith, Albert, Vernon1 aZhao, Jing-Hua1 aAmin, Najaf1 aVedantam, Sailaja1 aShin, So-Youn1 aHaritunians, Talin1 aFu, Mao1 aFeitosa, Mary, F1 aKumari, Meena1 aHalldorsson, Bjarni, V1 aTikkanen, Emmi1 aMangino, Massimo1 aHayward, Caroline1 aSong, Ci1 aArnold, Alice, M1 aAulchenko, Yurii, S1 aOostra, Ben, A1 aCampbell, Harry1 aCupples, Adrienne, L1 aDavis, Kathryn, E1 aDöring, Angela1 aEiriksdottir, Gudny1 aEstrada, Karol1 aFernández-Real, José, Manuel1 aGarcia, Melissa1 aGieger, Christian1 aGlazer, Nicole, L1 aGuiducci, Candace1 aHofman, Albert1 aHumphries, Steve, E1 aIsomaa, Bo1 aJacobs, Leonie, C1 aJula, Antti1 aKarasik, David1 aKarlsson, Magnus, K1 aKhaw, Kay-Tee1 aKim, Lauren, J1 aKivimaki, Mika1 aKlopp, Norman1 aKuhnel, Brigitte1 aKuusisto, Johanna1 aLiu, Yongmei1 aLjunggren, Osten1 aLorentzon, Mattias1 aLuben, Robert, N1 aMcKnight, Barbara1 aMellström, Dan1 aMitchell, Braxton, D1 aMooser, Vincent1 aMoreno, José, Maria1 aMännistö, Satu1 aO'Connell, Jeffery, R1 aPascoe, Laura1 aPeltonen, Leena1 aPeral, Belén1 aPerola, Markus1 aPsaty, Bruce, M1 aSalomaa, Veikko1 aSavage, David, B1 aSemple, Robert, K1 aSkaric-Juric, Tatjana1 aSigurdsson, Gunnar1 aSong, Kijoung, S1 aSpector, Timothy, D1 aSyvänen, Ann-Christine1 aTalmud, Philippa, J1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVidal-Puig, Antonio1 aWild, Sarah, H1 aWright, Alan, F1 aClegg, Deborah, J1 aSchadt, Eric1 aWilson, James, F1 aRudan, Igor1 aRipatti, Samuli1 aBorecki, Ingrid, B1 aShuldiner, Alan, R1 aIngelsson, Erik1 aJansson, John-Olov1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aGroop, Leif1 aKiel, Douglas, P1 aRivadeneira, Fernando1 aWalker, Mark1 aBarroso, Inês1 aVollenweider, Peter1 aWaeber, Gérard1 aChambers, John, C1 aKooner, Jaspal, S1 aSoranzo, Nicole1 aHirschhorn, Joel, N1 aStefansson, Kari1 aWichmann, H-Erich1 aOhlsson, Claes1 aO'Rahilly, Stephen1 aWareham, Nicholas, J1 aSpeliotes, Elizabeth, K1 aFox, Caroline, S1 aLaakso, Markku1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/130102615nas a2200481 4500008004100000022001400041245014100055210006900196260001300265300001300278490000600291520118600297653002701483653001901510653001101529653001901540653001701559653001801576653003401594653001301628653001101641653002101652653003801673653001101711653002201722653002001744653003101764653003601795653001301831653003001844100002101874700002001895700001601915700001901931700001901950700001901969700001901988700002402007700001802031700002502049700002302074856003602097 2011 eng d a1553-740400aGenome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci.0 aGenomewide association analysis of soluble ICAM1 concentration r c2011 Apr ae10013740 v73 aSoluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P = 5.8 × 10(-9)), RELA (rs1049728, P = 2.7 × 10(-16)), and SH2B3 (rs3184504, P = 2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.
10aABO Blood-Group System10aCohort Studies10aFemale10aGene Frequency10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aI-kappa B Kinase10aIntercellular Adhesion Molecule-110aLipase10aMembrane Proteins10aModels, Genetic10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide10aProteins10aTranscription Factor RelA1 aParé, Guillaume1 aRidker, Paul, M1 aRose, Lynda1 aBarbalic, Maja1 aDupuis, Josée1 aDehghan, Abbas1 aBis, Joshua, C1 aBenjamin, Emelia, J1 aShiffman, Dov1 aParker, Alexander, N1 aChasman, Daniel, I uhttps://chs-nhlbi.org/node/128707169nas a2202257 4500008004100000022001400041245010400055210006900159260001600228300001200244490000700256520086500263653001001128653004001138653003401178653001101212653004301223653003101266100002601297700001801323700002001341700002001361700001901381700001601400700001801416700001901434700002601453700002501479700001801504700002601522700002001548700001701568700002001585700002101605700002001626700001801646700002401664700001901688700001901707700002001726700002501746700002101771700002401792700002301816700002001839700002201859700002901881700001901910700002801929700002101957700002201978700002602000700002302026700002402049700001802073700001902091700001902110700002102129700002302150700002102173700001802194700001602212700002802228700002202256700001702278700002002295700001702315700002002332700001902352700002602371700001602397700001702413700001702430700002002447700001802467700001902485700001902504700002102523700002202544700001802566700001902584700002002603700001802623700001802641700002202659700001902681700001902700700002002719700001702739700002302756700001902779700002102798700002002819700001802839700002402857700001902881700002102900700001602921700002302937700001902960700002202979700001903001700001803020700002403038700001803062700002303080700002103103700002203124700002103146700002303167700002203190700002103212700001903233700002603252700002003278700002203298700001603320700001803336700002403354700001703378700001903395700002803414700002003442700002203462700002203484700002003506700001903526700001703545700002103562700002603583700002203609700001903631700002403650700001903674700001903693700002003712700002703732700001803759700002603777700001803803700002003821700002803841700002003869700002003889700002203909700001603931700002403947700001903971700001803990700002004008700001704028700002204045700001904067700002504086700002604111700002204137700001904159700001904178700001904197700002004216700001604236700002204252700002204274700002004296700001504316700002204331700001904353700002204372700002304394700002604417700001904443700002104462700002204483700002004505700002204525700002004547700002304567700001804590700002704608700002604635700001804661700002404679700002304703700002504726700001704751700002404768700002104792710004104813710002104854856003604875 2011 eng d a1546-171800aGenome-wide association and large-scale follow up identifies 16 new loci influencing lung function.0 aGenomewide association and largescale follow up identifies 16 ne c2011 Sep 25 a1082-900 v433 aPulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
10aChild10aEuropean Continental Ancestry Group10aGenome-Wide Association Study10aHumans10aPulmonary Disease, Chronic Obstructive10aRespiratory Function Tests1 aArtigas, Maria, Soler1 aLoth, Daan, W1 aWain, Louise, V1 aGharib, Sina, A1 aObeidat, Ma'en1 aTang, Wenbo1 aZhai, Guangju1 aZhao, Jing Hua1 aSmith, Albert, Vernon1 aHuffman, Jennifer, E1 aAlbrecht, Eva1 aJackson, Catherine, M1 aEvans, David, M1 aCadby, Gemma1 aFornage, Myriam1 aManichaikul, Ani1 aLopez, Lorna, M1 aJohnson, Toby1 aAldrich, Melinda, C1 aAspelund, Thor1 aBarroso, Inês1 aCampbell, Harry1 aCassano, Patricia, A1 aCouper, David, J1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aGarcia, Melissa1 aGieger, Christian1 aGislason, Gauti, Kjartan1 aGrkovic, Ivica1 aHammond, Christopher, J1 aHancock, Dana, B1 aHarris, Tamara, B1 aRamasamy, Adaikalavan1 aHeckbert, Susan, R1 aHeliövaara, Markku1 aHomuth, Georg1 aHysi, Pirro, G1 aJames, Alan, L1 aJankovic, Stipan1 aJoubert, Bonnie, R1 aKarrasch, Stefan1 aKlopp, Norman1 aKoch, Beate1 aKritchevsky, Stephen, B1 aLauner, Lenore, J1 aLiu, Yongmei1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aLumley, Thomas1 aBalushi, Khalid, A Al1 aAng, Wei, Q1 aBarr, Graham1 aBeilby, John1 aBlakey, John, D1 aBoban, Mladen1 aBoraska, Vesna1 aBrisman, Jonas1 aBritton, John, R1 aBrusselle, Guy, G1 aCooper, Cyrus1 aCurjuric, Ivan1 aDahgam, Santosh1 aDeary, Ian, J1 aEbrahim, Shah1 aEijgelsheim, Mark1 aFrancks, Clyde1 aGaysina, Darya1 aGranell, Raquel1 aGu, Xiangjun1 aHankinson, John, L1 aHardy, Rebecca1 aHarris, Sarah, E1 aHenderson, John1 aHenry, Amanda1 aHingorani, Aroon, D1 aHofman, Albert1 aHolt, Patrick, G1 aHui, Jennie1 aHunter, Michael, L1 aImboden, Medea1 aJameson, Karen, A1 aKerr, Shona, M1 aKolcic, Ivana1 aKronenberg, Florian1 aLiu, Jason, Z1 aMarchini, Jonathan1 aMcKeever, Tricia1 aMorris, Andrew, D1 aOlin, Anna-Carin1 aPorteous, David, J1 aPostma, Dirkje, S1 aRich, Stephen, S1 aRing, Susan, M1 aRivadeneira, Fernando1 aRochat, Thierry1 aSayer, Avan Aihie1 aSayers, Ian1 aSly, Peter, D1 aSmith, George Davey1 aSood, Akshay1 aStarr, John, M1 aUitterlinden, André, G1 aVonk, Judith, M1 aWannamethee, Goya1 aWhincup, Peter, H1 aWijmenga, Cisca1 aWilliams, Dale1 aWong, Andrew1 aMangino, Massimo1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aNorth, Kari, E1 aOmenaas, Ernst1 aPalmer, Lyle, J1 aPietiläinen, Kirsi, H1 aPin, Isabelle1 aEk, Ozren, Pola Sbrev1 aPouta, Anneli1 aPsaty, Bruce, M1 aHartikainen, Anna-Liisa1 aRantanen, Taina1 aRipatti, Samuli1 aRotter, Jerome, I1 aRudan, Igor1 aRudnicka, Alicja, R1 aSchulz, Holger1 aShin, So-Youn1 aSpector, Tim, D1 aSurakka, Ida1 aVitart, Veronique1 aVölzke, Henry1 aWareham, Nicholas, J1 aWarrington, Nicole, M1 aWichmann, H-Erich1 aWild, Sarah, H1 aWilk, Jemma, B1 aWjst, Matthias1 aWright, Alan, F1 aZgaga, Lina1 aZemunik, Tatijana1 aPennell, Craig, E1 aNyberg, Fredrik1 aKuh, Diana1 aHolloway, John, W1 aBoezen, Marike1 aLawlor, Debbie, A1 aMorris, Richard, W1 aProbst-Hensch, Nicole1 aKaprio, Jaakko1 aWilson, James, F1 aHayward, Caroline1 aKähönen, Mika1 aHeinrich, Joachim1 aMusk, Arthur, W1 aJarvis, Deborah, L1 aGläser, Sven1 aJarvelin, Marjo-Riitta1 aStricker, Bruno, H Ch1 aElliott, Paul1 aO'Connor, George, T1 aStrachan, David, P1 aLondon, Stephanie, J1 aHall, Ian, P1 aGudnason, Vilmundur1 aTobin, Martin, D1 aInternational Lung Cancer Consortium1 aGIANT Consortium uhttps://chs-nhlbi.org/node/609605055nas a2201153 4500008004100000022001400041245009900055210006900154260001300223300001100236490000700247520175600254653000902010653002202019653002002041653003202061653002402093653001902117653004002136653001102176653001902187653003802206653003402244653001302278653001102291653002602302653003102328653000902359653001602368653002302384653002902407653003602436653003002472653001902502100002002521700002302541700001902564700002002583700002002603700002002623700002502643700001902668700002402687700001902711700002202730700002102752700002202773700002002795700002102815700002102836700002002857700001802877700002102895700001902916700002302935700002402958700002202982700001803004700002203022700002603044700002103070700002203091700002003113700002003133700001403153700002603167700001903193700002603212700002003238700002303258700002103281700002403302700002803326700001603354700002303370700001903393700002003412700001803432700002003450700002203470700002203492700002103514700002303535700002203558700002003580700002403600700002203624700002103646700002003667700002003687700002403707700002703731700002203758700002203780700002003802700002103822700002203843856003603865 2011 eng d a1531-824900aGenome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.0 aGenomewide association studies of cerebral white matter lesion b c2011 Jun a928-390 v693 aOBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).
INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
10aAged10aAged, 80 and over10aCerebral Cortex10aChromosomes, Human, Pair 1710aCognition Disorders10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLeukoencephalopathies10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aMovement Disorders10aNerve Fibers, Myelinated10aPolymorphism, Single Nucleotide10aResidence Characteristics10aRNA, Messenger1 aFornage, Myriam1 aDebette, Stephanie1 aBis, Joshua, C1 aSchmidt, Helena1 aIkram, Arfan, M1 aDufouil, Carole1 aSigurdsson, Sigurdur1 aLumley, Thomas1 aDeStefano, Anita, L1 aFazekas, Franz1 aVrooman, Henri, A1 aShibata, Dean, K1 aMaillard, Pauline1 aZijdenbos, Alex1 aSmith, Albert, V1 aGudnason, Haukur1 ade Boer, Renske1 aCushman, Mary1 aMazoyer, Bernard1 aHeiss, Gerardo1 aVernooij, Meike, W1 aEnzinger, Christian1 aGlazer, Nicole, L1 aBeiser, Alexa1 aKnopman, David, S1 aCavalieri, Margherita1 aNiessen, Wiro, J1 aHarris, Tamara, B1 aPetrovic, Katja1 aLopez, Oscar, L1 aAu, Rhoda1 aLambert, Jean-Charles1 aHofman, Albert1 aGottesman, Rebecca, F1 aGarcia, Melissa1 aHeckbert, Susan, R1 aAtwood, Larry, D1 aCatellier, Diane, J1 aUitterlinden, André, G1 aYang, Qiong1 aSmith, Nicholas, L1 aAspelund, Thor1 aRomero, Jose, R1 aRice, Kenneth1 aTaylor, Kent, D1 aNalls, Michael, A1 aRotter, Jerome, I1 aSharrett, Richey1 aDuijn, Cornelia, M1 aAmouyel, Philippe1 aWolf, Philip, A1 aGudnason, Vilmundur1 avan der Lugt, Aad1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aTzourio, Christophe1 aBreteler, Monique, M B1 aMosley, Thomas, H1 aSchmidt, Reinhold1 aLongstreth, W T1 aDeCarli, Charles1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/129803920nas a2200721 4500008004100000022001400041245017000055210006900225260001600294300001200310490000700322520181400329653001002143653002202153653000902175653001202184653001402196653001502210653004002225653001102265653001702276653003802293653003402331653001302365653000902378653001102387653002702398653000902425653001602434653003102450653003802481653003602519653001402555653001602569100001802585700002202603700002402625700001802649700001702667700002202684700002002706700001802726700002502744700002102769700002002790700001602810700002302826700002602849700002002875700001402895700002102909700002402930700002102954700002202975700002302997700002503020700002203045700002503067700002103092700001903113710003003132856003603162 2011 eng d a1460-208300aGenome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.0 aGenomewide association study for serum urate concentrations and c2011 Oct 15 a4056-680 v203 aSerum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.
10aAdult10aAfrican Americans10aAged10aAnimals10aCHO Cells10aCricetinae10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGout10aHumans10aLoss of Heterozygosity10aMale10aMiddle Aged10aOrganic Anion Transporters10aOrganic Cation Transport Proteins10aPolymorphism, Single Nucleotide10aUric Acid10aYoung Adult1 aTin, Adrienne1 aWoodward, Owen, M1 aKao, Wen Hong Linda1 aLiu, Ching-Ti1 aLu, Xiaoning1 aNalls, Michael, A1 aShriner, Daniel1 aSemmo, Mariam1 aAkylbekova, Ermeg, L1 aWyatt, Sharon, B1 aHwang, Shih-Jen1 aYang, Qiong1 aZonderman, Alan, B1 aAdeyemo, Adebowale, A1 aPalmer, Cameron1 aMeng, Yan1 aReilly, Muredach1 aShlipak, Michael, G1 aSiscovick, David1 aEvans, Michele, K1 aRotimi, Charles, N1 aFlessner, Michael, F1 aKöttgen, Michael1 aCupples, Adrienne, L1 aFox, Caroline, S1 aKöttgen, Anna1 aCARe and CHARGE Consortia uhttps://chs-nhlbi.org/node/130504132nas a2200709 4500008004100000022001400041245010500055210006900160260001600229300001200245490000700257520206100264653000902325653003102334653001902365653004002384653001102424653003402435653001102469653004902480653003302529653000902562653003602571100002202607700002602629700002002655700002202675700002202697700002002719700002202739700002002761700001702781700002102798700001602819700001802835700001802853700001802871700001702889700001902906700002002925700002202945700002302967700001902990700002203009700002203031700002203053700001903075700001803094700002303112700002103135700001903156700002403175700002003199700002503219700002203244700002003266700002303286700002503309700002703334700002503361856003603386 2011 eng d a1460-208300aA genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.0 agenomewide association study identifies novel loci associated wi c2011 Mar 15 a1241-510 v203 aInsulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
10aAged10aChromosomes, Human, Pair 710aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aPolymorphism, Single Nucleotide1 aKaplan, Robert, C1 aPetersen, Ann-Kristin1 aChen, Ming-Huei1 aTeumer, Alexander1 aGlazer, Nicole, L1 aDöring, Angela1 aLam, Carolyn, S P1 aFriedrich, Nele1 aNewman, Anne1 aMüller, Martina1 aYang, Qiong1 aHomuth, Georg1 aCappola, Anne1 aKlopp, Norman1 aSmith, Holly1 aErnst, Florian1 aPsaty, Bruce, M1 aWichmann, H-Erich1 aSawyer, Douglas, B1 aBiffar, Reiner1 aRotter, Jerome, I1 aGieger, Christian1 aSullivan, Lisa, S1 aVölzke, Henry1 aRice, Kenneth1 aSpyroglou, Ariadni1 aKroemer, Heyo, K1 aChen, Y-D, Ida1 aManolopoulou, Jenny1 aNauck, Matthias1 aStrickler, Howard, D1 aGoodarzi, Mark, O1 aReincke, Martin1 aPollak, Michael, N1 aBidlingmaier, Martin1 aVasan, Ramachandran, S1 aWallaschofski, Henri uhttps://chs-nhlbi.org/node/126109449nas a2203037 4500008004100000022001400041245011300055210006900168260001600237300001200253490000700265520102300272653001301295653001901308653002501327653002201352653001701374653003401391653001101425653001701436653002701453653003601480100002001516700002601536700002201562700001401584700001801598700002301616700002101639700002101660700002001681700002101701700002001722700001601742700002201758700002001780700001801800700001801818700001901836700001901855700001601874700002601890700001901916700001701935700001601952700001701968700002001985700001802005700001802023700001702041700002002058700001902078700002102097700002402118700001602142700001902158700002002177700002002197700002002217700001602237700002102253700002402274700002202298700002302320700002002343700003102363700002502394700002202419700001702441700002202458700002102480700002002501700001902521700001802540700002702558700002402585700001702609700002202626700001902648700001702667700003302684700002602717700002502743700002802768700002002796700002702816700002002843700001902863700002402882700002002906700002002926700001802946700001902964700002202983700002103005700001703026700001903043700002203062700002003084700002203104700002003126700001903146700001503165700002403180700002103204700001903225700001803244700001703262700002003279700001803299700002403317700001403341700001703355700001603372700001903388700002303407700001803430700002303448700001703471700001603488700002403504700001903528700003003547700002003577700002403597700002403621700002003645700001803665700002603683700002303709700002403732700002403756700002003780700001703800700001803817700002103835700001803856700002003874700001803894700001503912700002003927700001803947700002303965700002103988700002004009700002104029700001704050700001904067700002204086700002204108700001904130700002304149700002004172700001904192700002104211700001704232700001704249700001704266700003004283700001804313700001704331700001704348700002204365700002204387700002004409700001904429700002004448700002204468700001704490700001904507700002004526700001804546700002104564700002404585700002004609700002104629700001904650700002304669700001704692700002204709700002304731700002404754700002004778700002204798700002304820700001604843700002104859700002504880700002804905700002204933700002004955700001604975700002204991700001805013700002205031700002305053700001905076700002205095700002105117700001905138700002005157700002305177700002505200700002305225700002105248700002005269700002205289700002005311700002005331700002005351700002305371700001805394700002105412700002105433700002105454700002005475700002105495700002005516700002205536700002005558700002505578700001905603700002105622700001905643700001905662700002305681700002505704700003005729700002205759700002105781700002105802700002105823700002005844700002705864700002605891700002505917700002405942700002905966700001705995700002406012700002006036700002306056700002006079700002106099700001806120700002306138710002706161710002306188710002406211710005006235710002506285710002206310710002806332710001506360856003606375 2011 eng d a1546-171800aGenome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.0 aGenomewide association study identifies six new loci influencing c2011 Sep 11 a1005-110 v433 aNumerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
10aArteries10aBlood Pressure10aCase-Control Studies10aFollow-Up Studies10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide1 aWain, Louise, V1 aVerwoert, Germaine, C1 aO'Reilly, Paul, F1 aShi, Gang1 aJohnson, Toby1 aJohnson, Andrew, D1 aBochud, Murielle1 aRice, Kenneth, M1 aHenneman, Peter1 aSmith, Albert, V1 aEhret, Georg, B1 aAmin, Najaf1 aLarson, Martin, G1 aMooser, Vincent1 aHadley, David1 aDörr, Marcus1 aBis, Joshua, C1 aAspelund, Thor1 aEsko, Tõnu1 aJanssens, Cecile, J W1 aZhao, Jing Hua1 aHeath, Simon1 aLaan, Maris1 aFu, Jingyuan1 aPistis, Giorgio1 aLuan, Jian'an1 aArora, Pankaj1 aLucas, Gavin1 aPirastu, Nicola1 aPichler, Irene1 aJackson, Anne, U1 aWebster, Rebecca, J1 aZhang, Feng1 aPeden, John, F1 aSchmidt, Helena1 aTanaka, Toshiko1 aCampbell, Harry1 aIgl, Wilmar1 aMilaneschi, Yuri1 aHottenga, Jouke-Jan1 aVitart, Veronique1 aChasman, Daniel, I1 aTrompet, Stella1 aBragg-Gresham, Jennifer, L1 aAlizadeh, Behrooz, Z1 aChambers, John, C1 aGuo, Xiuqing1 aLehtimäki, Terho1 aKuhnel, Brigitte1 aLopez, Lorna, M1 aPolasek, Ozren1 aBoban, Mladen1 aNelson, Christopher, P1 aMorrison, Alanna, C1 aPihur, Vasyl1 aGanesh, Santhi, K1 aHofman, Albert1 aKundu, Suman1 aMattace-Raso, Francesco, U S1 aRivadeneira, Fernando1 aSijbrands, Eric, J G1 aUitterlinden, André, G1 aHwang, Shih-Jen1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aLaitinen, Jaana1 aPouta, Anneli1 aZitting, Paavo1 aMcArdle, Wendy, L1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGlazer, Nicole, L1 aTaylor, Kent, D1 aHarris, Tamara, B1 aAlavere, Helene1 aHaller, Toomas1 aKeis, Aime1 aTammesoo, Mari-Liis1 aAulchenko, Yurii1 aBarroso, Inês1 aKhaw, Kay-Tee1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aEyheramendy, Susana1 aOrg, Elin1 aSõber, Siim1 aLu, Xiaowen1 aNolte, Ilja, M1 aPenninx, Brenda, W1 aCorre, Tanguy1 aMasciullo, Corrado1 aSala, Cinzia1 aGroop, Leif1 aVoight, Benjamin, F1 aMelander, Olle1 aO'Donnell, Christopher, J1 aSalomaa, Veikko1 ad'Adamo, Adamo, Pio1 aFabretto, Antonella1 aFaletra, Flavio1 aUlivi, Sheila1 aDel Greco, Fabiola, M1 aFacheris, Maurizio1 aCollins, Francis, S1 aBergman, Richard, N1 aBeilby, John, P1 aHung, Joseph1 aMusk, William1 aMangino, Massimo1 aShin, So-Youn1 aSoranzo, Nicole1 aWatkins, Hugh1 aGoel, Anuj1 aHamsten, Anders1 aGider, Pierre1 aLoitfelder, Marisa1 aZeginigg, Marion1 aHernandez, Dena1 aNajjar, Samer, S1 aNavarro, Pau1 aWild, Sarah, H1 aCorsi, Anna Maria1 aSingleton, Andrew1 aGeus, Eco, J C1 aWillemsen, Gonneke1 aParker, Alex, N1 aRose, Lynda, M1 aBuckley, Brendan1 aStott, David1 aOrrù, Marco1 aUda, Manuela1 avan der Klauw, Melanie, M1 aZhang, Weihua1 aLi, Xinzhong1 aScott, James1 aChen, Yii-Der Ida1 aBurke, Gregory, L1 aKähönen, Mika1 aViikari, Jorma1 aDöring, Angela1 aMeitinger, Thomas1 aDavies, Gail1 aStarr, John, M1 aEmilsson, Valur1 aPlump, Andrew1 aLindeman, Jan, H1 aHoen, Peter, A C 't1 aKönig, Inke, R1 aFelix, Janine, F1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aBreteler, Monique1 aDebette, Stephanie1 aDeStefano, Anita, L1 aFornage, Myriam1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aHolm, Hilma1 aStefansson, Kari1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aSamani, Nilesh, J1 aPreuss, Michael1 aRudan, Igor1 aHayward, Caroline1 aDeary, Ian, J1 aWichmann, H-Erich1 aRaitakari, Olli, T1 aPalmas, Walter1 aKooner, Jaspal, S1 aStolk, Ronald, P1 aJukema, Wouter1 aWright, Alan, F1 aBoomsma, Dorret, I1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWilson, James, F1 aFerrucci, Luigi1 aSchmidt, Reinhold1 aFarrall, Martin1 aSpector, Tim, D1 aPalmer, Lyle, J1 aTuomilehto, Jaakko1 aPfeufer, Arne1 aGasparini, Paolo1 aSiscovick, David1 aAltshuler, David1 aLoos, Ruth, J F1 aToniolo, Daniela1 aSnieder, Harold1 aGieger, Christian1 aMeneton, Pierre1 aWareham, Nicholas, J1 aOostra, Ben, A1 aMetspalu, Andres1 aLauner, Lenore1 aRettig, Rainer1 aStrachan, David, P1 aBeckmann, Jacques, S1 aWitteman, Jacqueline, C M1 aErdmann, Jeanette1 aDijk, Ko Willems1 aBoerwinkle, Eric1 aBoehnke, Michael1 aRidker, Paul, M1 aJarvelin, Marjo-Riitta1 aChakravarti, Aravinda1 aAbecasis, Goncalo, R1 aGudnason, Vilmundur1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aRao, Dabeeru, C1 aTobin, Martin, D1 aElliott, Paul1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aEchoGen consortium1 aAortaGen Consortium1 aCHARGE Consortium Heart Failure Working Group1 aKidneyGen Consortium1 aCKDGen Consortium1 aCardiogenics consortium1 aCardioGram uhttps://chs-nhlbi.org/node/132403421nas a2200829 4500008004100000022001400041245004600055210004200101260001300143300001600156490000700172520116200179653001001341653003801351653003401389653001301423653001101436653001401447100001901461700001601480700002301496700002301519700002201542700001801564700002401582700002101606700002001627700002301647700001701670700001201687700001801699700002401717700001901741700002101760700002101781700001801802700002401820700002001844700002201864700002301886700001901909700001901928700002101947700001901968700002001987700002202007700002002029700002202049700002202071700002302093700002002116700002002136700002202156700002002178700002602198700002102224700002002245700002002265700002502285700002502310700002902335700002202364700002002386700002402406700001902430700001702449700002402466700002002490700002202510700002302532856003602555 2011 eng d a1558-149700aA genome-wide association study of aging.0 agenomewide association study of aging c2011 Nov a2109.e15-280 v323 aHuman longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.
10aAging10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLongevity1 aWalter, Stefan1 aAtzmon, Gil1 aDemerath, Ellen, W1 aGarcia, Melissa, E1 aKaplan, Robert, C1 aKumari, Meena1 aLunetta, Kathryn, L1 aMilaneschi, Yuri1 aTanaka, Toshiko1 aTranah, Gregory, J1 aVölker, Uwe1 aYu, Lei1 aArnold, Alice1 aBenjamin, Emelia, J1 aBiffar, Reiner1 aBuchman, Aron, S1 aBoerwinkle, Eric1 aCouper, David1 aDe Jager, Philip, L1 aEvans, Denis, A1 aHarris, Tamara, B1 aHoffmann, Wolfgang1 aHofman, Albert1 aKarasik, David1 aKiel, Douglas, P1 aKocher, Thomas1 aKuningas, Maris1 aLauner, Lenore, J1 aLohman, Kurt, K1 aLutsey, Pamela, L1 aMackenbach, Johan1 aMarciante, Kristin1 aPsaty, Bruce, M1 aReiman, Eric, M1 aRotter, Jerome, I1 aSeshadri, Sudha1 aShardell, Michelle, D1 aSmith, Albert, V1 aDuijn, Cornelia1 aWalston, Jeremy1 aZillikens, Carola, M1 aBandinelli, Stefania1 aBaumeister, Sebastian, E1 aBennett, David, A1 aFerrucci, Luigi1 aGudnason, Vilmundur1 aKivimaki, Mika1 aLiu, Yongmei1 aMurabito, Joanne, M1 aNewman, Anne, B1 aTiemeier, Henning1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/130702348nas a2200469 4500008004100000022001400041245010400055210006900159260001300228300001000241490000600251520105900257653000901316653002201325653001001347653001901357653002801376653001901404653001101423653000901434653001101443653001401454653000901468653001601477653002801493653002001521100002001541700002001561700002701581700002201608700002101630700002001651700002301671700002101694700001901715700001901734700002601753700002301779700002301802700001701825856003601842 2011 eng d a1945-458900aHealth and function of participants in the Long Life Family Study: A comparison with other cohorts.0 aHealth and function of participants in the Long Life Family Stud c2011 Jan a63-760 v33 aIndividuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.
10aAged10aAged, 80 and over10aAging10aBlood Pressure10aCardiovascular Diseases10aCohort Studies10aFemale10aGait10aHumans10aLongevity10aMale10aMiddle Aged10aPsychomotor Performance10aResearch Design1 aNewman, Anne, B1 aGlynn, Nancy, W1 aTaylor, Christopher, A1 aSebastiani, Paola1 aPerls, Thomas, T1 aMayeux, Richard1 aChristensen, Kaare1 aZmuda, Joseph, M1 aBarral, Sandra1 aLee, Joseph, H1 aSimonsick, Eleanor, M1 aWalston, Jeremy, D1 aYashin, Anatoli, I1 aHadley, Evan uhttps://chs-nhlbi.org/node/126304122nas a2201045 4500008004100000022001400041245014200055210006900197260001300266300001300279490000600292520107900298653001001377653000901387653001201396653003101408653002701439653004001466653001101506653001701517653003801534653003401572653001101606653000901617653001601626653002701642653003601669100001901705700002101724700002201745700002901767700002201796700002101818700002901839700002201868700002301890700002301913700002501936700002301961700002901984700002302013700002202036700001502058700001902073700002002092700002602112700001902138700003002157700002802187700002102215700001702236700002402253700002302277700001902300700002002319700002202339700001602361700001702377700002302394700001202417700001902429700001702448700002102465700001802486700002002504700002002524700002502544700002202569700002402591700001902615700002102634700002202655700002502677700001802702700001802720700002502738700002302763700002402786700003002810700002302840700001802863700002702881700001802908700002502926700002602951700001902977700002302996700002103019856003603040 2011 eng d a1553-740400aIdentification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.0 aIdentification of a sudden cardiac death susceptibility locus at c2011 Jun ae10021580 v73 aSudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).
10aAdult10aAged10aAlleles10aChromosomes, Human, Pair 210aDeath, Sudden, Cardiac10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMyocardial Contraction10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aJunttila, Juhani1 aGoyette, Philippe1 aHuertas-Vazquez, Adriana1 aEijgelsheim, Mark1 aBlom, Marieke, T1 aNewton-Cheh, Christopher1 aReinier, Kyndaron1 aTeodorescu, Carmen1 aUy-Evanado, Audrey1 aCarter-Monroe, Naima1 aKaikkonen, Kari, S1 aKortelainen, Marja-Leena1 aBoucher, Gabrielle1 aLagacé, Caroline1 aMoes, Anna1 aZhao, XiaoQing1 aKolodgie, Frank1 aRivadeneira, Fernando1 aHofman, Albert1 aWitteman, Jacqueline, C M1 aUitterlinden, André, G1 aMarsman, Roos, F1 aPazoki, Raha1 aBardai, Abdennasser1 aKoster, Rudolph, W1 aDehghan, Abbas1 aHwang, Shih-Jen1 aBhatnagar, Pallav1 aPost, Wendy1 aHilton, Gina1 aPrineas, Ronald, J1 aLi, Man1 aKöttgen, Anna1 aEhret, Georg1 aBoerwinkle, Eric1 aCoresh, Josef1 aKao, Linda, W H1 aPsaty, Bruce, M1 aTomaselli, Gordon, F1 aSotoodehnia, Nona1 aSiscovick, David, S1 aBurke, Greg, L1 aMarbán, Eduardo1 aSpooner, Peter, M1 aCupples, Adrienne, L1 aJui, Jonathan1 aGunson, Karen1 aKesaniemi, Antero, Y1 aWilde, Arthur, A M1 aTardif, Jean-Claude1 aO'Donnell, Christopher, J1 aBezzina, Connie, R1 aVirmani, Renu1 aStricker, Bruno, H C H1 aTan, Hanno, L1 aAlbert, Christine, M1 aChakravarti, Aravinda1 aRioux, John, D1 aHuikuri, Heikki, V1 aChugh, Sumeet, S uhttps://chs-nhlbi.org/node/130402266nas a2200241 4500008004100000022001400041245010800055210006900163260001600232300001200248490000600260520153300266100001901799700002201818700002301840700001701863700002001880700002301900700002401923700002101947700002001968856003601988 2011 eng d a2160-677300aThe Impact of Sleep-Disordered Breathing on Body Mass Index (BMI): The Sleep Heart Health Study (SHHS).0 aImpact of SleepDisordered Breathing on Body Mass Index BMI The S c2011 Dec 08 a159-1680 v33 aINTRODUCTION: It is well known that obesity is a risk factor for sleep-disordered breathing (SDB). However, whether SDB predicts increase in BMI is not well defined. Data from the Sleep Heart Health Study (SHHS) were analyzed to determine whether SDB predicts longitudinal increase in BMI, adjusted for confounding factors. METHODS: A full-montage unattended home polysomnogram (PSG) and body anthropometric measurements were obtained approximately five years apart in 3001 participants. Apnea-hypopnea index (AHI) was categorized using clinical thresholds: < 5 (normal), ≥ 5 to <15 (mild sleep apnea), and ≥ 15 (moderate to severe sleep apnea). Linear regression was used to examine the association between the three AHI groups and increased BMI. The model included age, gender, race, baseline BMI, and change in AHI as covariates. RESULTS: Mean (SD) age was 62.2 years (10.14), 55.2% were female and 76.1% were Caucasian. Five-year increase in BMI was modest with a mean (SD) change of 0.53 (2.62) kg/m(2) (p=0.071). A multivariate regression model showed that subjects with a baseline AHI between 5-15 had a mean increase in BMI of 0.22 kg/m(2) (p=0.055) and those with baseline AHI ≥ 15 had a BMI increase of 0.51 kg/m(2) (p<0.001) compared to those with baseline AHI of <5. CONCLUSION: Our findings suggest that there is a positive association between severity of SDB and subsequent increased BMI over approximately 5 years. This observation may help explain why persons with SDB have difficulty losing weight.
1 aBrown, Mark, A1 aGoodwin, James, L1 aSilva, Graciela, E1 aBehari, Ajay1 aNewman, Anne, B1 aPunjabi, Naresh, M1 aResnick, Helaine, E1 aRobbins, John, A1 aQuan, Stuart, F uhttps://chs-nhlbi.org/node/156602802nas a2200469 4500008004100000022001400041245009700055210006900152260000900221300001000230490000700240520155000247653000901797653002801806653001501834653001501849653002401864653001101888653001501899653003101914653001101945653001101956653002001967653000901987653001601996653002202012653001702034653002202051100002302073700001602096700002102112700001602133700001602149700001702165700002502182700001602207700002202223700001602245700001702261700001802278856003602296 2011 eng d a1421-967000aKidney function decline in the elderly: impact of lipoprotein-associated phospholipase A(2).0 aKidney function decline in the elderly impact of lipoproteinasso c2011 a512-80 v343 aBACKGROUND: Whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels are associated with kidney function decline has not been well studied.
METHODS: We investigated associations of Lp-PLA(2) antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m(2) per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m(2)).
RESULTS: Mean age was 72 ± 5 years. Average eGFRcys decline was -1.79 ml/min/1.73 m(2) (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA(2) antigen, eGFRcys decline was faster among persons in the second, β -0.31 (95% CI -0.52, -0.10), third -0.19 (-0.41, 0.02) and fourth quartiles -0.26 (-0.48, -0.04) after full adjustment. Persons in the highest quartile of Lp-PLA(2) antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA(2) activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m(2)) at baseline.
CONCLUSION: Higher levels of Lp-PLA(2) antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.
10aAged10aCardiovascular Diseases10aCreatinine10aCystatin C10aDisease Progression10aFemale10aGeriatrics10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Diseases10aMale10aMiddle Aged10aPhospholipases A210aRisk Factors10aTreatment Outcome1 aPeralta, Carmen, A1 aKatz, Ronit1 aShlipak, Michael1 aDubin, Ruth1 aDeBoer, Ian1 aJenny, Nancy1 aFitzpatrick, Annette1 aKoro, Carol1 aKestenbaum, Bryan1 aIx, Joachim1 aSarnak, Mark1 aCushman, Mary uhttps://chs-nhlbi.org/node/134903026nas a2200469 4500008004100000022001400041245008000055210006900135260001300204300001000217490000700227520177200234653000902006653002202015653001002037653002002047653002802067653001902095653001602114653002102130653002202151653001102173653001102184653001702195653001502212653002502227653000902252653002402261653001202285653001102297653001302308100002802321700002402349700002102373700002402394700002002418700002002438700002202458700002202480700001802502856003602520 2011 eng d a1758-535X00aLeukocyte telomere length and mortality in the Cardiovascular Health Study.0 aLeukocyte telomere length and mortality in the Cardiovascular He c2011 Apr a421-90 v663 aBACKGROUND: Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.
METHODS: We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992-1993 and survived through 1997-1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.
RESULTS: A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22-2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32-5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95-3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.
CONCLUSION: These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.
10aAged10aAged, 80 and over10aAging10aBody Mass Index10aCardiovascular Diseases10aCause of Death10aComorbidity10aCoronary Disease10aDiabetes Mellitus10aFemale10aHumans10aHypertension10aLeukocytes10aLongitudinal Studies10aMale10aProspective Studies10aSmoking10aStroke10aTelomere1 aFitzpatrick, Annette, L1 aKronmal, Richard, A1 aKimura, Masayuki1 aGardner, Jeffrey, P1 aPsaty, Bruce, M1 aJenny, Nancy, S1 aTracy, Russell, P1 aHardikar, Sheetal1 aAviv, Abraham uhttps://chs-nhlbi.org/node/126503031nas a2200361 4500008004100000022001400041245018100055210006900236260001300305300001100318490000700329520192100336653005102257653000902308653002802317653002802345653003002373653001102403653001102414653000902425653003202434653002402466653001702490100001702507700001602524700001302540700001502553700001602568700001602584700001502600700001802615856003602633 2011 eng d a1432-042800aLipoprotein-associated phospholipase A(2) and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study.0 aLipoproteinassociated phospholipase A2 and future risk of subcli c2011 Feb a329-330 v543 aAIMS/HYPOTHESIS: Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA(2) levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.
METHODS: We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.
RESULTS: At baseline, Lp-PLA(2) mass did not differ significantly by type 2 diabetes status; however, Lp-PLA(2) activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA(2) (OR 1.68 [95% CI 1.31-2.15] vs OR 1.67 [95% CI 1.30-2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA(2) activity.
CONCLUSIONS/INTERPRETATION: In this older cohort, differences in Lp-PLA(2) activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aCardiovascular Diseases10aCross-Sectional Studies10aDiabetes Mellitus, Type 210aFemale10aHumans10aMale10aProportional Hazards Models10aProspective Studies10aRisk Factors1 aNelson, T, L1 aKamineni, A1 aPsaty, B1 aCushman, M1 aJenny, N, S1 aHokanson, J1 aFurberg, C1 aMukamal, K, J uhttps://chs-nhlbi.org/node/125003188nas a2200553 4500008004100000022001400041245012300055210006900178260001300247300000900260490000700269520163300276653001001909653000901919653002001928653002501948653003001973653001602003653001202019653001102031653001802042653003402060653001302094653001102107653001202118653002702130653000902157653002702166653002702193653001602220653003602236653001502272100002202287700002202309700001802331700001802349700001302367700001702380700001902397700002802416700002202444700002502466700002302491700002002514700002002534700002502554700001902579856003602598 2011 eng d a1098-227200aMeta-analysis of gene-environment interaction: joint estimation of SNP and SNP × environment regression coefficients.0 aMetaanalysis of geneenvironment interaction joint estimation of c2011 Jan a11-80 v353 aINTRODUCTION: Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies.
METHODS: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples.
RESULTS: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.
10aAdult10aAged10aBody Mass Index10aConfidence Intervals10aDiabetes Mellitus, Type 210aEnvironment10aFasting10aFemale10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aInsulin10aLeast-Squares Analysis10aMale10aMathematical Computing10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aPPAR gamma1 aManning, Alisa, K1 aLaValley, Michael1 aLiu, Ching-Ti1 aRice, Kenneth1 aAn, Ping1 aLiu, Yongmei1 aMiljkovic, Iva1 aRasmussen-Torvik, Laura1 aHarris, Tamara, B1 aProvince, Michael, A1 aBorecki, Ingrid, B1 aFlorez, Jose, C1 aMeigs, James, B1 aCupples, Adrienne, L1 aDupuis, Josée uhttps://chs-nhlbi.org/node/125805459nas a2201501 4500008004100000022001400041245016600055210006900221260001600290300001000306490000700316520120500323653001001528653000901538653001001547653002001557653003501577653001901612653002801631653004001659653001701699653003801716653001801754653003401772653001301806653001001819653001101829653001601840653001401856653002801870653003601898653001701934100001901951700002001970700002301990700001802013700002502031700001802056700001902074700002102093700002502114700002002139700002202159700002502181700002202206700001802228700002002246700002302266700001902289700001602308700001602324700001702340700002502357700002202382700002002404700002302424700002002447700001802467700001902485700002002504700002002524700002102544700001802565700002602583700001702609700001902626700002302645700002002668700002302688700002402711700001802735700001802753700001902771700002302790700002202813700002402835700001702859700002402876700002102900700002102921700002002942700001802962700002102980700001703001700001903018700002303037700002403060700002203084700002203106700001903128700002103147700001803168700002003186700001903206700002203225700002503247700002303272700002503295700002003320700002103340700002303361700002703384700002203411700002003433700002003453700002103473700001203494700002303506700001703529700002103546700001803567700002003585700002103605700001903626700002103645700002403666700002003690700002503710700001903735700002403754700002003778700001803798700002503816700002403841700003003865710002603895856003603921 2011 eng d a1546-171800aMeta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.0 aMetaanalysis of genomewide association studies from the CHARGE c c2011 Sep 11 a940-70 v433 aCarotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
10aAdult10aAged10aAging10aAtherosclerosis10aCarotid Intima-Media Thickness10aCohort Studies10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMiddle Aged10aPhenotype10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aRisk Factors1 aBis, Joshua, C1 aKavousi, Maryam1 aFranceschini, Nora1 aIsaacs, Aaron1 aAbecasis, Goncalo, R1 aSchminke, Ulf1 aPost, Wendy, S1 aSmith, Albert, V1 aCupples, Adrienne, L1 aMarkus, Hugh, S1 aSchmidt, Reinhold1 aHuffman, Jennifer, E1 aLehtimäki, Terho1 aBaumert, Jens1 aMünzel, Thomas1 aHeckbert, Susan, R1 aDehghan, Abbas1 aNorth, Kari1 aOostra, Ben1 aBevan, Steve1 aStoegerer, Eva-Maria1 aHayward, Caroline1 aRaitakari, Olli1 aMeisinger, Christa1 aSchillert, Arne1 aSanna, Serena1 aVölzke, Henry1 aCheng, Yu-Ching1 aThorsson, Bolli1 aFox, Caroline, S1 aRice, Kenneth1 aRivadeneira, Fernando1 aNambi, Vijay1 aHalperin, Eran1 aPetrovic, Katja, E1 aPeltonen, Leena1 aWichmann, Erich, H1 aSchnabel, Renate, B1 aDörr, Marcus1 aParsa, Afshin1 aAspelund, Thor1 aDemissie, Serkalem1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTaylor, Kent1 aUitterlinden, Andre1 aCouper, David, J1 aSitzer, Matthias1 aKähönen, Mika1 aIllig, Thomas1 aWild, Philipp, S1 aOrrù, Marco1 aLüdemann, Jan1 aShuldiner, Alan, R1 aEiriksdottir, Gudny1 aWhite, Charles, C1 aRotter, Jerome, I1 aHofman, Albert1 aSeissler, Jochen1 aZeller, Tanja1 aUsala, Gianluca1 aErnst, Florian1 aLauner, Lenore, J1 aD'Agostino, Ralph, B1 aO'Leary, Daniel, H1 aBallantyne, Christie1 aThiery, Joachim1 aZiegler, Andreas1 aLakatta, Edward, G1 aChilukoti, Ravi, Kumar1 aHarris, Tamara, B1 aWolf, Philip, A1 aPsaty, Bruce, M1 aPolak, Joseph, F1 aLi, Xia1 aRathmann, Wolfgang1 aUda, Manuela1 aBoerwinkle, Eric1 aKlopp, Norman1 aSchmidt, Helena1 aWilson, James, F1 aViikari, Jorma1 aKoenig, Wolfgang1 aBlankenberg, Stefan1 aNewman, Anne, B1 aWitteman, Jacqueline1 aHeiss, Gerardo1 avan Duijn, Cornelia1 aScuteri, Angelo1 aHomuth, Georg1 aMitchell, Braxton, D1 aGudnason, Vilmundur1 aO'Donnell, Christopher, J1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/132306092nas a2201597 4500008004100000022001400041245012900055210006900184260001600253300001000269490000800279520159300287653001501880653002301895653002801918653003801946653003401984653001102018653001702029653001502046100001902061700001902080700001902099700001902118700002402137700001302161700002002174700002502194700002302219700002002242700001802262700002302280700002702303700002202330700002102352700002102373700001902394700002102413700001702434700001902451700002502470700001902495700002002514700002002534700002102554700002402575700001702599700002002616700002002636700002002656700002302676700002102699700002002720700001702740700001702757700001902774700001902793700002202812700002202834700002302856700002202879700002202901700002202923700002102945700002602966700002102992700002503013700001803038700001803056700002003074700001303094700002303107700002103130700001903151700001903170700001903189700001803208700001703226700002203243700001703265700004103282700002003323700002003343700001903363700002003382700002403402700001903426700002503445700001903470700001703489700001803506700001403524700002403538700001703562700002203579700001703601700002403618700001603642700002103658700002303679700002103702700002203723700001603745700002303761700002203784700002803806700002703834700001803861700001803879700002003897700002603917700002103943700002703964700002003991700002204011700002504033700002004058700002304078700001904101700002004120700002204140700002604162700002304188700002004211700002004231700002404251700002004275700001804295700002104313700002804334700003004362700002404392700001904416700002304435856003604458 2011 eng d a1524-453900aMeta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.0 aMetaanalysis of genomewide association studies in 80 000 subject c2011 Feb 22 a731-80 v1233 aBACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.
METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.
CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aRisk Factors10aVasculitis1 aDehghan, Abbas1 aDupuis, Josée1 aBarbalic, Maja1 aBis, Joshua, C1 aEiriksdottir, Gudny1 aLu, Chen1 aPellikka, Niina1 aWallaschofski, Henri1 aKettunen, Johannes1 aHenneman, Peter1 aBaumert, Jens1 aStrachan, David, P1 aFuchsberger, Christian1 aVitart, Veronique1 aWilson, James, F1 aParé, Guillaume1 aNaitza, Silvia1 aRudock, Megan, E1 aSurakka, Ida1 aGeus, Eco, J C1 aAlizadeh, Behrooz, Z1 aGuralnik, Jack1 aShuldiner, Alan1 aTanaka, Toshiko1 aZee, Robert, Y L1 aSchnabel, Renate, B1 aNambi, Vijay1 aKavousi, Maryam1 aRipatti, Samuli1 aNauck, Matthias1 aSmith, Nicholas, L1 aSmith, Albert, V1 aSundvall, Jouko1 aScheet, Paul1 aLiu, Yongmei1 aRuokonen, Aimo1 aRose, Lynda, M1 aLarson, Martin, G1 aHoogeveen, Ron, C1 aFreimer, Nelson, B1 aTeumer, Alexander1 aTracy, Russell, P1 aLauner, Lenore, J1 aBuring, Julie, E1 aYamamoto, Jennifer, F1 aFolsom, Aaron, R1 aSijbrands, Eric, J G1 aPankow, James1 aElliott, Paul1 aKeaney, John, F1 aSun, Wei1 aSarin, Antti-Pekka1 aFontes, João, D1 aBadola, Sunita1 aAstor, Brad, C1 aHofman, Albert1 aPouta, Anneli1 aWerdan, Karl1 aGreiser, Karin, H1 aKuss, Oliver1 aMeyer zu Schwabedissen, Henriette, E1 aThiery, Joachim1 aJamshidi, Yalda1 aNolte, Ilja, M1 aSoranzo, Nicole1 aSpector, Timothy, D1 aVölzke, Henry1 aParker, Alexander, N1 aAspelund, Thor1 aBates, David1 aYoung, Lauren1 aTsui, Kim1 aSiscovick, David, S1 aGuo, Xiuqing1 aRotter, Jerome, I1 aUda, Manuela1 aSchlessinger, David1 aRudan, Igor1 aHicks, Andrew, A1 aPenninx, Brenda, W1 aThorand, Barbara1 aGieger, Christian1 aCoresh, Joe1 aWillemsen, Gonneke1 aHarris, Tamara, B1 aUitterlinden, André, G1 aJarvelin, Marjo-Riitta1 aRice, Kenneth1 aRadke, Dörte1 aSalomaa, Veikko1 avan Dijk, Ko, Willems1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aFerrucci, Luigi1 aGibson, Quince, D1 aBandinelli, Stefania1 aSnieder, Harold1 aBoomsma, Dorret, I1 aXiao, Xiangjun1 aCampbell, Harry1 aHayward, Caroline1 aPramstaller, Peter, P1 aDuijn, Cornelia, M1 aPeltonen, Leena1 aPsaty, Bruce, M1 aGudnason, Vilmundur1 aRidker, Paul, M1 aHomuth, Georg1 aKoenig, Wolfgang1 aBallantyne, Christie, M1 aWitteman, Jacqueline, C M1 aBenjamin, Emelia, J1 aPerola, Markus1 aChasman, Daniel, I uhttps://chs-nhlbi.org/node/126707496nas a2202305 4500008004100000022001400041245006700055210006600122260001600188300001000204490000800214520114000222653001201362653002001374653001401394653002801408653002401436653001101460653003001471653001901501653001801520653003401538653001801572653001101590653001901601653001901620653002901639653002701668653001401695653002301709100002201732700002601754700001601780700001801796700002001814700002001834700002901854700001901883700002301902700001801925700002001943700001801963700002001981700002002001700002002021700002102041700002202062700001702084700001802101700002602119700001902145700002202164700002002186700002402206700002402230700001802254700002202272700001802294700001602312700002002328700002202348700002102370700001802391700002302409700001502432700002602447700002002473700002002493700002102513700002502534700001702559700002902576700001902605700001902624700002302643700002202666700002202688700002102710700001702731700001702748700002302765700001902788700002002807700001802827700002202845700002002867700001802887700001402905700002102919700001902940700002202959700002202981700001903003700002803022700002303050700002803073700001803101700001803119700002003137700002103157700001903178700002103197700003103218700002003249700002503269700001903294700002103313700002003334700002403354700002203378700001803400700002503418700002503443700002103468700002003489700001803509700002003527700001903547700002303566700001803589700002603607700001803633700001903651700002203670700002203692700001903714700001703733700002203750700002303772700002403795700002203819700002403841700001703865700002303882700002003905700001903925700002203944700002303966700002203989700001704011700001904028700002104047700001804068700001704086700001804103700002804121700002304149700001704172700002204189700002204211700002304233700001804256700002004274700001904294700002104313700002504334700002104359700002204380700002104402700001904423700002304442700002004465700002304485700002304508700001804531700001804549700002204567700002204589700002704611700002404638700002304662700002004685700002404705700002504729700002804754700001904782700002004801700002404821700001604845700002204861700001904883700002204902700002104924700002104945700001904966700002104985700002105006700001805027700002105045700002005066700002405086700002405110700002005134856003605154 2011 eng d a1476-468700aNew gene functions in megakaryopoiesis and platelet formation.0 aNew gene functions in megakaryopoiesis and platelet formation c2011 Nov 30 a201-80 v4803 aPlatelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
10aAnimals10aBlood Platelets10aCell Size10aDrosophila melanogaster10aDrosophila Proteins10aEurope10aGene Expression Profiling10aGene Silencing10aGenome, Human10aGenome-Wide Association Study10aHematopoiesis10aHumans10aMegakaryocytes10aPlatelet Count10aProtein Interaction Maps10aTranscription, Genetic10aZebrafish10aZebrafish Proteins1 aGieger, Christian1 aRadhakrishnan, Aparna1 aCvejic, Ana1 aTang, Weihong1 aPorcu, Eleonora1 aPistis, Giorgio1 aSerbanovic-Canic, Jovana1 aElling, Ulrich1 aGoodall, Alison, H1 aLabrune, Yann1 aLopez, Lorna, M1 aMägi, Reedik1 aMeacham, Stuart1 aOkada, Yukinori1 aPirastu, Nicola1 aSorice, Rossella1 aTeumer, Alexander1 aVoss, Katrin1 aZhang, Weihua1 aRamirez-Solis, Ramiro1 aBis, Joshua, C1 aEllinghaus, David1 aGögele, Martin1 aHottenga, Jouke-Jan1 aLangenberg, Claudia1 aKovacs, Peter1 aO'Reilly, Paul, F1 aShin, So-Youn1 aEsko, Tõnu1 aHartiala, Jaana1 aKanoni, Stavroula1 aMurgia, Federico1 aParsa, Afshin1 aStephens, Jonathan1 aHarst, Pim1 avan der Schoot, Ellen1 aAllayee, Hooman1 aAttwood, Antony1 aBalkau, Beverley1 aBastardot, François1 aBasu, Saonli1 aBaumeister, Sebastian, E1 aBiino, Ginevra1 aBomba, Lorenzo1 aBonnefond, Amélie1 aCambien, Francois1 aChambers, John, C1 aCucca, Francesco1 aD'Adamo, Pio1 aDavies, Gail1 ade Boer, Rudolf, A1 aGeus, Eco, J C1 aDöring, Angela1 aElliott, Paul1 aErdmann, Jeanette1 aEvans, David, M1 aFalchi, Mario1 aFeng, Wei1 aFolsom, Aaron, R1 aFrazer, Ian, H1 aGibson, Quince, D1 aGlazer, Nicole, L1 aHammond, Chris1 aHartikainen, Anna-Liisa1 aHeckbert, Susan, R1 aHengstenberg, Christian1 aHersch, Micha1 aIllig, Thomas1 aLoos, Ruth, J F1 aJolley, Jennifer1 aKhaw, Kay, Tee1 aKuhnel, Brigitte1 aKyrtsonis, Marie-Christine1 aLagou, Vasiliki1 aLloyd-Jones, Heather1 aLumley, Thomas1 aMangino, Massimo1 aMaschio, Andrea1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMemari, Yasin1 aMitchell, Braxton, D1 aMontgomery, Grant, W1 aNakamura, Yusuke1 aNauck, Matthias1 aNavis, Gerjan1 aNöthlings, Ute1 aNolte, Ilja, M1 aPorteous, David, J1 aPouta, Anneli1 aPramstaller, Peter, P1 aPullat, Janne1 aRing, Susan, M1 aRotter, Jerome, I1 aRuggiero, Daniela1 aRuokonen, Aimo1 aSala, Cinzia1 aSamani, Nilesh, J1 aSambrook, Jennifer1 aSchlessinger, David1 aSchreiber, Stefan1 aSchunkert, Heribert1 aScott, James1 aSmith, Nicholas, L1 aSnieder, Harold1 aStarr, John, M1 aStumvoll, Michael1 aTakahashi, Atsushi1 aTang, W, H Wilson1 aTaylor, Kent1 aTenesa, Albert1 aThein, Swee, Lay1 aTönjes, Anke1 aUda, Manuela1 aUlivi, Sheila1 avan Veldhuisen, Dirk, J1 aVisscher, Peter, M1 aVölker, Uwe1 aWichmann, H-Erich1 aWiggins, Kerri, L1 aWillemsen, Gonneke1 aYang, Tsun-Po1 aZhao, Jing, Hua1 aZitting, Paavo1 aBradley, John, R1 aDedoussis, George, V1 aGasparini, Paolo1 aHazen, Stanley, L1 aMetspalu, Andres1 aPirastu, Mario1 aShuldiner, Alan, R1 avan Pelt, Joost1 aZwaginga, Jaap-Jan1 aBoomsma, Dorret, I1 aDeary, Ian, J1 aFranke, Andre1 aFroguel, Philippe1 aGanesh, Santhi, K1 aJarvelin, Marjo-Riitta1 aMartin, Nicholas, G1 aMeisinger, Christa1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aWareham, Nicholas, J1 aAkkerman, Jan-Willem, N1 aCiullo, Marina1 aDeloukas, Panos1 aGreinacher, Andreas1 aJupe, Steve1 aKamatani, Naoyuki1 aKhadake, Jyoti1 aKooner, Jaspal, S1 aPenninger, Josef1 aProkopenko, Inga1 aStemple, Derek1 aToniolo, Daniela1 aWernisch, Lorenz1 aSanna, Serena1 aHicks, Andrew, A1 aRendon, Augusto1 aFerreira, Manuel, A1 aOuwehand, Willem, H1 aSoranzo, Nicole uhttps://chs-nhlbi.org/node/135503344nas a2200517 4500008004100000022001400041245014800055210006900203260001600272300001100288490000800299520172900307653002602036653003402062653001802096653003202114653002502146653003402171653001102205653003302216653003102249653005202280653001402332653001902346653002002365653001702385653001802402100002002420700002302440700001902463700002802482700002102510700002202531700002702553700001902580700002402599700002202623700002102645700001902666700001902685700002402704700002302728700002402751710001502775856003602790 2011 eng d a1476-625600aThe Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study.0 aNext PAGE in understanding complex traits design for the analysi c2011 Oct 01 a849-590 v1743 aGenetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the "phenome-wide association study" approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser.
10aEpidemiologic Methods10aEpidemiologic Research Design10aEthnic Groups10aGenetic Association Studies10aGenetics, Population10aGenome-Wide Association Study10aHumans10aInterinstitutional Relations10aMultifactorial Inheritance10aNational Human Genome Research Institute (U.S.)10aPhenotype10aPilot Projects10aResearch Design10aRisk Factors10aUnited States1 aMatise, Tara, C1 aAmbite, Jose, Luis1 aBuyske, Steven1 aCarlson, Christopher, S1 aCole, Shelley, A1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aHeiss, Gerardo1 aKooperberg, Charles1 aLe Marchand, Loic1 aManolio, Teri, A1 aNorth, Kari, E1 aPeters, Ulrike1 aRitchie, Marylyn, D1 aHindorff, Lucia, A1 aHaines, Jonathan, L1 aPAGE Study uhttps://chs-nhlbi.org/node/131303083nas a2200469 4500008004100000022001400041245012500055210006900180260001300249300001100262490000600273520170600279653002101985653000902006653001502015653002802030653001902058653002502077653002702102653001102129653001102140653001402151653002602165653000902191653001602200653003102216653002202247653003002269653003202299653002602331653002002357653002102377653001702398653001802415100002302433700002202456700002702478700002402505700002402529700002402553856003602577 2011 eng d a1556-387100aN-terminal pro-B-type natriuretic peptide is associated with sudden cardiac death risk: the Cardiovascular Health Study.0 aNterminal proBtype natriuretic peptide is associated with sudden c2011 Feb a228-330 v83 aBACKGROUND: Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality as well as with sudden death in women.
OBJECTIVE: The purpose of this study was to examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
METHODS: The risk of SCD associated with baseline NT-proBNP was examined in 5,447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP.
RESULTS: Over a median follow-up of 12.5 years (maximum 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% confidence interval [2.9, 6.1]; P <.001) in the highest quintile compared with in the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the fifth versus the first quintile of 2.5 (95% confidence interval [1.6, 3.8]; P <.001).
CONCLUSION: NT-proBNP provides information regarding the risk of SCD in a community-based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.
10aAge Distribution10aAged10aBiomarkers10aCardiovascular Diseases10aCohort Studies10aConfidence Intervals10aDeath, Sudden, Cardiac10aFemale10aHumans10aIncidence10aKaplan-Meier Estimate10aMale10aMiddle Aged10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aProportional Hazards Models10aRetrospective Studies10aRisk Assessment10aSex Distribution10aTime Factors10aUnited States1 aPatton, Kristen, K1 aSotoodehnia, Nona1 aDeFilippi, Christopher1 aSiscovick, David, S1 aGottdiener, John, S1 aKronmal, Richard, A uhttps://chs-nhlbi.org/node/124203388nas a2200553 4500008004100000022001400041245012700055210006900182260001300251300001300264490000600277520170800283653002201991653002302013653001802036653001802054653004002072653003202112653003802144653001802182653001102200653002302211653002302234653001402257653002602271653003602297653003402333653003002367653002202397100002202419700001802441700001902459700002102478700002102499700002002520700002302540700002402563700002002587700002102607700002602628700002002654700002402674700002202698700002002720700002202740700001902762700001702781856003602798 2011 eng d a1553-740400aA phenomics-based strategy identifies loci on APOC1, BRAP, and PLCG1 associated with metabolic syndrome phenotype domains.0 aphenomicsbased strategy identifies loci on APOC1 BRAP and PLCG1 c2011 Oct ae10023220 v73 aDespite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Association Resource Consortium participants to identify loci associated with the clustering of metabolic phenotypes. Six phenotype domains (atherogenic dyslipidemia, vascular dysfunction, vascular inflammation, pro-thrombotic state, central obesity, and elevated plasma glucose) encompassing 19 quantitative traits were examined. Principal components analysis was used to reduce the dimension of each domain such that >55% of the trait variance was represented within each domain. We then applied a statistically efficient and computational feasible multivariate approach that related eight principal components from the six domains to 250,000 imputed SNPs using an additive genetic model and including demographic covariates. In European Americans, we identified 606 genome-wide significant SNPs representing 19 loci. Many of these loci were associated with only one trait domain, were consistent with results in African Americans, and overlapped with published findings, for instance central obesity and FTO. However, our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. These pleiotropic loci may help characterize metabolic dysregulation and identify targets for intervention.
10aAfrican Americans10aApolipoprotein C-I10aBlood Glucose10aDyslipidemias10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenome, Human10aHumans10aMetabolic Syndrome10aObesity, Abdominal10aPhenotype10aPhospholipase C gamma10aPolymorphism, Single Nucleotide10aQuantitative Trait, Heritable10aUbiquitin-Protein Ligases10aVascular Diseases1 aAvery, Christy, L1 aHe, Qianchuan1 aNorth, Kari, E1 aAmbite, José, L1 aBoerwinkle, Eric1 aFornage, Myriam1 aHindorff, Lucia, A1 aKooperberg, Charles1 aMeigs, James, B1 aPankow, James, S1 aPendergrass, Sarah, A1 aPsaty, Bruce, M1 aRitchie, Marylyn, D1 aRotter, Jerome, I1 aTaylor, Kent, D1 aWilkens, Lynne, R1 aHeiss, Gerardo1 aLin, Dan, Yu uhttps://chs-nhlbi.org/node/134502559nas a2200349 4500008004100000022001400041245009700055210006900152260001600221300001200237490000800249520158900257653000901846653001501855653003401870653001301904653001101917653001101928653000901939653003001948653001201978653001601990653001402006100002302020700002202043700001902065700002502084700002002109700002402129700002002153856003602173 2011 eng d a1476-625600aSeasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study.0 aSeasonal variation in 25hydroxyvitamin D concentrations in the c c2011 Dec 15 a1363-720 v1743 aLow circulating concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with adverse health outcomes in diverse populations. However, 25(OH)D concentrations vary seasonally with varying exposure to sunlight, so single measurements may poorly reflect long-term 25(OH)D exposure. The authors investigated cyclical trends in average serum 25(OH)D concentrations among 2,298 individuals enrolled in the Cardiovascular Health Study of community-based older adults (1992-1993). A sinusoidal model closely approximated observed 25(OH)D concentrations and fit the data significantly better than did a mean model (P < 0.0001). The mean annual 25(OH)D concentration was 25.1 ng/mL (95% confidence interval: 24.7, 25.5), and the mean peak-trough difference was 9.6 ng/mL (95% confidence interval: 8.5, 10.7). Male sex, higher latitude of study site, and greater physical activity levels were associated with larger peak-trough difference in 25(OH)D concentration (each P < 0.05). Serum concentrations of intact parathyroid hormone and bone-specific alkaline phosphatase also varied in a sinusoidal fashion (P < 0.0001), inversely to 25(OH)D. In conclusion, serum 25(OH)D varies in a sinusoidal manner, with large seasonal differences relative to mean concentration and laboratory evidence of biologic sequelae. Single 25(OH)D measurements might not capture overall vitamin D status, and the extent of misclassification could vary by demographic and behavioral factors. Accounting for collection time may reduce bias in research studies and improve decision-making in clinical care.
10aAged10aBiomarkers10aContinental Population Groups10aExercise10aFemale10aHumans10aMale10aResidence Characteristics10aSeasons10aSex Factors10aVitamin D1 aShoben, Abigail, B1 aKestenbaum, Bryan1 aLevin, Gregory1 aHoofnagle, Andrew, N1 aPsaty, Bruce, M1 aSiscovick, David, S1 ade Boer, Ian, H uhttps://chs-nhlbi.org/node/135304370nas a2200613 4500008004100000022001400041245016100055210006900216260001600285300001200301490000800313520260000321653001602921653001902937653002002956653002802976653001603004653002103020653002203041653001103063653001103074653000903085653001603094653002303110653003203133653002403165653002003189653001603209653001203225653001203237653002403249653002003273110004003293700001903333700002103352700003003373700002003403700001903423700001903442700001903461700002003480700002203500700002803522700001703550700002003567700001803587700001903605700001903624700001803643700002303661700001903684700001703703856003603720 2011 eng d a1474-547X00aSeparate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies.0 aSeparate and combined associations of bodymass index and abdomin c2011 Mar 26 a1085-950 v3773 aBACKGROUND: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.
METHODS: We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) higher BMI, 12.6 cm higher waist circumference, and 0.083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.
RESULTS: Individual records were available for 221,934 people in 17 countries (14,297 incident cardiovascular disease outcomes; 1.87 million person-years at risk). Serial adiposity assessments were made in up to 63,821 people (mean interval 5.7 years [SD 3.9]). In people with BMI of 20 kg/m(2) or higher, HRs for cardiovascular disease were 1.23 (95% CI 1.17-1.29) with BMI, 1.27 (1.20-1.33) with waist circumference, and 1.25 (1.19-1.31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1.07 (1.03-1.11) with BMI, 1.10 (1.05-1.14) with waist circumference, and 1.12 (1.08-1.15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of -0.0001, -0.0001, and 0.0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement -0.19%, -0.05%, and -0.05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0.95, 95% CI 0.93-0.97) than for waist circumference (0.86, 0.83-0.89) or waist-to-hip ratio (0.63, 0.57-0.70).
INTERPRETATION: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.
FUNDING: British Heart Foundation and UK Medical Research Council.
10aAge Factors10aBlood Pressure10aBody Mass Index10aCardiovascular Diseases10aCholesterol10aCholesterol, HDL10aDiabetes Mellitus10aFemale10aHumans10aMale10aMiddle Aged10aObesity, Abdominal10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aSex Factors10aSmoking10aSystole10aWaist Circumference10aWaist-Hip Ratio1 aEmerging Risk Factors Collaboration1 aWormser, David1 aKaptoge, Stephen1 aDi Angelantonio, Emanuele1 aWood, Angela, M1 aPennells, Lisa1 aThompson, Alex1 aSarwar, Nadeem1 aKizer, Jorge, R1 aLawlor, Debbie, A1 aNordestgaard, Børge, G1 aRidker, Paul1 aSalomaa, Veikko1 aStevens, June1 aWoodward, Mark1 aSattar, Naveed1 aCollins, Rory1 aThompson, Simon, G1 aWhitlock, Gary1 aDanesh, John uhttps://chs-nhlbi.org/node/156302877nas a2200361 4500008004100000022001400041245011400055210006900169260001300238300001100251490000700262520185800269653000902127653002202136653002802158653002002186653001102206653001102217653000902228653000902237653002202246100002002268700002102288700002202309700002102331700002202352700002002374700002002394700002402414700002102438700002002459856003602479 2011 eng d a1758-535X00aSubclinical vascular disease burden and risk for death and cardiovascular events in older community dwellers.0 aSubclinical vascular disease burden and risk for death and cardi c2011 Sep a986-930 v663 aBACKGROUND: Individual measures and previous composite measures of subclinical vascular disease defined high risk for cardiovascular events, but did not detect low and modest risk. A different approach might better describe the spectrum from low to high risk. Methods and Results. In the Cardiovascular Health Study, 3,252 participants without history of clinical cardiovascular disease (M ± SD 74.3 years ± 5.1, 63% women, 17% African Americans) had noninvasive vascular assessments in 1992-1993. We assigned a score of 0, 1, or 2 (no, mild, or severe abnormalities) to ankle-arm index, electrocardiogram, and common carotid intima-media thickness, based on clinical cutoffs. A summary index (range 0-6, absent to severe disease) summed individual scores. Abdominal aortic ultrasound and brain magnetic resonance imaging were collected in a subsample. Mortality and incident cardiovascular events were identified through June 2008. Event and death rates increased across index grades. Comparing grades 1 to 5+ with absent disease, and adjusting for demographics, hazard ratios for cardiovascular events within 8 years ranged from 1.1 (95% confidence interval 0.8-1.6) to 4.7 (3.4-6.9) and, for mortality, from 1.5 (1.0-2.3) to 5.0 (3.3-7.7) (p for trend across grades <.001 for both outcomes). Adjustment for cardiovascular risk factors did not substantially change the associations. The index improved mortality risk classification over demographics and risk factors in participants who did not die during the follow-up. Including in the index the aortic ultrasound and the brain magnetic resonance imaging further improved risk classification.
CONCLUSIONS: Older adults with minimal subclinical vascular disease had low cardiovascular events risk and mortality. This approach might more fully account for vascular burden.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aCost of Illness10aFemale10aHumans10aMale10aRisk10aVascular Diseases1 aInzitari, Marco1 aArnold, Alice, M1 aPatel, Kushang, V1 aMercer, Laina, D1 aKarlamangla, Arun1 aDing, Jingzhong1 aPsaty, Bruce, M1 aWilliamson, Jeff, D1 aKuller, Lewis, H1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/130003259nas a2200445 4500008004100000022001400041245015400055210006900209260001300278300001200291490000700303520194900310653000902259653002202268653001002290653001902300653002102319653002602340653001102366653001802377653001102395653001702406653000902423653002602432653001602458653001102474653001802485100001802503700003102521700003102552700002902583700002102612700002702633700002202660700002802682700002702710700002002737700002002757856003602777 2011 eng d a1468-201X00aSystolic blood pressure and incident heart failure in the elderly. The Cardiovascular Health Study and the Health, Ageing and Body Composition Study.0 aSystolic blood pressure and incident heart failure in the elderl c2011 Aug a1304-110 v973 aBACKGROUND: The exact form of the association between systolic blood pressure (SBP) and heart failure (HF) risk in the elderly remains incompletely defined, especially in individuals not receiving antihypertensive drugs.
OBJECTIVE: To examine the association between SBP and HF risk in the elderly.
DESIGN: Competing-risks proportional hazards modelling of incident HF risk, using 10-year follow-up data from two NIH-sponsored cohort studies: the Cardiovascular Health Study (inception: 1989-90 and 1992-3) and the Health ABC Study (inception: 1997-8).
SETTING: Community-based cohorts.
PARTICIPANTS: 4408 participants (age, 72.8 (4.9) years; 53.1% women, 81.7% white; 18.3% black) without prevalent HF and not receiving antihypertensive drugs at baseline.
MAIN OUTCOME MEASURES: Incident HF, defined as first adjudicated hospitalisation for HF.
RESULTS: Over 10 years, 493 (11.2%) participants developed HF. Prehypertension (120-139 mm Hg), stage 1 (140-159 mm Hg), and stage 2 (≥160 mm Hg) hypertension were associated with escalating HF risk; HRs versus optimal SBP (<120 mm Hg) in competing-risks models controlling for clinical characteristics were 1.63 (95% CI 1.23 to 2.16; p=0.001), 2.21 (95% CI 1.65 to 2.96; p<0.001) and 2.60 (95% CI 1.85 to 3.64; p<0.001), respectively. Overall 255/493 (51.7%) HF events occurred in participants with SBP <140 mm Hg at baseline. Increasing SBP was associated with higher HF risk in women than in men; no race-SBP interaction was seen. In analyses with continuous SBP, HF risk had a continuous positive association with SBP to levels as low as 113 mm Hg in men and 112 mm Hg in women.
CONCLUSIONS: There is a continuous positive association between SBP and HF risk in the elderly for levels of SBP as low as <115 mm Hg; over half of incident HF events occur in individuals with SBP <140 mm Hg.
10aAged10aAged, 80 and over10aAging10aBlood Pressure10aBody Composition10aEpidemiologic Methods10aFemale10aHeart Failure10aHumans10aHypertension10aMale10aMyocardial Infarction10aSex Factors10aStroke10aStroke Volume1 aButler, Javed1 aKalogeropoulos, Andreas, P1 aGeorgiopoulou, Vasiliki, V1 aBibbins-Domingo, Kirsten1 aNajjar, Samer, S1 aSutton-Tyrrell, Kim, C1 aHarris, Tamara, B1 aKritchevsky, Stephen, B1 aLloyd-Jones, Donald, M1 aNewman, Anne, B1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/129404525nas a2200901 4500008004100000022001400041245012800055210006900183260001300252300001200265490000700277520189900284653001802183653003002201653001902231653001102250653003602261653000902297653002302306100002202329700002702351700002502378700001402403700002602417700002002443700002102463700002002484700002402504700002402528700002302552700002602575700002002601700001802621700002002639700002002659700002302679700002302702700002002725700002102745700001902766700002202785700002302807700001702830700002102847700002402868700001502892700001702907700002002924700001802944700002102962700002502983700002803008700002803036700002203064700002503086700002103111700002103132700002503153700002103178700002503199700001803224700002103242700001903263700002403282700002003306700002803326700002203354700002003376700002303396700003003419700002503449700002403474700002003498700002003518700002503538710002403563856003603587 2011 eng d a1939-327X00aTotal zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.0 aTotal zinc intake may modify the glucoseraising effect of a zinc c2011 Sep a2407-160 v603 aOBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.
RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.
RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.
CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.
10aBlood Glucose10aCation Transport Proteins10aCohort Studies10aHumans10aPolymorphism, Single Nucleotide10aZinc10aZinc Transporter 81 aKanoni, Stavroula1 aNettleton, Jennifer, A1 aHivert, Marie-France1 aYe, Zheng1 avan Rooij, Frank, J A1 aShungin, Dmitry1 aSonestedt, Emily1 aNgwa, Julius, S1 aWojczynski, Mary, K1 aLemaitre, Rozenn, N1 aGustafsson, Stefan1 aAnderson, Jennifer, S1 aTanaka, Toshiko1 aHindy, George1 aSaylor, Georgia1 aRenstrom, Frida1 aBennett, Amanda, J1 aDuijn, Cornelia, M1 aFlorez, Jose, C1 aFox, Caroline, S1 aHofman, Albert1 aHoogeveen, Ron, C1 aHouston, Denise, K1 aHu, Frank, B1 aJacques, Paul, F1 aJohansson, Ingegerd1 aLind, Lars1 aLiu, Yongmei1 aMcKeown, Nicola1 aOrdovas, Jose1 aPankow, James, S1 aSijbrands, Eric, J G1 aSyvänen, Ann-Christine1 aUitterlinden, André, G1 aYannakoulia, Mary1 aZillikens, Carola, M1 aWareham, Nick, J1 aProkopenko, Inga1 aBandinelli, Stefania1 aForouhi, Nita, G1 aCupples, Adrienne, L1 aLoos, Ruth, J1 aHallmans, Göran1 aDupuis, Josée1 aLangenberg, Claudia1 aFerrucci, Luigi1 aKritchevsky, Stephen, B1 aMcCarthy, Mark, I1 aIngelsson, Erik1 aBorecki, Ingrid, B1 aWitteman, Jacqueline, C M1 aOrho-Melander, Marju1 aSiscovick, David, S1 aMeigs, James, B1 aFranks, Paul, W1 aDedoussis, George, V1 aMAGIC investigators uhttps://chs-nhlbi.org/node/130803030nas a2200517 4500008004100000022001400041245010800055210006900163260001300232300001100245490000700256520161100263653000901874653002801883653001601911653002701927653002201954653001101976653002201987653001102009653001702020653001402037653001102051653000902062653001602071653001302087653002402100653003202124653001702156653002602173653001802199653001402217100001502231700001602246700002402262700002202286700002002308700002002328700002002348700002102368700002002389700002402409700002102433700002202454856003602476 2011 eng d a1524-456300aVitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study.0 aVitamin D parathyroid hormone and sudden cardiac death results f c2011 Dec a1021-80 v583 aRecent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-OHD ≥20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 events per 1000 for PTH <65 pg/mL and 4 events per 1000 for PTH ≥65 pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.
10aAged10aCardiovascular Diseases10aComorbidity10aDeath, Sudden, Cardiac10aDiabetes Mellitus10aFemale10aFollow-Up Studies10aHumans10aHypertension10aIncidence10aKidney10aMale10aMiddle Aged10aMinerals10aParathyroid Hormone10aProportional Hazards Models10aRisk Factors10aSocioeconomic Factors10aUnited States10aVitamin D1 aDeo, Rajat1 aKatz, Ronit1 aShlipak, Michael, G1 aSotoodehnia, Nona1 aPsaty, Bruce, M1 aSarnak, Mark, J1 aFried, Linda, F1 aChonchol, Michel1 ade Boer, Ian, H1 aEnquobahrie, Daniel1 aSiscovick, David1 aKestenbaum, Bryan uhttps://chs-nhlbi.org/node/135005540nas a2201357 4500008004100000022001400041245007400055210006900129260001300198300001200211490000700223520169700230653001701927653001901944653001101963653001001974653003401984653001102018653000902029653002702038653003602065653002802101653003102129653002402160100001802184700001902202700003102221700001602252700002502268700001202293700002102305700002402326700002502350700001402375700001702389700001802406700001802424700001902442700002802461700001902489700002502508700002402533700002302557700002502580700002102605700001602626700002602642700001902668700002102687700001902708700002002727700002102747700002102768700002402789700001702813700002002830700001302850700002102863700002502884700001802909700002002927700003002947700002102977700002702998700002203025700002903047700002103076700002303097700001603120700002003136700001903156700002003175700002303195700002203218700002403240700002003264700001703284700002703301700003103328700002303359700002003382700002103402700001503423700002803438700001903466700002303485700002503508700002403533700001903557700001903576700001703595700002503612700002603637700001903663700002203682700002103704700002703725700002603752700002803778700002503806700002403831700002003855700002203875700002403897700002003921700002103941700002503962700002603987700002304013700001904036700002604055700002104081700002504102700001904127856003604146 2012 eng d a1523-468100aAssessment of gene-by-sex interaction effect on bone mineral density.0 aAssessment of genebysex interaction effect on bone mineral densi c2012 Oct a2051-640 v273 aSexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.
10aBone Density10aCohort Studies10aFemale10aGenes10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aReproducibility of Results10aSex Characteristics1 aLiu, Ching-Ti1 aEstrada, Karol1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aEvangelou, Evangelos1 aLi, Guo1 aMinster, Ryan, L1 aCarless, Melanie, A1 aKammerer, Candace, M1 aOei, Ling1 aZhou, Yanhua1 aAlonso, Nerea1 aDailiana, Zoe1 aEriksson, Joel1 aGarcía-Giralt, Natalia1 aGiroux, Sylvie1 aHusted, Lise, Bjerre1 aKhusainova, Rita, I1 aKoromila, Theodora1 aKung, Annie, Waichee1 aLewis, Joshua, R1 aMasi, Laura1 aMencej-Bedrac, Simona1 aNogues, Xavier1 aPatel, Millan, S1 aPrezelj, Janez1 aRichards, Brent1 aSham, Pak, Chung1 aSpector, Timothy1 aVandenput, Liesbeth1 aXiao, Su-Mei1 aZheng, Hou-Feng1 aZhu, Kun1 aBalcells, Susana1 aBrandi, Maria, Luisa1 aFrost, Morten1 aGoltzman, David1 aGonzález-Macías, Jesús1 aKarlsson, Magnus1 aKhusnutdinova, Elza, K1 aKollia, Panagoula1 aLangdahl, Bente, Lomholt1 aLjunggren, Osten1 aLorentzon, Mattias1 aMarc, Janja1 aMellström, Dan1 aOhlsson, Claes1 aOlmos, José, M1 aRalston, Stuart, H1 aRiancho, José, A1 aRousseau, François1 aUrreizti, Roser1 aVan Hul, Wim1 aZarrabeitia, María, T1 aCastano-Betancourt, Martha1 aDemissie, Serkalem1 aGrundberg, Elin1 aHerrera, Lizbeth1 aKwan, Tony1 aMedina-Gómez, Carolina1 aPastinen, Tomi1 aSigurdsson, Gunnar1 aThorleifsson, Gudmar1 aVanmeurs, Joyce, Bj1 aBlangero, John1 aHofman, Albert1 aLiu, Yongmei1 aMitchell, Braxton, D1 aO'Connell, Jeffrey, R1 aOostra, Ben, A1 aRotter, Jerome, I1 aStefansson, Kari1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aThorsteinsdottir, Unnur1 aTylavsky, Frances, A1 aUitterlinden, Andre1 aCauley, Jane, A1 aHarris, Tamara, B1 aIoannidis, John, Pa1 aPsaty, Bruce, M1 aRobbins, John, A1 aZillikens, Carola, M1 aVanduijn, Cornelia, M1 aPrince, Richard, L1 aKarasik, David1 aRivadeneira, Fernando1 aKiel, Douglas, P1 aCupples, Adrienne, L1 aHsu, Yi-Hsiang uhttps://chs-nhlbi.org/node/155607377nas a2201945 4500008004100000022001400041245014700055210006900202260001600271300001100287490000600298520192200304653001002226653001602236653000902252653002202261653001202283653002502295653003102320653001902351653004202370653001102412653003402423653001302457653001902470653001102489653002002500653000902520653001602529653003302545653001402578653003602592653001702628653001602645100002402661700002202685700002002707700001602727700002102743700001702764700002002781700002002801700002002821700001902841700001702860700002202877700002302899700002502922700001702947700002202964700002502986700002003011700001903031700002303050700002203073700001903095700002103114700001803135700002203153700001503175700002203190700002203212700002003234700002503254700002103279700002403300700001603324700001803340700002703358700002103385700002503406700001903431700001803450700002603468700002103494700002303515700001903538700002403557700002503581700002003606700001803626700003003644700002203674700002003696700002103716700002203737700001903759700002003778700001803798700002403816700001903840700001903859700001803878700002703896700001803923700002303941700002803964700002103992700001604013700001904029700001704048700002304065700001804088700002104106700001804127700002004145700001804165700002904183700002104212700002004233700003004253700001904283700002304302700002304325700001904348700002004367700002104387700001404408700002604422700002204448700002204470700002204492700002104514700002004535700002604555700002804581700001904609700002304628700001904651700002104670700002004691700001804711700002204729700001604751700002904767700002404796700002104820700002004841700001904861700002504880700002204905700002404927700002504951700001704976700002004993700002005013700001905033700001605052700002305068700002005091700002305111700001705134700002005151700002205171700002105193700003005214700001705244700002205261700002305283700002105306700001905327700002505346700002405371856003605395 2012 eng d a1942-326800aAssociation between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.0 aAssociation between chromosome 9p21 variants and the anklebrachi c2012 Feb 01 a100-120 v53 aBACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).
CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
10aAdult10aAge Factors10aAged10aAged, 80 and over10aAlleles10aAnkle Brachial Index10aChromosomes, Human, Pair 910aCohort Studies10aCyclin-Dependent Kinase Inhibitor p1510aFemale10aGenome-Wide Association Study10aGenotype10aHapMap Project10aHumans10aLogistic Models10aMale10aMiddle Aged10aPeripheral Vascular Diseases10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aSex Factors1 aMurabito, Joanne, M1 aWhite, Charles, C1 aKavousi, Maryam1 aSun, Yan, V1 aFeitosa, Mary, F1 aNambi, Vijay1 aLamina, Claudia1 aSchillert, Arne1 aCoassin, Stefan1 aBis, Joshua, C1 aBroer, Linda1 aCrawford, Dana, C1 aFranceschini, Nora1 aFrikke-Schmidt, Ruth1 aHaun, Margot1 aHolewijn, Suzanne1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aKiechl, Stefan1 aKollerits, Barbara1 aMontasser, May, E1 aNolte, Ilja, M1 aRudock, Megan, E1 aSenft, Andrea1 aTeumer, Alexander1 aHarst, Pim1 aVitart, Veronique1 aWaite, Lindsay, L1 aWood, Andrew, R1 aWassel, Christina, L1 aAbsher, Devin, M1 aAllison, Matthew, A1 aAmin, Najaf1 aArnold, Alice1 aAsselbergs, Folkert, W1 aAulchenko, Yurii1 aBandinelli, Stefania1 aBarbalic, Maja1 aBoban, Mladen1 aBrown-Gentry, Kristin1 aCouper, David, J1 aCriqui, Michael, H1 aDehghan, Abbas1 aHeijer, Martin, den1 aDieplinger, Benjamin1 aDing, Jingzhong1 aDörr, Marcus1 aEspinola-Klein, Christine1 aFelix, Stephan, B1 aFerrucci, Luigi1 aFolsom, Aaron, R1 aFraedrich, Gustav1 aGibson, Quince1 aGoodloe, Robert1 aGunjaca, Grgo1 aHaltmayer, Meinhard1 aHeiss, Gerardo1 aHofman, Albert1 aKieback, Arne1 aKiemeney, Lambertus, A1 aKolcic, Ivana1 aKullo, Iftikhar, J1 aKritchevsky, Stephen, B1 aLackner, Karl, J1 aLi, Xiaohui1 aLieb, Wolfgang1 aLohman, Kurt1 aMeisinger, Christa1 aMelzer, David1 aMohler, Emile, R1 aMudnic, Ivana1 aMueller, Thomas1 aNavis, Gerjan1 aOberhollenzer, Friedrich1 aOlin, Jeffrey, W1 aO'Connell, Jeff1 aO'Donnell, Christopher, J1 aPalmas, Walter1 aPenninx, Brenda, W1 aPetersmann, Astrid1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRantner, Barbara1 aRice, Ken1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSeldenrijk, Adrie1 aStadler, Marietta1 aSummerer, Monika1 aTanaka, Toshiko1 aTybjaerg-Hansen, Anne1 aUitterlinden, André, G1 aGilst, Wiek, H1 aVermeulen, Sita, H1 aWild, Sarah, H1 aWild, Philipp, S1 aWilleit, Johann1 aZeller, Tanja1 aZemunik, Tatijana1 aZgaga, Lina1 aAssimes, Themistocles, L1 aBlankenberg, Stefan1 aBoerwinkle, Eric1 aCampbell, Harry1 aCooke, John, P1 ade Graaf, Jacqueline1 aHerrington, David1 aKardia, Sharon, L R1 aMitchell, Braxton, D1 aMurray, Anna1 aMünzel, Thomas1 aNewman, Anne, B1 aOostra, Ben, A1 aRudan, Igor1 aShuldiner, Alan, R1 aSnieder, Harold1 aDuijn, Cornelia, M1 aVölker, Uwe1 aWright, Alan, F1 aWichmann, H-Erich1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aLiu, Yongmei1 aHayward, Caroline1 aBorecki, Ingrid, B1 aZiegler, Andreas1 aNorth, Kari, E1 aCupples, Adrienne, L1 aKronenberg, Florian uhttps://chs-nhlbi.org/node/135903102nas a2200565 4500008004100000022001400041245014200055210006900197260000900266300001100275490000600286520151100292653001001803653002201813653000901835653001201844653004001856653001101896653003201907653001701939653003801956653001301994653001102007653000902018653001602027653001402043653003602057653002002093653002902113100002102142700002002163700001502183700002102198700001402219700002202233700001602255700001702271700002002288700002402308700001902332700002002351700002502371700001102396700002202407700001702429700001702446700001802463700001902481856003602500 2012 eng d a1932-620300aAssociation of genetic loci with sleep apnea in European Americans and African-Americans: the Candidate Gene Association Resource (CARe).0 aAssociation of genetic loci with sleep apnea in European America c2012 ae488360 v73 aAlthough obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study.Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×10(-6). Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts.Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.
10aAdult10aAfrican Americans10aAged10aAlleles10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenotype10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aPolysomnography10aSleep Apnea, Obstructive1 aPatel, Sanjay, R1 aGoodloe, Robert1 aDe, Gourab1 aKowgier, Matthew1 aWeng, Jia1 aBuxbaum, Sarah, G1 aCade, Brian1 aFulop, Tibor1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aHillman, David1 aLarkin, Emma, K1 aLauderdale, Diane, S1 aLi, Li1 aMukherjee, Sutapa1 aPalmer, Lyle1 aZee, Phyllis1 aZhu, Xiaofeng1 aRedline, Susan uhttps://chs-nhlbi.org/node/617803599nas a2200457 4500008004100000022001400041245008200055210006900137260001600206300001100222490000800233520234700241653001002588653000902598653002202607653002002629653001602649653002802665653001902693653003002712653001102742653001102753653002502764653000902789653001602798653001202814653001502826653001802841100002702859700002902886700001902915700001902934700002102953700002202974700002302996700001503019700002403034700002903058700001803087856003603105 2012 eng d a1538-359800aAssociation of weight status with mortality in adults with incident diabetes.0 aAssociation of weight status with mortality in adults with incid c2012 Aug 08 a581-900 v3083 aCONTEXT: Type 2 diabetes in normal-weight adults (body mass index [BMI] <25) is a representation of the metabolically obese normal-weight phenotype with unknown mortality consequences.
OBJECTIVE: To test the association of weight status with mortality in adults with new-onset diabetes in order to minimize the influence of diabetes duration and voluntary weight loss on mortality.
DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 5 longitudinal cohort studies: Atherosclerosis Risk in Communities study, 1990-2006; Cardiovascular Health Study, 1992-2008; Coronary Artery Risk Development in Young Adults, 1987-2011; Framingham Offspring Study, 1979-2007; and Multi-Ethnic Study of Atherosclerosis, 2002-2011. A total of 2625 participants with incident diabetes contributed 27,125 person-years of follow-up. Included were men and women (age >40 years) who developed incident diabetes based on fasting glucose 126 mg/dL or greater or newly initiated diabetes medication and who had concurrent measurements of BMI. Participants were classified as normal weight if their BMI was 18.5 to 24.99 or overweight/obese if BMI was 25 or greater.
MAIN OUTCOME MEASURES: Total, cardiovascular, and noncardiovascular mortality.
RESULTS: The proportion of adults who were normal weight at the time of incident diabetes ranged from 9% to 21% (overall 12%). During follow-up, 449 participants died: 178 from cardiovascular causes and 253 from noncardiovascular causes (18 were not classified). The rates of total, cardiovascular, and noncardiovascular mortality were higher in normal-weight participants (284.8, 99.8, and 198.1 per 10,000 person-years, respectively) than in overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). After adjustment for demographic characteristics and blood pressure, lipid levels, waist circumference, and smoking status, hazard ratios comparing normal-weight participants with overweight/obese participants for total, cardiovascular, and noncardiovascular mortality were 2.08 (95% CI, 1.52-2.85), 1.52 (95% CI, 0.89-2.58), and 2.32 (95% CI, 1.55-3.48), respectively.
CONCLUSION: Adults who were normal weight at the time of incident diabetes had higher mortality than adults who are overweight or obese.
10aAdult10aAged10aAged, 80 and over10aBody Mass Index10aBody Weight10aCardiovascular Diseases10aCause of Death10aDiabetes Mellitus, Type 210aFemale10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aObesity10aOverweight10aUnited States1 aCarnethon, Mercedes, R1 aDe Chavez, Peter, John D1 aBiggs, Mary, L1 aLewis, Cora, E1 aPankow, James, S1 aBertoni, Alain, G1 aGolden, Sherita, H1 aLiu, Kiang1 aMukamal, Kenneth, J1 aCampbell-Jenkins, Brenda1 aDyer, Alan, R uhttps://chs-nhlbi.org/node/140203420nas a2200517 4500008004100000022001400041245023700055210006900292260001600361300001000377490000600387520182700393653000902220653002202229653002802251653002102279653002102300653004002321653001102361653002502372653003402397653001302431653001102444653000902455653001602464653003602480653001702516653001102533653001802544100001902562700002102581700002002602700002302622700001802645700001902663700002302682700002302705700001402728700002002742700001602762700002002778700001902798700002502817700002402842856003602866 2012 eng d a1942-326800aAssociations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study.0 aAssociations between incident ischemic stroke events and stroke c2012 Apr 01 a210-60 v53 aBACKGROUND: Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.
METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomics and Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were significantly associated with [corrected] IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.
CONCLUSIONS: Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aFemale10aGenetics, Population10aGenome-Wide Association Study10aGenomics10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke10aTriglycerides1 aCarty, Cara, L1 aBůzková, Petra1 aFornage, Myriam1 aFranceschini, Nora1 aCole, Shelley1 aHeiss, Gerardo1 aHindorff, Lucia, A1 aHoward, Barbara, V1 aMann, Sue1 aMartin, Lisa, W1 aZhang, Ying1 aMatise, Tara, C1 aPrentice, Ross1 aReiner, Alexander, P1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/137103754nas a2200493 4500008004100000022001400041245014600055210006900201260001600270300001200286490000800298520227800306653000902584653001602593653002802609653001902637653002702656653001102683653003102694653001102725653002802736653000902764653001602773653001702789100002102806700002502827700001902852700002002871700001902891700003202910700001802942700002302960700001902983700002303002700002203025700002603047700002403073700001803097700002103115700001803136700002203154710004803176856003603224 2012 eng d a1474-547X00aAssociations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.0 aAssociations of kidney disease measures with mortality and endst c2012 Nov 10 a1662-730 v3803 aBACKGROUND: Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown.
METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes.
FINDINGS: We analysed data for 1,024,977 participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75,306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21,237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2-1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m(2) [vs 95 mL/min per 1·73 m(2)], HR 1·35; 95% CI 1·18-1·55; vs 1·33; 1·19-1·48 and at ACR 30 mg/g [vs 5 mg/g], 1·50; 1·35-1·65 vs 1·52; 1·38-1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts.
INTERPRETATION: Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes.
FUNDING: US National Kidney Foundation.
10aAged10aAlbuminuria10aCardiovascular Diseases10aCause of Death10aDiabetic Nephropathies10aFemale10aGlomerular Filtration Rate10aHumans10aKidney Failure, Chronic10aMale10aMiddle Aged10aRisk Factors1 aFox, Caroline, S1 aMatsushita, Kunihiro1 aWoodward, Mark1 aBilo, Henk, J G1 aChalmers, John1 aHeerspink, Hiddo, J Lambers1 aLee, Brian, J1 aPerkins, Robert, M1 aRossing, Peter1 aSairenchi, Toshimi1 aTonelli, Marcello1 aVassalotti, Joseph, A1 aYamagishi, Kazumasa1 aCoresh, Josef1 ade Jong, Paul, E1 aWen, Chi-Pang1 aNelson, Robert, G1 aChronic Kidney Disease Prognosis Consortium uhttps://chs-nhlbi.org/node/608601592nas a2200265 4500008004100000022001400041245010100055210006900156260001600225300001200241490000700253520078800260653001801048653001901066653002501085653001101110653002401121653002601145653003001171100002801201700002201229700001901251700002001270856003601290 2012 eng d a1097-025800aBootstrap-based inference on the difference in the means of two correlated functional processes.0 aBootstrapbased inference on the difference in the means of two c c2012 Nov 20 a3223-400 v313 aWe propose nonparametric inference methods on the mean difference between two correlated functional processes. We compare methods that (1) incorporate different levels of smoothing of the mean and covariance; (2) preserve the sampling design; and (3) use parametric and nonparametric estimation of the mean functions. We apply our method to estimating the mean difference between average normalized δ power of sleep electroencephalograms for 51 subjects with severe sleep apnea and 51 matched controls in the first 4 h after sleep onset. We obtain data from the Sleep Heart Health Study, the largest community cohort study of sleep. Although methods are applied to a single case study, they can be applied to a large number of studies that have correlated functional data.
10aBiostatistics10aCohort Studies10aConfidence Intervals10aHumans10aModels, Statistical10aSleep Apnea Syndromes10aStatistics, Nonparametric1 aCrainiceanu, Ciprian, M1 aStaicu, Ana-Maria1 aRay, Shubankar1 aPunjabi, Naresh uhttps://chs-nhlbi.org/node/154603117nas a2200469 4500008004100000022001400041245009100055210006900146260001300215300001100228490000700239520180300246653000902049653002502058653004302083653002102126653001902147653003702166653001402203653002402217653001102241653001502252653002002267653001102287653002502298653000902323653002302332653002702355653002202382653000902404653002002413100001602433700001802449700002102467700001502488700002202503700001802525700002402543700002002567700002402587856003602611 2012 eng d a1531-825700aCardiovascular physiology in premotor Parkinson's disease: a neuroepidemiologic study.0 aCardiovascular physiology in premotor Parkinsons disease a neuro c2012 Jul a988-950 v273 aChanges in cardiovascular physiology in Parkinson's disease (PD) are common and may occur prior to diagnostic parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability, and carotid stenosis with the risk of PD diagnosis in the Cardiovascular Health Study, a community-based cohort of older adults. ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24-hour Holter monitoring), and any carotid stenosis (≥1%) by ultrasound were modeled as primary predictors of incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least 1 of the following: self-report, antiparkinsonian medication use, and ICD-9. If unadjusted models were significant, they were adjusted or stratified by age, sex, and smoking status, and those in which predictors were still significant (P ≤ .05) were also adjusted for race, diabetes, total cholesterol, low-density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke, and C-reactive protein. Of 5888 participants, 154 incident PD cases were identified over 14 years of follow-up. After adjusting models with all covariates, those with any ECG abnormality (odds ratio [OR], 1.45; 95% CI, 1.02-2.07; P = .04) or any carotid stenosis (OR, 2.40; 95% CI, 1.40-4.09; P = .001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors. This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential premotor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset.
10aAged10aAntiparkinson Agents10aCardiovascular Physiological Phenomena10aCarotid Stenosis10aCohort Studies10aData Interpretation, Statistical10aDizziness10aElectrocardiography10aFemale10aHeart Rate10aHospitalization10aHumans10aLongitudinal Studies10aMale10aMovement Disorders10aNeurologic Examination10aParkinson Disease10aRisk10aUltrasonography1 aJain, Samay1 aTon, Thanh, G1 aPerera, Subashan1 aZheng, Yan1 aStein, Phyllis, K1 aThacker, Evan1 aStrotmeyer, Elsa, S1 aNewman, Anne, B1 aLongstreth, Will, T uhttps://chs-nhlbi.org/node/139103965nas a2200493 4500008004100000022001400041245019200055210006900247260001600316300001200332490000800344520243000352653002802782653003502810653002402845653002202869653001102891653002602902653001402928653002002942653001102962100002402973700002102997700002003018700002603038700001903064700002603083700001703109700002303126700002603149700002803175700001903203700002003222700002303242700001503265700002103280700002803301700001203329700002503341700002103366700002303387710002503410856003603435 2012 eng d a1474-547X00aCarotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data.0 aCarotid intimamedia thickness progression to predict cardiovascu c2012 Jun 02 a2053-620 v3793 aBACKGROUND: Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association.
METHODS: We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis.
FINDINGS: Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02).
INTERPRETATION: The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.
FUNDING: Deutsche Forschungsgemeinschaft.
10aCardiovascular Diseases10aCarotid Intima-Media Thickness10aDisease Progression10aFollow-Up Studies10aHumans10aMyocardial Infarction10aPrognosis10aRisk Assessment10aStroke1 aLorenz, Matthias, W1 aPolak, Joseph, F1 aKavousi, Maryam1 aMathiesen, Ellisiv, B1 aVölzke, Henry1 aTuomainen, Tomi-Pekka1 aSander, Dirk1 aPlichart, Matthieu1 aCatapano, Alberico, L1 aRobertson, Christine, M1 aKiechl, Stefan1 aRundek, Tatjana1 aDesvarieux, Moïse1 aLind, Lars1 aSchmid, Caroline1 aDasMahapatra, Pronabesh1 aGao, Lu1 aZiegelbauer, Kathrin1 aBots, Michiel, L1 aThompson, Simon, G1 aPROG-IMT Study Group uhttps://chs-nhlbi.org/node/138203276nas a2200541 4500008004100000022001400041245008700055210006900142260001300211300001100224490000600235520180000241653001602041653000902057653002202066653001502088653002002103653001502123653002202138653001102160653003102171653002702202653001902229653001102248653002402259653001402283653001202297653002302309653002802332653001102360653002002371653001802391653000902409653003202418653002002450653001702470653001802487100001502505700003002520700001902550700001902569700002402588700002002612700002202632700002402654700002002678856003602698 2012 eng d a1555-905X00aChronic kidney disease, insulin resistance, and incident diabetes in older adults.0 aChronic kidney disease insulin resistance and incident diabetes c2012 Apr a588-940 v73 aBACKGROUND AND OBJECTIVES: Insulin resistance is a complication of advanced CKD. Insulin resistance is less well characterized in earlier stages of CKD. The response of the pancreatic β cell, effects on glucose tolerance, and risk of diabetes are not clear.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Health Study included 4680 adults without baseline diabetes. The Chronic Kidney Disease Epidemiology Collaboration creatinine equation was used to obtain the estimated GFR (eGFR). Insulin resistance was evaluated as fasting insulin concentration. The insulin sensitivity index, β cell function, and glucose tolerance were assessed by oral glucose tolerance testing. Incident diabetes was defined as fasting glucose ≥126 mg/dl, nonfasting glucose ≥200 mg/dl, or use of glucose-lowering medications.
RESULTS: Mean age was 72.5 years (range, 65-98 years). Mean eGFR was 72.2 (SD 17.1) ml/min per 1.73 m(2). After adjustment, each 10 ml/min per 1.73 m(2) lower eGFR was associated with a 2.2% higher fasting insulin concentration (95% confidence interval [CI], 1.4%, 2.9%; P<0.001) and a 1.1% lower insulin sensitivity index (95% CI, 0.03%, 2.2%; P=0.04). Surprisingly, eGFR was associated with an augmented β cell function index (P<0.001), lower 2-hour glucose concentration (P=0.002), and decreased risk of glucose intolerance (P=0.006). Over a median 12 years' follow-up, 437 participants (9.3%) developed diabetes. eGFR was not associated with the risk of incident diabetes.
CONCLUSIONS: Among older adults, lower eGFR was associated with insulin resistance. However, with lower eGFR, β cell function was appropriately augmented and risks of impaired glucose tolerance and incident diabetes were not increased.
10aAge Factors10aAged10aAged, 80 and over10aBiomarkers10aChronic Disease10aCreatinine10aDiabetes Mellitus10aFemale10aGlomerular Filtration Rate10aGlucose Tolerance Test10aHealth Surveys10aHumans10aHypoglycemic Agents10aIncidence10aInsulin10aInsulin Resistance10aInsulin-Secreting Cells10aKidney10aKidney Diseases10aLinear Models10aMale10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aUnited States1 aPham, Hien1 aRobinson-Cohen, Cassianne1 aBiggs, Mary, L1 aIx, Joachim, H1 aMukamal, Kenneth, J1 aFried, Linda, F1 aKestenbaum, Bryan1 aSiscovick, David, S1 ade Boer, Ian, H uhttps://chs-nhlbi.org/node/136803078nas a2200517 4500008004100000022001400041245013000055210006900185260001300254300001000267490000700277520169000284653001001974653000901984653001801993653001902011653003002030653002402060653001202084653001102096653002202107653001302129653001102142653000902153653001602162653002002178653003602198653003202234653002402266653000902290100001802299700001302317700001302330700001502343700001602358700001802374700001302392700001702405700001702422700001602439700002002455700001702475700001502492700001702507856003602524 2012 eng d a1432-042800aCommon genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism.0 aCommon genetic variants differentially influence the transition c2012 Feb a331-90 v553 aAIMS/HYPOTHESIS: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes.
METHODS: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n = 16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype.
RESULTS: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p = 1 × 10(-4)), nominally greater at GCK and SLC30A8 (p < 0.05) and nominally smaller at IGF2BP2 (p = 0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings.
CONCLUSIONS/INTERPRETATION: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.
10aAdult10aAged10aBlood Glucose10aCohort Studies10aDiabetes Mellitus, Type 210aDisease Progression10aFasting10aFemale10aGenetic Variation10aGenotype10aHumans10aMale10aMiddle Aged10aModels, Genetic10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aRegression Analysis10aRisk1 aWalford, G, A1 aGreen, T1 aNeale, B1 aIsakova, T1 aRotter, J I1 aGrant, S, F A1 aFox, C S1 aPankow, J, S1 aWilson, J, G1 aMeigs, J, B1 aSiscovick, D, S1 aBowden, D, W1 aDaly, M, J1 aFlorez, J, C uhttps://chs-nhlbi.org/node/156104730nas a2200541 4500008004100000022001400041245013100055210006900186260001600255300001200271490000800283520307700291653003903368653000903407653001503416653003703431653002803468653001903496653003203515653004003547653001103587653003103598653001103629653002803640653000903668653001603677653002403693653002003717653001603737100002503753700002703778700001903805700002603824700002103850700001703871700002703888700001903915700002003934700002203954700002203976700001803998700001804016700002304034700002604057700002104083710004804104856003604152 2012 eng d a1538-359800aComparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate.0 aComparison of risk prediction using the CKDEPI equation and the c2012 May 09 a1941-510 v3073 aCONTEXT: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation more accurately estimates glomerular filtration rate (GFR) than the Modification of Diet in Renal Disease (MDRD) Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking.
OBJECTIVE: To evaluate risk implications of estimated GFR using the CKD-EPI equation compared with the MDRD Study equation in populations with a broad range of demographic and clinical characteristics.
DESIGN, SETTING, AND PARTICIPANTS: A meta-analysis of data from 1.1 million adults (aged ≥ 18 years) from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts. Data transfer and analyses were conducted between March 2011 and March 2012.
MAIN OUTCOME MEASURES: All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years).
RESULTS: Estimated GFR was classified into 6 categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m(2)) by both equations. Compared with the MDRD Study equation, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR <60 mL/min/1.73 m(2)) was reduced from 8.7% to 6.3%. In estimated GFR of 45 to 59 mL/min/1.73 m(2) by the MDRD Study equation, 34.7% of participants were reclassified to estimated GFR of 60 to 89 mL/min/1.73 m(2) by the CKD-EPI equation and had lower incidence rates (per 1000 person-years) for the outcomes of interest (9.9 vs 34.5 for all-cause mortality, 2.7 vs 13.0 for cardiovascular mortality, and 0.5 vs 0.8 for ESRD) compared with those not reclassified. The corresponding adjusted hazard ratios were 0.80 (95% CI, 0.74-0.86) for all-cause mortality, 0.73 (95% CI, 0.65-0.82) for cardiovascular mortality, and 0.49 (95% CI, 0.27-0.88) for ESRD. Similar findings were observed in other estimated GFR categories by the MDRD Study equation. Net reclassification improvement based on estimated GFR categories was significantly positive for all outcomes (range, 0.06-0.13; all P < .001). Net reclassification improvement was similarly positive in most subgroups defined by age (<65 years and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in the high-risk and CKD cohorts were largely consistent with the general population cohorts.
CONCLUSION: The CKD-EPI equation classified fewer individuals as having CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.
10aAfrican Continental Ancestry Group10aAged10aAlgorithms10aAsian Continental Ancestry Group10aCardiovascular Diseases10aCohort Studies10aDecision Support Techniques10aEuropean Continental Ancestry Group10aFemale10aGlomerular Filtration Rate10aHumans10aKidney Failure, Chronic10aMale10aMiddle Aged10aModels, Theoretical10aRisk Assessment10aSex Factors1 aMatsushita, Kunihiro1 aMahmoodi, Bakhtawar, K1 aWoodward, Mark1 aEmberson, Jonathan, R1 aJafar, Tazeen, H1 aJee, Sun, Ha1 aPolkinghorne, Kevan, R1 aShankar, Anoop1 aSmith, David, H1 aTonelli, Marcello1 aWarnock, David, G1 aWen, Chi-Pang1 aCoresh, Josef1 aGansevoort, Ron, T1 aHemmelgarn, Brenda, R1 aLevey, Andrew, S1 aChronic Kidney Disease Prognosis Consortium uhttps://chs-nhlbi.org/node/138503141nas a2200685 4500008004100000022001400041245018100055210006900236260001300305300001100318490000700329520115600336653001001492653000901502653002201511653001201533653003001545653001101575653003801586653003401624653001301658653001101671653000901682653001701691653001601708653002201724653000901746653001701755100002701772700002501799700002201824700002101846700002201867700001501889700001901904700002301923700002401946700002301970700002401993700002002017700002502037700001902062700002302081700001502104700002102119700002002140700001802160700002402178700002602202700001902228700002202247700002302269700002302292700001902315700001902334700002202353700002302375700002102398856003602419 2012 eng d a1939-327X00aConsistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium.0 aConsistent directions of effect for established type 2 diabetes c2012 Jun a1642-70 v613 aCommon genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.
10aAdult10aAged10aAged, 80 and over10aAlleles10aDiabetes Mellitus, Type 210aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMetagenomics10aMiddle Aged10aPopulation Groups10aRisk10aRisk Factors1 aHaiman, Christopher, A1 aFesinmeyer, Megan, D1 aSpencer, Kylee, L1 aBůzková, Petra1 aVoruganti, Saroja1 aWan, Peggy1 aHaessler, Jeff1 aFranceschini, Nora1 aMonroe, Kristine, R1 aHoward, Barbara, V1 aJackson, Rebecca, D1 aFlorez, Jose, C1 aKolonel, Laurence, N1 aBuyske, Steven1 aGoodloe, Robert, J1 aLiu, Simin1 aManson, JoAnn, E1 aMeigs, James, B1 aWaters, Kevin1 aMukamal, Kenneth, J1 aPendergrass, Sarah, A1 aShrader, Peter1 aWilkens, Lynne, R1 aHindorff, Lucia, A1 aAmbite, Jose, Luis1 aNorth, Kari, E1 aPeters, Ulrike1 aCrawford, Dana, C1 aLe Marchand, Loïc1 aPankow, James, S uhttps://chs-nhlbi.org/node/663302996nas a2200433 4500008004100000022001400041245013100055210006900186260001300255300001100268490000700279520163600286653003901922653000901961653002201970653002801992653004002020653001102060653002202071653001102093653004902104653004902153653003302202653002502235653000902260653001402269653003002283653001702313100002202330700002102352700002102373700002502394700002202419700002102441700002102462700002302483700002002506856003602526 2012 eng d a1945-719700aDecline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study.0 aDecline in circulating insulinlike growth factors and mortality c2012 Jun a1970-60 v973 aBACKGROUND: The association between changes in IGF-I and IGF binding protein (IGFBP) levels and mortality in older adults is unknown.
STUDY DESIGN: Participants were 997 persons 77 to 100 yr old enrolled in the Cardiovascular Health Study All Stars Study. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were assessed at two study examinations (1996-1997 and 2005-2006). Mortality was assessed between 2006 and 2010.
RESULTS: Cumulative mortality (CM) was similar among individuals who had at least 10% decreases over time in IGF-I levels (CM = 29.6%), individuals who had at least 10% increases over time in IGF-I levels (CM = 24.7%), and individuals who had IGF-I levels remaining within ±10% over time (CM = 23.5%). Adjusted for age, sex, race, diabetes, body mass index, creatinine, albumin, and C-reactive protein, decreasing IGF-I level had no significant association with overall cancer mortality or noncancer mortality. Levels of IGFBP-1 increased markedly over time by 38% (median). Individuals with the largest increases in IGFBP-1 level over time had significantly increased risk of mortality. The adjusted hazard ratio per sd of IGFBP-1 change was 1.40 for overall cancer mortality (95% confidence interval = 1.10, 1.77; P = 0.01) and 1.14 for noncancer mortality (95% confidence interval = 1.02, 1.27; P = 0.02). Changes in IGFBP-3 levels were not significantly associated with mortality.
CONCLUSION: Among older adults, decreasing IGF-I level over time does not predict subsequent all-cause mortality, whereas increasing IGFBP-1 predicts increased risk of mortality.
10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHumans10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aLongitudinal Studies10aMale10aMortality10aPredictive Value of Tests10aRisk Factors1 aKaplan, Robert, C1 aBůzková, Petra1 aCappola, Anne, R1 aStrickler, Howard, D1 aMcGinn, Aileen, P1 aMercer, Laina, D1 aArnold, Alice, M1 aPollak, Michael, N1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/137403876nas a2200469 4500008004100000022001400041245016300055210006900218260001600287300001100303490000800314520247600322653000902798653002202807653001502829653001902844653002102863653004002884653001102924653001102935653001402946653000902960653002402969653002602993653001603019653002403035653002003059653001703079653001803096100002303114700002603137700002003163700002503183700002403208700002003232700001903252700002203271700002003293700002703313700003003340856003603370 2012 eng d a1539-370400aDevelopment and validation of a coronary risk prediction model for older U.S. and European persons in the Cardiovascular Health Study and the Rotterdam Study.0 aDevelopment and validation of a coronary risk prediction model f c2012 Sep 18 a389-970 v1573 aBACKGROUND: Risk scores for prediction of coronary heart disease (CHD) in older adults are needed.
OBJECTIVE: To develop a sex-specific CHD risk prediction model for older adults that accounts for competing risks for death.
DESIGN: 2 observational cohort studies, using data from 4946 participants in the Cardiovascular Health Study (CHS) and 4303 participants in the Rotterdam Study (RS).
SETTING: Community settings in the United States (CHS) and Rotterdam, the Netherlands (RS).
PARTICIPANTS: Persons aged 65 years or older who were free of cardiovascular disease.
MEASUREMENTS: A composite of nonfatal myocardial infarction and coronary death.
RESULTS: During a median follow-up of 16.5 and 14.9 years, 1166 CHS and 698 RS participants had CHD events, respectively. Deaths from noncoronary causes largely exceeded the number of CHD events, complicating accurate CHD risk predictions. The prediction model had moderate ability to discriminate between events and nonevents (c-statistic, 0.63 in both U.S. and European men and 0.67 and 0.68 in U.S. and European women). The model was well-calibrated; predicted risks were in good agreement with observed risks. Compared with the Framingham point scores, the prediction model classified elderly U.S. persons into higher risk categories but elderly European persons into lower risk categories. Differences in classification accuracy were not consistent and depended on cohort and sex. Adding newer cardiovascular risk markers to the model did not substantially improve performance.
LIMITATION: The model may be less applicable in nonwhite populations, and the comparison Framingham model was not designed for adults older than 79 years.
CONCLUSION: A CHD risk prediction model that accounts for deaths from noncoronary causes among older adults provided well-calibrated risk estimates but was not substantially more accurate than Framingham point scores. Moreover, adding newer risk markers did not improve accuracy. These findings emphasize the difficulties of predicting CHD risk in elderly persons and the need to improve these predictions.
PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; The Netherlands Organisation for Scientific Research; and the Netherlands Organisation for Health Research and Development.
10aAged10aAged, 80 and over10aAlgorithms10aCause of Death10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aHumans10aIncidence10aMale10aModels, Statistical10aMultivariate Analysis10aNetherlands10aProspective Studies10aRisk Assessment10aRisk Factors10aUnited States1 aKoller, Michael, T1 aLeening, Maarten, J G1 aWolbers, Marcel1 aSteyerberg, Ewout, W1 aHunink, M, G Myriam1 aSchoop, Rotraut1 aHofman, Albert1 aBucher, Heiner, C1 aPsaty, Bruce, M1 aLloyd-Jones, Donald, M1 aWitteman, Jacqueline, C M uhttps://chs-nhlbi.org/node/140804113nas a2200817 4500008004100000022001400041245022200055210006900277260001300346300001100359490000700370520161000377653005101987653000902038653002802047653002102075653001102096653001702107653003402124653001102158653000902169653001602178653002202194653003602216100002102252700001902273700001902292700001902311700001902330700001802349700001302367700002302380700002802403700002002431700002502451700002402476700002102500700002602521700002202547700002602569700002302595700002002618700002102638700002402659700002702683700001902710700002202729700002302751700002402774700002002798700002402818700002302842700003202865700002002897700002202917700002102939700001902960700001802979700001802997700002603015700002203041700002203063700002803085700002103113700003003134700002203164700002103186700002403207700002803231856003603259 2012 eng d a1522-964500aEight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies.0 aEight genetic loci associated with variation in lipoproteinassoc c2012 Jan a238-510 v333 aAIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.
CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aCoronary Artery Disease10aCoronary Disease10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPhospholipases A210aPolymorphism, Single Nucleotide1 aGrallert, Harald1 aDupuis, Josée1 aBis, Joshua, C1 aDehghan, Abbas1 aBarbalic, Maja1 aBaumert, Jens1 aLu, Chen1 aSmith, Nicholas, L1 aUitterlinden, André, G1 aRoberts, Robert1 aKhuseyinova, Natalie1 aSchnabel, Renate, B1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aHoogeveen, Ron, C1 aFontes, João, Daniel1 aMeisinger, Christa1 aKeaney, John, F1 aLemaitre, Rozenn1 aAulchenko, Yurii, S1 aVasan, Ramachandran, S1 aEllis, Stephen1 aHazen, Stanley, L1 aDuijn, Cornelia, M1 aNelson, Jeanenne, J1 aMärz, Winfried1 aSchunkert, Heribert1 aMcPherson, Ruth, M1 aStirnadel-Farrant, Heide, A1 aPsaty, Bruce, M1 aGieger, Christian1 aSiscovick, David1 aHofman, Albert1 aIllig, Thomas1 aCushman, Mary1 aYamamoto, Jennifer, F1 aRotter, Jerome, I1 aLarson, Martin, G1 aStewart, Alexandre, F R1 aBoerwinkle, Eric1 aWitteman, Jacqueline, C M1 aTracy, Russell, P1 aKoenig, Wolfgang1 aBenjamin, Emelia, J1 aBallantyne, Christie, M uhttps://chs-nhlbi.org/node/134103528nas a2200721 4500008004100000022001400041245014600055210006900201260000900270300001100279490000600290520139200296653002201688653002801710653004001738653002101778653002101799653002301820653001901843653001901862653003401881653001301915653001101928653002301939653003601962653002801998100001902026700001302045700001902058700001602077700002902093700002202122700002302144700002202167700002302189700002102212700002102233700002202254700002102276700001802297700002202315700002502337700002302362700002202385700001702407700002002424700002402444700001202468700002302480700002002503700002602523700002202549700002802571700002402599700001802623700002102641700002102662700002702683700001902710700002202729700001902751856003602770 2012 eng d a1932-620300aEvaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.0 aEvaluation of the metabochip genotyping array in African America c2012 ae356510 v73 aThe Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
10aAfrican Americans10aCardiovascular Diseases10aCholesterol Ester Transfer Proteins10aCholesterol, HDL10aCholesterol, LDL10aChromosomes, Human10aCohort Studies10aGene Frequency10aGenome-Wide Association Study10aGenotype10aHumans10aMetabolic Diseases10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aBuyske, Steven1 aWu, Ying1 aCarty, Cara, L1 aCheng, Iona1 aAssimes, Themistocles, L1 aDumitrescu, Logan1 aHindorff, Lucia, A1 aMitchell, Sabrina1 aAmbite, Jose, Luis1 aBoerwinkle, Eric1 aBůzková, Petra1 aCarlson, Chris, S1 aCochran, Barbara1 aDuggan, David1 aEaton, Charles, B1 aFesinmeyer, Megan, D1 aFranceschini, Nora1 aHaessler, Jeffrey1 aJenny, Nancy1 aKang, Hyun, Min1 aKooperberg, Charles1 aLin, Yi1 aLe Marchand, Loïc1 aMatise, Tara, C1 aRobinson, Jennifer, G1 aRodriguez, Carlos1 aSchumacher, Fredrick, R1 aVoight, Benjamin, F1 aYoung, Alicia1 aManolio, Teri, A1 aMohlke, Karen, L1 aHaiman, Christopher, A1 aPeters, Ulrike1 aCrawford, Dana, C1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/663403996nas a2200625 4500008004100000022001400041245008800055210006900143260000900212300001300221490000600234520220300240653002202443653000902465653002602474653002402500653004002524653001102564653003802575653003402613653001102647653002702658653000902685653001702694653001602711653003602727653002802763653003402791653001702825653001602842653001802858100002202876700002402898700001902922700001802941700001602959700001902975700001902994700001803013700002503031700002303056700002003079700001703099700002303116700001903139700002103158700002203179700002103201700002403222700002703246700002103273700002103294700001903315856003603334 2012 eng d a1553-740400aFine-mapping and initial characterization of QT interval loci in African Americans.0 aFinemapping and initial characterization of QT interval loci in c2012 ae10028700 v83 aThe QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.
10aAfrican Americans10aAged10aComputational Biology10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMale10aMetagenomics10aMiddle Aged10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRisk Factors10aTachycardia10aUnited States1 aAvery, Christy, L1 aSethupathy, Praveen1 aBuyske, Steven1 aHe, Qianchuan1 aLin, Dan-Yu1 aArking, Dan, E1 aCarty, Cara, L1 aDuggan, David1 aFesinmeyer, Megan, D1 aHindorff, Lucia, A1 aJeff, Janina, M1 aKlein, Liviu1 aPatton, Kristen, K1 aPeters, Ulrike1 aShohet, Ralph, V1 aSotoodehnia, Nona1 aYoung, Alicia, M1 aKooperberg, Charles1 aHaiman, Christopher, A1 aMohlke, Karen, L1 aWhitsel, Eric, A1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/608308598nas a2202365 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520193500238653005002173653001602223653002002239653002602259653001102285653002202296653003402318653001102352653000902363653002602372653001402398653003602412653001302448653002302461100001502484700002002499700002202519700002202541700002802563700002302591700001902614700002502633700003202658700001802690700001902708700002602727700003102753700001902784700001802803700002002821700001202841700001702853700002202870700002502892700002002917700002002937700001602957700002002973700001902993700001903012700001803031700002103049700001803070700002603088700001903114700002103133700002003154700002103174700001903195700002103214700002003235700001903255700003503274700002403309700002103333700001803354700001503372700002803387700001903415700003403434700001803468700001803486700002003504700002203524700002103546700002103567700002503588700002903613700002303642700001603665700002003681700002203701700001403723700002303737700001603760700001803776700001903794700002203813700001903835700002103854700002203875700002203897700002003919700002103939700002303960700002003983700002004003700001804023700002104041700002304062700002404085700001904109700001804128700002704146700001804173700001704191700002204208700001904230700001904249700002404268700002604292700002104318700001704339700002004356700001904376700002004395700002004415700002004435700002504455700002004480700002404500700002204524700002004546700001604566700001904582700002104601700001904622700002304641700002304664700002504687700002504712700002404737700002304761700002504784700002104809700002104830700002104851700002404872700002104896700002204917700002404939700002804963700001704991700002305008700001905031700001805050700002105068700003005089700002605119700002205145700002405167700002005191700002705211700001905238700002305257700002005280700002105300700002005321700002405341700001505365700002005380700001805400700001905418700002805437700002505465700002805490700002605518700002505544700002705569700002305596700002505619700002405644700001905668700002205687700001805709700002005727700001905747700002205766700002205788700002105810700002105831700002405852700002005876700002505896700002405921700002205945700002305967700002105990700002006011700002006031700002806051700002106079700002506100700002406125700002406149700002306173856003606196 2012 eng d a1476-468700aFTO genotype is associated with phenotypic variability of body mass index.0 aFTO genotype is associated with phenotypic variability of body m c2012 Oct 11 a267-720 v4903 aThere is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Height10aBody Mass Index10aCo-Repressor Proteins10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteins10aRepressor Proteins1 aYang, Jian1 aLoos, Ruth, J F1 aPowell, Joseph, E1 aMedland, Sarah, E1 aSpeliotes, Elizabeth, K1 aChasman, Daniel, I1 aRose, Lynda, M1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aMägi, Reedik1 aWaite, Lindsay1 aSmith, Albert, Vernon1 aYerges-Armstrong, Laura, M1 aMonda, Keri, L1 aHadley, David1 aMahajan, Anubha1 aLi, Guo1 aKapur, Karen1 aVitart, Veronique1 aHuffman, Jennifer, E1 aWang, Sophie, R1 aPalmer, Cameron1 aEsko, Tõnu1 aFischer, Krista1 aZhao, Jing Hua1 aDemirkan, Ayse1 aIsaacs, Aaron1 aFeitosa, Mary, F1 aLuan, Jian'an1 aHeard-Costa, Nancy, L1 aWhite, Charles1 aJackson, Anne, U1 aPreuss, Michael1 aZiegler, Andreas1 aEriksson, Joel1 aKutalik, Zoltán1 aFrau, Francesca1 aNolte, Ilja, M1 avan Vliet-Ostaptchouk, Jana, V1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aVerweij, Niek1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aEstrada, Karol1 aBragg-Gresham, Jennifer, Lynn1 aSanna, Serena1 aSidore, Carlo1 aTyrer, Jonathan1 aTeumer, Alexander1 aProkopenko, Inga1 aMangino, Massimo1 aLindgren, Cecilia, M1 aAssimes, Themistocles, L1 aShuldiner, Alan, R1 aHui, Jennie1 aBeilby, John, P1 aMcArdle, Wendy, L1 aHall, Per1 aHaritunians, Talin1 aZgaga, Lina1 aKolcic, Ivana1 aPolasek, Ozren1 aZemunik, Tatijana1 aOostra, Ben, A1 aJunttila, Juhani1 aGrönberg, Henrik1 aSchreiber, Stefan1 aPeters, Annette1 aHicks, Andrew, A1 aStephens, Jonathan1 aFoad, Nicola, S1 aLaitinen, Jaana1 aPouta, Anneli1 aKaakinen, Marika1 aWillemsen, Gonneke1 aVink, Jacqueline, M1 aWild, Sarah, H1 aNavis, Gerjan1 aAsselbergs, Folkert, W1 aHomuth, Georg1 aJohn, Ulrich1 aIribarren, Carlos1 aHarris, Tamara1 aLauner, Lenore1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBoerwinkle, Eric1 aCadby, Gemma1 aPalmer, Lyle, J1 aJames, Alan, L1 aMusk, Arthur, W1 aIngelsson, Erik1 aPsaty, Bruce, M1 aBeckmann, Jacques, S1 aWaeber, Gérard1 aVollenweider, Peter1 aHayward, Caroline1 aWright, Alan, F1 aRudan, Igor1 aGroop, Leif, C1 aMetspalu, Andres1 aKhaw, Kay, Tee1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aProvince, Michael, A1 aWareham, Nicholas, J1 aTardif, Jean-Claude1 aHuikuri, Heikki, V1 aCupples, Adrienne, L1 aAtwood, Larry, D1 aFox, Caroline, S1 aBoehnke, Michael1 aCollins, Francis, S1 aMohlke, Karen, L1 aErdmann, Jeanette1 aSchunkert, Heribert1 aHengstenberg, Christian1 aStark, Klaus1 aLorentzon, Mattias1 aOhlsson, Claes1 aCusi, Daniele1 aStaessen, Jan, A1 avan der Klauw, Melanie, M1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aJolley, Jennifer, D1 aRipatti, Samuli1 aJarvelin, Marjo-Riitta1 aGeus, Eco, J C1 aBoomsma, Dorret, I1 aPenninx, Brenda1 aWilson, James, F1 aCampbell, Harry1 aChanock, Stephen, J1 aHarst, Pim1 aHamsten, Anders1 aWatkins, Hugh1 aHofman, Albert1 aWitteman, Jacqueline, C1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aZillikens, Carola, M1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aAbecasis, Goncalo, R1 aSchlessinger, David1 aSchipf, Sabine1 aStumvoll, Michael1 aTönjes, Anke1 aSpector, Tim, D1 aNorth, Kari, E1 aLettre, Guillaume1 aMcCarthy, Mark, I1 aBerndt, Sonja, I1 aHeath, Andrew, C1 aMadden, Pamela, A F1 aNyholt, Dale, R1 aMontgomery, Grant, W1 aMartin, Nicholas, G1 aMcKnight, Barbara1 aStrachan, David, P1 aHill, William, G1 aSnieder, Harold1 aRidker, Paul, M1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N1 aGoddard, Michael, E1 aVisscher, Peter, M uhttps://chs-nhlbi.org/node/617505476nas a2201057 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2012 eng d a1879-148400aGenetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.0 aGenetic determinants of the anklebrachial index a metaanalysis o c2012 May a138-470 v2223 aBACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.
METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.
RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.
CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
10aAdult10aAfrican Americans10aAged10aAnkle Brachial Index10aAryl Hydrocarbon Hydroxylases10aCytochrome P-450 CYP2B610aEuropean Continental Ancestry Group10aFemale10aHumans10aMale10aMiddle Aged10aOxidoreductases, N-Demethylating10aPeripheral Arterial Disease10aPolymorphism, Single Nucleotide10aRisk Factors10aTranscription Factor 7-Like 2 Protein1 aWassel, Christina, L1 aLamina, Claudia1 aNambi, Vijay1 aCoassin, Stefan1 aMukamal, Kenneth, J1 aGanesh, Santhi, K1 aJacobs, David, R1 aFranceschini, Nora1 aPapanicolaou, George, J1 aGibson, Quince1 aYanek, Lisa, R1 aHarst, Pim1 aFerguson, Jane, F1 aCrawford, Dana, C1 aWaite, Lindsay, L1 aAllison, Matthew, A1 aCriqui, Michael, H1 aMcDermott, Mary, M1 aMehra, Reena1 aCupples, Adrienne, L1 aHwang, Shih-Jen1 aRedline, Susan1 aKaplan, Robert, C1 aHeiss, Gerardo1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aTaylor, Herman, A1 aEraso, Luis, H1 aHaun, Margot1 aLi, Mingyao1 aMeisinger, Christa1 aO'Connell, Jeffrey, R1 aShuldiner, Alan, R1 aTybjærg-Hansen, Anne1 aFrikke-Schmidt, Ruth1 aKollerits, Barbara1 aRantner, Barbara1 aDieplinger, Benjamin1 aStadler, Marietta1 aMueller, Thomas1 aHaltmayer, Meinhard1 aKlein-Weigel, Peter1 aSummerer, Monika1 aWichmann, H-Erich1 aAsselbergs, Folkert, W1 aNavis, Gerjan1 aLeach, Irene, Mateo1 aBrown-Gentry, Kristin1 aGoodloe, Robert1 aAssimes, Themistocles, L1 aBecker, Diane, M1 aCooke, John, P1 aAbsher, Devin, M1 aOlin, Jeffrey, W1 aMitchell, Braxton, D1 aReilly, Muredach, P1 aMohler, Emile, R1 aNorth, Kari, E1 aReiner, Alexander, P1 aKronenberg, Florian1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/586406059nas a2201225 4500008004100000022001400041245014700055210006900202260001300271300001100284490000700295520244300302653001902745653002302764653003802787653003402825653001102859653001702870653001102887100002102898700002002919700002702939700001902966700002302985700002003008700002003028700002003048700001803068700001703086700002803103700001903131700001903150700002203169700001903191700002303210700002403233700002503257700002303282700002703305700002003332700002203352700002403374700003003398700002003428700002203448700002103470700001803491700002303509700002203532700001903554700001703573700001903590700001703609700001903626700001903645700001803664700002603682700002603708700002303734700002303757700001503780700001703795700002303812700002303835700001503858700002003873700002203893700001903915700001603934700002503950700002703975700001904002700002704021700002404048700002804072700001904100700001904119700002204138700002104160700002104181700001804202700002504220700001904245700002204264700002504286700001704311700001904328700002204347700002004369700002604389700002804415700001904443700001904462700002704481700002004508700002304528700002104551700002204572700002104594700002104615700002004636710009604656710004504752856003604797 2012 eng d a1474-446500aGenetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.0 aGenetic risk factors for ischaemic stroke and its subtypes the M c2012 Nov a951-620 v113 aBACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.
METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.
FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.
INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.
FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).
10aBrain Ischemia10aDatabases, Genetic10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aRisk Factors10aStroke1 aTraylor, Matthew1 aFarrall, Martin1 aHolliday, Elizabeth, G1 aSudlow, Cathie1 aHopewell, Jemma, C1 aCheng, Yu-Ching1 aFornage, Myriam1 aIkram, Arfan, M1 aMalik, Rainer1 aBevan, Steve1 aThorsteinsdottir, Unnur1 aNalls, Mike, A1 aLongstreth, Wt1 aWiggins, Kerri, L1 aYadav, Sunaina1 aParati, Eugenio, A1 aDeStefano, Anita, L1 aWorrall, Bradford, B1 aKittner, Steven, J1 aKhan, Muhammad, Saleem1 aReiner, Alex, P1 aHelgadottir, Anna1 aAchterberg, Sefanja1 aFernandez-Cadenas, Israel1 aAbboud, Sherine1 aSchmidt, Reinhold1 aWalters, Matthew1 aChen, Wei-Min1 aRingelstein, Bernd1 aO'Donnell, Martin1 aHo, Weang, Kee1 aPera, Joanna1 aLemmens, Robin1 aNorrving, Bo1 aHiggins, Peter1 aBenn, Marianne1 aSale, Michele1 aKuhlenbäumer, Gregor1 aDoney, Alexander, S F1 aVicente, Astrid, M1 aDelavaran, Hossein1 aAlgra, Ale1 aDavies, Gail1 aOliveira, Sofia, A1 aPalmer, Colin, N A1 aDeary, Ian1 aSchmidt, Helena1 aPandolfo, Massimo1 aMontaner, Joan1 aCarty, Cara1 ade Bakker, Paul, I W1 aKostulas, Konstantinos1 aFerro, Jose, M1 avan Zuydam, Natalie, R1 aValdimarsson, Einar1 aNordestgaard, Børge, G1 aLindgren, Arne1 aThijs, Vincent1 aSlowik, Agnieszka1 aSaleheen, Danish1 aParé, Guillaume1 aBerger, Klaus1 aThorleifsson, Gudmar1 aHofman, Albert1 aMosley, Thomas, H1 aMitchell, Braxton, D1 aFurie, Karen1 aClarke, Robert1 aLevi, Christopher1 aSeshadri, Sudha1 aGschwendtner, Andreas1 aBoncoraglio, Giorgio, B1 aSharma, Pankaj1 aBis, Joshua, C1 aGretarsdottir, Solveig1 aPsaty, Bruce, M1 aRothwell, Peter, M1 aRosand, Jonathan1 aMeschia, James, F1 aStefansson, Kari1 aDichgans, Martin1 aMarkus, Hugh, S1 aAustralian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2)1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/586304322nas a2200625 4500008004100000022001400041245010600055210006900161260001600230300001300246490000800259520250400267653004502771653000902816653002002825653001902845653001102864653002202875653001302897653001802910653001102928653005502939653000902994653002703003653002603030653001403056653003603070653002603106653002803132653000903160653002503169653001403194653003003208100002203238700003003260700002003290700002303310700001703333700001703350700002803367700002003395700002003415700002003435700002503455700002203480700002003502700002303522700001903545700001703564700001603581700002003597700002103617700002203638856003603660 2012 eng d a1538-359800aGenetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.0 aGenetic variants and associations of 25hydroxyvitamin D concentr c2012 Nov 14 a1898-9050 v3083 aCONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.
OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.
DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.
MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.
RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.
CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.
10a25-Hydroxyvitamin D3 1-alpha-Hydroxylase10aAged10aChronic Disease10aCohort Studies10aFemale10aGenetic Variation10aGenotype10aHip Fractures10aHumans10aLow Density Lipoprotein Receptor-Related Protein-210aMale10aMeta-Analysis as Topic10aMyocardial Infarction10aNeoplasms10aPolymorphism, Single Nucleotide10aReceptors, Calcitriol10aReceptors, Cell Surface10aRisk10aSteroid Hydroxylases10aVitamin D10aVitamin D3 24-Hydroxylase1 aLevin, Gregory, P1 aRobinson-Cohen, Cassianne1 ade Boer, Ian, H1 aHouston, Denise, K1 aLohman, Kurt1 aLiu, Yongmei1 aKritchevsky, Stephen, B1 aCauley, Jane, A1 aTanaka, Toshiko1 aFerrucci, Luigi1 aBandinelli, Stefania1 aPatel, Kushang, V1 aHagström, Emil1 aMichaëlsson, Karl1 aMelhus, Håkan1 aWang, Thomas1 aWolf, Myles1 aPsaty, Bruce, M1 aSiscovick, David1 aKestenbaum, Bryan uhttps://chs-nhlbi.org/node/155407422nas a2202413 4500008004100000022001400041245009100055210006900146260000900215300001300224490000600237520076400243653002201007653000901029653001201038653001401050653002901064653002701093653001801120653004001138653001101178653002201189653003001211653003401241653003101275653001101306653001101317653002801328653000901356653001601365653003401381653001401415100002201429700001901451700002201470700001901492700002301511700002701534700002001561700002001581700001801601700001901619700001201638700001601650700002001666700001601686700002501702700002401727700002601751700001901777700001801796700001801814700002101832700002601853700002301879700002001902700001201922700002301934700002201957700001801979700002001997700002702017700001702044700002502061700001902086700001802105700001902123700002202142700002702164700002102191700002102212700002202233700001602255700002202271700001802293700001902311700002102330700002002351700001902371700002302390700002002413700002202433700002202455700001902477700002402496700002502520700002102545700002002566700002602586700002002612700001702632700001902649700001902668700002302687700002302710700002002733700002502753700002302778700002102801700001802822700002002840700002202860700001802882700002202900700001802922700002102940700002402961700001602985700001903001700001903020700002003039700002003059700002203079700002003101700001903121700001903140700002203159700001903181700001803200700002103218700002003239700002003259700001703279700001903296700001803315700002203333700001803355700001903373700002803392700002603420700002403446700001903470700001703489700002203506700002203528700001903550700002203569700001903591700002003610700001903630700002203649700002203671700002003693700001903713700001603732700002303748700002303771700002503794700001803819700001403837700002403851700001703875700002103892700002403913700001703937700001703954700001903971700001903990700001904009700001904028700002404047700002004071700002104091700001804112700002104130700001904151700001904170700002904189700002404218700002104242700002404263700002304287700001804310700002204328700002004350700002404370700002304394700002004417700002404437700001704461700002004478700001604498700002004514700002104534700001804555700002604573700001904599700002104618700003004639700002204669700001704691700001804708700002104726700001804747700002304765700002304788700002004811700002104831710002604852710002004878710002004898710005404918856003604972 2012 eng d a1553-740400aGenome-wide association and functional follow-up reveals new loci for kidney function.0 aGenomewide association and functional followup reveals new loci c2012 ae10025840 v83 aChronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
10aAfrican Americans10aAged10aAnimals10aCaspase 910aCyclin-Dependent Kinases10aDEAD-box RNA Helicases10aDNA Helicases10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGene Knockdown Techniques10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aPhosphoric Diester Hydrolases10aZebrafish1 aPattaro, Cristian1 aKöttgen, Anna1 aTeumer, Alexander1 aGarnaas, Maija1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aTaliun, Daniel1 aLi, Man1 aGao, Xiaoyi1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aO'Seaghdha, Conall, M1 aGlazer, Nicole1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aJohnson, Andrew, D1 aGierman, Hinco, J1 aFeitosa, Mary1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aChouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aCavalieri, Margherita1 aRao, Madhumathi1 aHu, Frank, B1 aDemirkan, Ayse1 aOostra, Ben, A1 ade Andrade, Mariza1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aKolcic, Ivana1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aEndlich, Karlhans1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aKetkar, Shamika1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aGiulianini, Franco1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMetzger, Marie1 aMitchell, Paul1 aCiullo, Marina1 aKim, Stuart, K1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aSiscovick, David, S1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline, C M1 aHayward, Caroline1 aRidker, Paul1 aParsa, Afshin1 aBochud, Murielle1 aHeid, Iris, M1 aGoessling, Wolfram1 aChasman, Daniel, I1 aKao, Linda, W H1 aFox, Caroline, S1 aCARDIoGRAM consortium1 aICBP Consortium1 aCARe Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2) uhttps://chs-nhlbi.org/node/137705378nas a2201249 4500008004100000022001400041245010600055210006900161260001600230300001100246490000800257520186000265653000902125653001102134653002902145653003402174653001102208653000902219653001602228653002602244653003602270653004302306653002502349653003202374653001202406653001902418100001902437700002202456700002002478700001902498700002102517700002002538700002602558700002302584700002202607700001602629700001802645700001902663700001602682700002002698700002602718700002102744700002102765700001502786700002002801700002002821700002302841700002202864700002402886700001902910700001802929700002002947700001702967700001902984700002303003700001903026700002103045700002203066700001903088700001903107700001903126700001803145700001903163700002203182700002203204700001703226700002003243700002003263700001903283700002603302700002203328700001903350700002403369700002003393700002203413700001903435700002203454700002003476700002103496700002603517700002003543700002203563700002603585700001903611700002803630700002503658700002003683700001803703700002503721700002403746700001803770700002003788700002503808700002403833700001703857700002003874700002303894700002503917700001903942700002603961700002003987700001704007700002404024700002104048700002304069856003604092 2012 eng d a1535-497000aGenome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.0 aGenomewide association studies identify CHRNA53 and HTR4 in the c2012 Oct 01 a622-320 v1863 aRATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.
MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
10aAged10aFemale10aForced Expiratory Volume10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPulmonary Disease, Chronic Obstructive10aReceptors, Nicotinic10aReceptors, Serotonin, 5-HT410aSmoking10aVital Capacity1 aWilk, Jemma, B1 aShrine, Nick, R G1 aLoehr, Laura, R1 aZhao, Jing Hua1 aManichaikul, Ani1 aLopez, Lorna, M1 aSmith, Albert, Vernon1 aHeckbert, Susan, R1 aSmolonska, Joanna1 aTang, Wenbo1 aLoth, Daan, W1 aCurjuric, Ivan1 aHui, Jennie1 aCho, Michael, H1 aLatourelle, Jeanne, C1 aHenry, Amanda, P1 aAldrich, Melinda1 aBakke, Per1 aBeaty, Terri, H1 aBentley, Amy, R1 aBorecki, Ingrid, B1 aBrusselle, Guy, G1 aBurkart, Kristin, M1 aChen, Ting-Hsu1 aCouper, David1 aCrapo, James, D1 aDavies, Gail1 aDupuis, Josée1 aFranceschini, Nora1 aGulsvik, Amund1 aHancock, Dana, B1 aHarris, Tamara, B1 aHofman, Albert1 aImboden, Medea1 aJames, Alan, L1 aKhaw, Kay-Tee1 aLahousse, Lies1 aLauner, Lenore, J1 aLitonjua, Augusto1 aLiu, Yongmei1 aLohman, Kurt, K1 aLomas, David, A1 aLumley, Thomas1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aMusk, Arthur, W1 aMyers, Richard, H1 aNorth, Kari, E1 aPostma, Dirkje, S1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRivadeneira, Fernando1 aRochat, Thierry1 aRotter, Jerome, I1 aArtigas, Maria, Soler1 aStarr, John, M1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aZanen, Pieter1 aProvince, Michael, A1 aSilverman, Edwin, K1 aDeary, Ian, J1 aPalmer, Lyle, J1 aCassano, Patricia, A1 aGudnason, Vilmundur1 aBarr, Graham1 aLoos, Ruth, J F1 aStrachan, David, P1 aLondon, Stephanie, J1 aBoezen, Marike1 aProbst-Hensch, Nicole1 aGharib, Sina, A1 aHall, Ian, P1 aO'Connor, George, T1 aTobin, Martin, D1 aStricker, Bruno, H uhttps://chs-nhlbi.org/node/609205960nas a2201525 4500008004100000022001400041245011100055210006900166260001600235300001200251490000800263520152700271653004101798653003201839653005601871653001401927653002101941653001901962653002801981653003002009653003002039653003102069653001902100653003402119653001302153653001102166653002402177653002702201653001402228653001202242653003802254653003602292653001502328653003702343653002102380653002602401100001502427700002502442700002702467700002002494700001802514700002002532700001802552700002802570700002102598700002302619700002302642700002302665700002302688700002202711700002102733700001702754700002602771700001802797700001602815700002002831700002002851700002702871700001902898700002602917700003102943700001802974700001902992700002403011700002103035700002103056700001703077700002003094700002003114700001503134700002303149700002203172700002103194700001803215700002003233700002503253700002303278700002203301700002303323700001903346700001903365700002203384700001703406700001703423700002703440700001703467700001803484700002803502700002803530700002303558700001903581700001803600700003003618700002103648700001703669700002003686700001903706700002203725700001903747700001703766700001903783700002003802700002203822700002403844700001803868700002203886700002803908700002003936700002103956700001803977700002403995700002104019700002204040700002004062700002804082700001804110700002204128700002904150700002104179700002004200700001504220700001704235700003004252700002004282710002304302710002604325710001904351710002804370856003604398 2012 eng d a1528-002000aGenome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.0 aGenomewide association study for circulating levels of PAI1 prov c2012 Dec 06 a4873-810 v1203 aWe conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
10aAdaptor Proteins, Signal Transducing10aARNTL Transcription Factors10aATPases Associated with Diverse Cellular Activities10aCell Line10aCell Line, Tumor10aCohort Studies10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aGene Expression Profiling10aGene Expression Regulation10aGene Frequency10aGenome-Wide Association Study10aGenotype10aHumans10aLIM Domain Proteins10aMeta-Analysis as Topic10aMonocytes10aMucin-310aPlasminogen Activator Inhibitor 110aPolymorphism, Single Nucleotide10aPPAR gamma10aProteasome Endopeptidase Complex10aRNA Interference10aTranscription Factors1 aHuang, Jie1 aSabater-Lleal, Maria1 aAsselbergs, Folkert, W1 aTregouet, David1 aShin, So-Youn1 aDing, Jingzhong1 aBaumert, Jens1 aOudot-Mellakh, Tiphaine1 aFolkersen, Lasse1 aJohnson, Andrew, D1 aSmith, Nicholas, L1 aWilliams, Scott, M1 aIkram, Mohammad, A1 aKleber, Marcus, E1 aBecker, Diane, M1 aTruong, Vinh1 aMychaleckyj, Josyf, C1 aTang, Weihong1 aYang, Qiong1 aSennblad, Bengt1 aMoore, Jason, H1 aWilliams, Frances, M K1 aDehghan, Abbas1 aSilbernagel, Günther1 aSchrijvers, Elisabeth, M C1 aSmith, Shelly1 aKarakas, Mahir1 aTofler, Geoffrey, H1 aSilveira, Angela1 aNavis, Gerjan, J1 aLohman, Kurt1 aChen, Ming-Huei1 aPeters, Annette1 aGoel, Anuj1 aHopewell, Jemma, C1 aChambers, John, C1 aSaleheen, Danish1 aLundmark, Per1 aPsaty, Bruce, M1 aStrawbridge, Rona, J1 aBoehm, Bernhard, O1 aCarter, Angela, M1 aMeisinger, Christa1 aPeden, John, F1 aBis, Joshua, C1 aMcKnight, Barbara1 aOhrvik, John1 aTaylor, Kent1 aFranzosi, Maria Grazia1 aSeedorf, Udo1 aCollins, Rory1 aFranco-Cereceda, Anders1 aSyvänen, Ann-Christine1 aGoodall, Alison, H1 aYanek, Lisa, R1 aCushman, Mary1 aMüller-Nurasyid, Martina1 aFolsom, Aaron, R1 aBasu, Saonli1 aMatijevic, Nena1 aGilst, Wiek, H1 aKooner, Jaspal, S1 aHofman, Albert1 aDanesh, John1 aClarke, Robert1 aMeigs, James, B1 aKathiresan, Sekar1 aReilly, Muredach, P1 aKlopp, Norman1 aHarris, Tamara, B1 aWinkelmann, Bernhard, R1 aGrant, Peter, J1 aHillege, Hans, L1 aWatkins, Hugh1 aSpector, Timothy, D1 aBecker, Lewis, C1 aTracy, Russell, P1 aMärz, Winfried1 aUitterlinden, André, G1 aEriksson, Per1 aCambien, Francois1 aMorange, Pierre-Emmanuel1 aKoenig, Wolfgang1 aSoranzo, Nicole1 aHarst, Pim1 aLiu, Yongmei1 aO'Donnell, Christopher, J1 aHamsten, Anders1 aDIAGRAM Consortium1 aCARDIoGRAM consortium1 aC4D Consortium1 aCardiogenics consortium uhttps://chs-nhlbi.org/node/608905536nas a2201405 4500008004100000022001400041245012000055210006900175260000900244300001300253490000600266520151700272653002901789653002001818653001801838653003401856653002001890653002301910653001101933653000901944653002601953653003601979653004402015653004302059653002802102653001202130653003002142653001902172100002102191700002602212700002002238700001802258700002102276700002602297700001802323700001902341700001602360700002202376700002102398700002202419700001702441700001602458700001902474700001802493700001902511700002002530700002402550700001902574700002202593700001802615700001702633700002202650700002102672700001802693700001902711700001802730700002002748700001702768700002002785700002202805700002602827700001902853700002202872700002402894700002202918700001902940700002402959700002302983700002203006700002203028700002003050700001903070700002003089700001903109700002103128700001903149700002403168700002303192700002603215700002103241700002803262700001703290700001903307700002003326700002003346700002803366700002003394700002103414700002003435700002403455700001903479700002103498700001903519700002203538700001803560700002803578700002803606700001803634700002303652700001703675700002503692700001903717700002503736700002403761700002903785700002003814700002703834700002303861700002403884700001903908700001703927700002503944700002303969700002003992700001704012700001904029700002104048700002504069856003604094 2012 eng d a1553-740400aGenome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.0 aGenomewide joint metaanalysis of SNP and SNPbysmoking interactio c2012 ae10030980 v83 aGenome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
10aForced Expiratory Volume10aGene Expression10aGenome, Human10aGenome-Wide Association Study10aHLA-DQ Antigens10aHLA-DQ beta-Chains10aHumans10aLung10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels, Inwardly Rectifying10aPulmonary Disease, Chronic Obstructive10aReceptors, Cell Surface10aSmoking10aSOX9 Transcription Factor10aVital Capacity1 aHancock, Dana, B1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aHenry, Amanda1 aManichaikul, Ani1 aRamasamy, Adaikalavan1 aLoth, Daan, W1 aImboden, Medea1 aKoch, Beate1 aMcArdle, Wendy, L1 aSmith, Albert, V1 aSmolonska, Joanna1 aSood, Akshay1 aTang, Wenbo1 aWilk, Jemma, B1 aZhai, Guangju1 aZhao, Jing Hua1 aAschard, Hugues1 aBurkart, Kristin, M1 aCurjuric, Ivan1 aEijgelsheim, Mark1 aElliott, Paul1 aGu, Xiangjun1 aHarris, Tamara, B1 aJanson, Christer1 aHomuth, Georg1 aHysi, Pirro, G1 aLiu, Jason, Z1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aManning, Alisa, K1 aMarciante, Kristin, D1 aObeidat, Ma'en1 aPostma, Dirkje, S1 aAldrich, Melinda, C1 aBrusselle, Guy, G1 aChen, Ting-Hsu1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aHeinrich, Joachim1 aRotter, Jerome, I1 aWijmenga, Cisca1 aWilliams, Dale1 aBentley, Amy, R1 aHofman, Albert1 aLaurie, Cathy, C1 aLumley, Thomas1 aMorrison, Alanna, C1 aJoubert, Bonnie, R1 aRivadeneira, Fernando1 aCouper, David, J1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aWjst, Matthias1 aWain, Louise, V1 aVonk, Judith, M1 aUitterlinden, André, G1 aRochat, Thierry1 aRich, Stephen, S1 aPsaty, Bruce, M1 aO'Connor, George, T1 aNorth, Kari, E1 aMirel, Daniel, B1 aMeibohm, Bernd1 aLauner, Lenore, J1 aKhaw, Kay-Tee1 aHartikainen, Anna-Liisa1 aHammond, Christopher, J1 aGläser, Sven1 aMarchini, Jonathan1 aKraft, Peter1 aWareham, Nicholas, J1 aVölzke, Henry1 aStricker, Bruno, H C1 aSpector, Timothy, D1 aProbst-Hensch, Nicole, M1 aJarvis, Deborah1 aJarvelin, Marjo-Riitta1 aHeckbert, Susan, R1 aGudnason, Vilmundur1 aBoezen, Marike1 aBarr, Graham1 aCassano, Patricia, A1 aStrachan, David, P1 aFornage, Myriam1 aHall, Ian, P1 aDupuis, Josée1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/608805038nas a2201333 4500008004100000022001400041245007300055210006900128260000900197300000900206490000600215520172900221653001001950653002201960653000901982653003201991653003202023653001102055653001702066653003802083653002202121653003402143653001302177653001102190653000902201653001602210653002602226653001402252653003602266653001802302653002502320653001202345653002402357100001602381700001702397700001502414700001702429700001402446700002002460700001602480700001802496700001802514700001102532700001602543700001702559700001502576700002002591700001402611700001802625700001702643700001402660700001702674700001702691700001502708700001602723700001802739700001602757700001302773700001802786700001702804700001602821700001602837700001602853700001602869700001502885700002002900700001602920700002002936700002002956700001502976700001302991700001503004700001703019700001503036700001503051700001203066700001803078700001903096700001103115700001703126700001603143700001903159700001403178700002103192700001403213700001303227700001503240700001403255700001503269700002403284700001803308700002103326700002003347700001503367700001503382700001403397700001903411700001603430700001503446700001703461700001503478700001703493700001603510700001603526700001603542700001003558700001303568700001803581700002003599700001703619700001703636700001503653856003603668 2012 eng d a2158-318800aGenome-wide meta-analyses of smoking behaviors in African Americans.0 aGenomewide metaanalyses of smoking behaviors in African American c2012 ae1190 v23 aThe identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.
10aAdult10aAfrican Americans10aAged10aChromosomes, Human, Pair 1010aChromosomes, Human, Pair 1510aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteoglycans10aReceptors, Nicotinic10aSmoking10aStatistics as Topic1 aDavid, S, P1 aHamidovic, A1 aChen, G, K1 aBergen, A, W1 aWessel, J1 aKasberger, J, L1 aBrown, W, M1 aPetruzella, S1 aThacker, E, L1 aKim, Y1 aNalls, M, A1 aTranah, G, J1 aSung, Y, J1 aAmbrosone, C, B1 aArnett, D1 aBandera, E, V1 aBecker, D, M1 aBecker, L1 aBerndt, S, I1 aBernstein, L1 aBlot, W, J1 aBroeckel, U1 aBuxbaum, S, G1 aCaporaso, N1 aCasey, G1 aChanock, S, J1 aDeming, S, L1 aDiver, W, R1 aEaton, C, B1 aEvans, D, S1 aEvans, M, K1 aFornage, M1 aFranceschini, N1 aHarris, T B1 aHenderson, B, E1 aHernandez, D, G1 aHitsman, B1 aHu, J, J1 aHunt, S, C1 aIngles, S, A1 aJohn, E, M1 aKittles, R1 aKolb, S1 aKolonel, L, N1 aLe Marchand, L1 aLiu, Y1 aLohman, K, K1 aMcKnight, B1 aMillikan, R, C1 aMurphy, A1 aNeslund-Dudas, C1 aNyante, S1 aPress, M1 aPsaty, B M1 aRao, D, C1 aRedline, S1 aRodriguez-Gil, J, L1 aRybicki, B, A1 aSignorello, L, B1 aSingleton, A, B1 aSmoller, J1 aSnively, B1 aSpring, B1 aStanford, J, L1 aStrom, S, S1 aSwan, G, E1 aTaylor, K, D1 aThun, M, J1 aWilson, A, F1 aWitte, J, S1 aYamamura, Y1 aYanek, L, R1 aYu, K1 aZheng, W1 aZiegler, R, G1 aZonderman, A, B1 aJorgenson, E1 aHaiman, C, A1 aFurberg, H uhttps://chs-nhlbi.org/node/680408678nas a2202593 4500008004100000022001400041245012400055210006900179260001600248300001200264490000700276520126400283653001701547653002601564653004001590653003401630653001101664653001501675653002001690653003001710653003801740653003401778653001301812653001801825653001101843653005001854653005501904653002101959653000901980653004601989653001702035653002002052653003602072653002802108653001702136653001302153100001902166700002602185700002502211700001902236700002002255700002502275700001402300700002302314700001602337700001802353700002202371700001202393700001802405700002102423700002202444700002402466700001802490700001702508700003102525700002002556700001802576700001902594700002502613700002402638700001702662700002502679700002102704700002102725700001702746700001702763700002202780700001902802700002602821700001802847700002102865700002002886700002802906700001902934700002102953700002202974700002502996700002203021700002103043700001703064700002403081700002303105700001703128700002203145700002303167700002003190700001903210700002103229700001603250700002603266700002003292700001903312700002103331700001903352700001903371700002003390700002803410700002103438700001903459700002003478700002003498700002703518700001403545700001303559700002103572700002503593700002403618700001703642700002403659700001803683700002203701700001403723700001803737700002003755700003003775700002003805700002103825700002403846700001803870700002203888700002903910700002303939700001503962700002103977700002103998700001604019700002004035700003104055700002004086700003004106700001904136700002204155700002004177700002404197700002004221700002204241700002004263700001704283700001904300700002704319700002404346700003104370700002004401700002104421700002704442700002604469700001504495700001204510700001804522700002804540700002404568700001604592700002204608700002304630700002604653700002304679700002704702700002004729700001704749700002204766700001904788700002504807700002004832700002304852700002104875700002404896700001904920700002404939700002104963700002004984700002405004700001905028700002405047700001805071700001905089700001805108700002205126700001705148700002305165700002205188700002505210700002705235700002705262700001905289700001905308700002305327700002305350700002005373700001705393700001805410700002405428700002105452700002305473700002505496700002305521700002105544700002505565700002205590700002005612700002205632700002605654700002005680700002005700700002405720700002705744700002505771700002805796700001905824700001905843700002005862700002205882700002105904700002805925700002305953700002505976700002106001700002606022856003606048 2012 eng d a1546-171800aGenome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.0 aGenomewide metaanalysis identifies 56 bone mineral density loci c2012 Apr 15 a491-5010 v443 aBone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
10aBone Density10aComputational Biology10aEuropean Continental Ancestry Group10aExtracellular Matrix Proteins10aFemale10aFemur Neck10aFractures, Bone10aGene Expression Profiling10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGlycoproteins10aHumans10aIntercellular Signaling Peptides and Proteins10aLow Density Lipoprotein Receptor-Related Protein-510aLumbar Vertebrae10aMale10aMitochondrial Membrane Transport Proteins10aOsteoporosis10aPhosphoproteins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors10aSpectrin1 aEstrada, Karol1 aStyrkarsdottir, Unnur1 aEvangelou, Evangelos1 aHsu, Yi-Hsiang1 aDuncan, Emma, L1 aNtzani, Evangelia, E1 aOei, Ling1 aAlbagha, Omar, M E1 aAmin, Najaf1 aKemp, John, P1 aKoller, Daniel, L1 aLi, Guo1 aLiu, Ching-Ti1 aMinster, Ryan, L1 aMoayyeri, Alireza1 aVandenput, Liesbeth1 aWillner, Dana1 aXiao, Su-Mei1 aYerges-Armstrong, Laura, M1 aZheng, Hou-Feng1 aAlonso, Nerea1 aEriksson, Joel1 aKammerer, Candace, M1 aKaptoge, Stephen, K1 aLeo, Paul, J1 aThorleifsson, Gudmar1 aWilson, Scott, G1 aWilson, James, F1 aAalto, Ville1 aAlen, Markku1 aAragaki, Aaron, K1 aAspelund, Thor1 aCenter, Jacqueline, R1 aDailiana, Zoe1 aDuggan, David, J1 aGarcia, Melissa1 aGarcía-Giralt, Natalia1 aGiroux, Sylvie1 aHallmans, Göran1 aHocking, Lynne, J1 aHusted, Lise, Bjerre1 aJameson, Karen, A1 aKhusainova, Rita1 aKim, Ghi, Su1 aKooperberg, Charles1 aKoromila, Theodora1 aKruk, Marcin1 aLaaksonen, Marika1 aLaCroix, Andrea, Z1 aLee, Seung, Hun1 aLeung, Ping, C1 aLewis, Joshua, R1 aMasi, Laura1 aMencej-Bedrac, Simona1 aNguyen, Tuan, V1 aNogues, Xavier1 aPatel, Millan, S1 aPrezelj, Janez1 aRose, Lynda, M1 aScollen, Serena1 aSiggeirsdottir, Kristin1 aSmith, Albert, V1 aSvensson, Olle1 aTrompet, Stella1 aTrummer, Olivia1 avan Schoor, Natasja, M1 aWoo, Jean1 aZhu, Kun1 aBalcells, Susana1 aBrandi, Maria, Luisa1 aBuckley, Brendan, M1 aCheng, Sulin1 aChristiansen, Claus1 aCooper, Cyrus1 aDedoussis, George1 aFord, Ian1 aFrost, Morten1 aGoltzman, David1 aGonzález-Macías, Jesús1 aKähönen, Mika1 aKarlsson, Magnus1 aKhusnutdinova, Elza1 aKoh, Jung-Min1 aKollia, Panagoula1 aLangdahl, Bente, Lomholt1 aLeslie, William, D1 aLips, Paul1 aLjunggren, Osten1 aLorenc, Roman, S1 aMarc, Janja1 aMellström, Dan1 aObermayer-Pietsch, Barbara1 aOlmos, José, M1 aPettersson-Kymmer, Ulrika1 aReid, David, M1 aRiancho, José, A1 aRidker, Paul, M1 aRousseau, François1 aSlagboom, Eline1 aTang, Nelson, L S1 aUrreizti, Roser1 aVan Hul, Wim1 aViikari, Jorma1 aZarrabeitia, María, T1 aAulchenko, Yurii, S1 aCastano-Betancourt, Martha1 aGrundberg, Elin1 aHerrera, Lizbeth1 aIngvarsson, Thorvaldur1 aJohannsdottir, Hrefna1 aKwan, Tony1 aLi, Rui1 aLuben, Robert1 aMedina-Gómez, Carolina1 aPalsson, Stefan, Th1 aReppe, Sjur1 aRotter, Jerome, I1 aSigurdsson, Gunnar1 avan Meurs, Joyce, B J1 aVerlaan, Dominique1 aWilliams, Frances, M K1 aWood, Andrew, R1 aZhou, Yanhua1 aGautvik, Kaare, M1 aPastinen, Tomi1 aRaychaudhuri, Soumya1 aCauley, Jane, A1 aChasman, Daniel, I1 aClark, Graeme, R1 aCummings, Steven, R1 aDanoy, Patrick1 aDennison, Elaine, M1 aEastell, Richard1 aEisman, John, A1 aGudnason, Vilmundur1 aHofman, Albert1 aJackson, Rebecca, D1 aJones, Graeme1 aJukema, Wouter1 aKhaw, Kay-Tee1 aLehtimäki, Terho1 aLiu, Yongmei1 aLorentzon, Mattias1 aMcCloskey, Eugene1 aMitchell, Braxton, D1 aNandakumar, Kannabiran1 aNicholson, Geoffrey, C1 aOostra, Ben, A1 aPeacock, Munro1 aPols, Huibert, A P1 aPrince, Richard, L1 aRaitakari, Olli1 aReid, Ian, R1 aRobbins, John1 aSambrook, Philip, N1 aSham, Pak, Chung1 aShuldiner, Alan, R1 aTylavsky, Frances, A1 aDuijn, Cornelia, M1 aWareham, Nick, J1 aCupples, Adrienne, L1 aEcons, Michael, J1 aEvans, David, M1 aHarris, Tamara, B1 aKung, Annie, Wai Chee1 aPsaty, Bruce, M1 aReeve, Jonathan1 aSpector, Timothy, D1 aStreeten, Elizabeth, A1 aZillikens, Carola, M1 aThorsteinsdottir, Unnur1 aOhlsson, Claes1 aKarasik, David1 aRichards, Brent1 aBrown, Matthew, A1 aStefansson, Kari1 aUitterlinden, André, G1 aRalston, Stuart, H1 aIoannidis, John, P A1 aKiel, Douglas, P1 aRivadeneira, Fernando uhttps://chs-nhlbi.org/node/801603248nas a2200673 4500008004100000022001400041245010800055210006900163260001600232300001200248490000700260520130900267653003401576653001101610653003901621653001301660653002501673653003001698100002101728700002001749700002401769700002001793700002101813700002801834700002301862700001901885700002101904700001901925700001401944700002801958700002001986700002202006700002202028700002702050700002302077700002402100700001902124700001802143700002002161700002102181700002102202700002502223700002102248700002202269700001702291700001902308700002002327700002102347700001402368700002002382700001902402700002202421700002002443700001602463700002402479700001702503700001802520856003602538 2012 eng d a1460-208300aGenome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.0 aGenomewide metaanalysis points to CTC1 and ZNF676 as genes regul c2012 Dec 15 a5385-940 v213 aLeukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.
10aGenome-Wide Association Study10aHumans10aKruppel-Like Transcription Factors10aTelomere10aTelomere Homeostasis10aTelomere-Binding Proteins1 aMangino, Massimo1 aHwang, Shih-Jen1 aSpector, Timothy, D1 aHunt, Steven, C1 aKimura, Masayuki1 aFitzpatrick, Annette, L1 aChristiansen, Lene1 aPetersen, Inge1 aElbers, Clara, C1 aHarris, Tamara1 aChen, Wei1 aSrinivasan, Sathanur, R1 aKark, Jeremy, D1 aBenetos, Athanase1 aShamieh, Said, El1 aVisvikis-Siest, Sophie1 aChristensen, Kaare1 aBerenson, Gerald, S1 aValdes, Ana, M1 aViñuela, Ana1 aGarcia, Melissa1 aArnett, Donna, K1 aBroeckel, Ulrich1 aProvince, Michael, A1 aPankow, James, S1 aKammerer, Candace1 aLiu, Yongmei1 aNalls, Michael1 aTishkoff, Sarah1 aThomas, Fridtjof1 aZiv, Elad1 aPsaty, Bruce, M1 aBis, Joshua, C1 aRotter, Jerome, I1 aTaylor, Kent, D1 aSmith, Erin1 aSchork, Nicholas, J1 aLevy, Daniel1 aAviv, Abraham uhttps://chs-nhlbi.org/node/609001866nas a2200205 4500008004100000022001400041245016000055210006900215260000900284300001000293490000600303520117400309100002701483700002701510700002301537700002201560700002001582700002201602856003601624 2012 eng d a1948-175600aHemodynamic fluid shear stress response genes and carotid intima-media thickness: a candidate gene association analysis in the cardiovascular health study.0 aHemodynamic fluid shear stress response genes and carotid intima c2012 a174-80 v33 aOBJECTIVE: This study examined whether carotid artery intimal-medial thickness (cIMT) is associated with genetic variations (SNPs) in a hemodynamics-responsive gene pathway.
METHODS: Subjects were Cardiovascular Health Study participants free of cardiovascular events at baseline (N=3388). Genotype was measured using Illumina 370CNV HumanHap chip. Carotid IMT was measured using ultrasound. Estimated mean differences in cIMT per additional minor allele for 366 SNPs in MAP2K5, MAPK7, MEF2A/C, and KLF2 were adjusted for sex, age, clinic, and medication use. SNP-SNP interactions were examined using logic regression for 71 tagSNPs.
RESULTS: None of the associations was significant after correction for multiple comparisons; smallest P-value=0.065 for MAP2K5 and common cIMT. The best-performing logic regression tree combined two SNPs in MAP2K5-rs745212 and rs12905175- and common cIMT; this association was not significant, corrected P-value=0.062.
CONCLUSION: There was not strong evidence of association between genetic variants in a hemodynamics-responsive gene pathway and atherosclerosis among older adults.
1 aSuchy-Dicey, Astrid, M1 aEnquobahrie, Daniel, A1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aMcKnight, Barbara uhttps://chs-nhlbi.org/node/139404494nas a2200925 4500008004100000022001400041245008800055210006900143260001300212300001100225490000600236520191100242653001002153653002202163653000902185653002402194653004002218653001102258653002702269653002202296653001802318653003402336653001102370653000902381653001602390653003602406100001802442700002202460700002102482700002202503700001702525700001902542700002002561700002002581700001702601700002002618700001802638700002202656700002202678700002402700700002402724700001202748700002402760700002202784700001402806700001902820700001602839700001902855700002202874700001702896700002002913700002402933700001902957700002502976700002103001700002403022700002503046700002003071700002403091700002203115700002803137700001903165700002003184700001903204700002003223700001903243700002303262700002203285700002103307700002003328700001903348700002203367700001803389700002203407700002303429700002103452700002903473710003003502856003603532 2012 eng d a1942-326800aImpact of ancestry and common genetic variants on QT interval in African Americans.0 aImpact of ancestry and common genetic variants on QT interval in c2012 Dec a647-550 v53 aBACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.
METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.
CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.
10aAdult10aAfrican Americans10aAged10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aGenealogy and Heraldry10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aSmith, Gustav1 aAvery, Christy, L1 aEvans, Daniel, S1 aNalls, Michael, A1 aMeng, Yan, A1 aSmith, Erin, N1 aPalmer, Cameron1 aTanaka, Toshiko1 aMehra, Reena1 aButler, Anne, M1 aYoung, Taylor1 aBuxbaum, Sarah, G1 aKerr, Kathleen, F1 aBerenson, Gerald, S1 aSchnabel, Renate, B1 aLi, Guo1 aEllinor, Patrick, T1 aMagnani, Jared, W1 aChen, Wei1 aBis, Joshua, C1 aCurb, David1 aHsueh, Wen-Chi1 aRotter, Jerome, I1 aLiu, Yongmei1 aNewman, Anne, B1 aLimacher, Marian, C1 aNorth, Kari, E1 aReiner, Alexander, P1 aQuibrera, Miguel1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSolomon, Allen, J1 aSrinivasan, Sathanur, R1 aAlonso, Alvaro1 aWallace, Robert1 aRedline, Susan1 aZhang, Zhu-Ming1 aPost, Wendy, S1 aZonderman, Alan, B1 aTaylor, Herman, A1 aMurray, Sarah, S1 aFerrucci, Luigi1 aArking, Dan, E1 aEvans, Michele, K1 aFox, Ervin, R1 aSotoodehnia, Nona1 aHeckbert, Susan, R1 aWhitsel, Eric, A1 aNewton-Cheh, Christopher1 aCARe and COGENT consortia uhttps://chs-nhlbi.org/node/617902754nas a2200385 4500008004100000022001400041245009400055210006900149260001300218300001200231490000700243520167100250653000901921653002401930653001601954653002601970653001101996653001102007653000902018653001602027653001802043100002602061700002302087700002202110700002002132700002002152700002402172700002002196700002102216700002402237700002402261700002302285700002402308856003602332 2012 eng d a1522-964500aThe impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study.0 aimpact of height on the risk of atrial fibrillation the Cardiova c2012 Nov a2709-170 v333 aAIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice.
METHODS AND RESULTS: We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6%) and 568 (27.1%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)(women) per 10 cm 1.32, confidence interval (CI) 1.16-1.50, P < 0.0001; HR(men) per 10 cm 1.26, CI 1.11-1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32-1.65, without height, and HR 0.94, CI 0.85-1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height.
CONCLUSION: Independent from sex, increased height is significantly associated with the risk of AF.
10aAged10aAtrial Fibrillation10aBody Height10aEpidemiologic Methods10aFemale10aHumans10aMale10aSex Factors10aUnited States1 aRosenberg, Michael, A1 aPatton, Kristen, K1 aSotoodehnia, Nona1 aKaras, Maria, G1 aKizer, Jorge, R1 aZimetbaum, Peter, J1 aChang, James, D1 aSiscovick, David1 aGottdiener, John, S1 aKronmal, Richard, A1 aHeckbert, Susan, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/140703315nas a2200529 4500008004100000022001400041245007000055210006700125260001300192300001200205490000700217520186700224653000902091653002202100653001802122653001902140653002302159653002802182653002102210653002102231653001902252653001502271653001202286653001102298653003102309653001102340653002302351653001502374653000902389653001402398653003002412653003202442653002402474653001702498653001802515653002402533100002002557700001602577700002402593700002002617700001902637700002202656700002402678700002302702700002402725856003602749 2012 eng d a1935-554800aInsulin resistance, cystatin C, and mortality among older adults.0 aInsulin resistance cystatin C and mortality among older adults c2012 Jun a1355-600 v353 aOBJECTIVE: Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.
RESEARCH DESIGN AND METHODS: We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥ 65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).
RESULTS: A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6-41) and 11% (-3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4-43) and 4% (-12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.
CONCLUSIONS: Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.
10aAged10aAged, 80 and over10aBlood Glucose10aBlood Pressure10aC-Reactive Protein10aCardiovascular Diseases10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aCystatin C10aFasting10aFemale10aGlomerular Filtration Rate10aHumans10aInsulin Resistance10aLife Style10aMale10aMortality10aPredictive Value of Tests10aProportional Hazards Models10aRenal Insufficiency10aRisk Factors10aTriglycerides10aWaist Circumference1 ade Boer, Ian, H1 aKatz, Ronit1 aChonchol, Michel, B1 aFried, Linda, F1 aIx, Joachim, H1 aKestenbaum, Bryan1 aMukamal, Kenneth, J1 aPeralta, Carmen, A1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/137203458nas a2200481 4500008004100000022001400041245009100055210006900146260001300215300001100228490000700239520210500246653002202351653002502373653002802398653002802426653001502454653001502469653002202484653001102506653003102517653001102548653001702559653002002576653000902596653001502605653003202620653002602652653001702678653001802695100001902713700001602732700002002748700002002768700002302788700002302811700002102834700002102855700002402876700002002900700002002920856003602940 2012 eng d a1532-541500aKidney function and mortality in octogenarians: Cardiovascular Health Study All Stars.0 aKidney function and mortality in octogenarians Cardiovascular He c2012 Jul a1201-70 v603 aOBJECTIVES: To examine the association between kidney function and all-cause mortality in octogenarians.
DESIGN: Retrospective analysis of prospectively collected data.
SETTING: Community.
PARTICIPANTS: Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
MEASUREMENTS: Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFR(CR) ) and cystatin C one-variable (eGFR(CYS) ) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.
RESULTS: Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFR(CR) and all-cause mortality was U-shaped. In comparison with the reference quintile (64-75 mL/min per 1.73 m(2) ), the highest (≥ 75 mL/min per 1.73 m(2) ) and lowest (≤ 43 mL/min per 1.73 m(2) ) quintiles of eGFR(CR) were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36-4.55; HR = 2.28, 95% CI = 1.26-4.10, respectively). The association between eGFR(CYS) and all-cause mortality was linear in those with eGFR(CYS) of less than 60 mL/min per 1.73 m(2) , and in the multivariate analyses, the lowest quintile of eGFR(CYS) (<52 mL/min per 1.73 m(2) ) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12-3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m(2) ).
CONCLUSION: Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFR(CR) and all-cause mortality differed from that observed with eGFR(CYS) ; the relationship was U-shaped for eGFR(CR) , whereas the risk was primarily present in the lowest quintile for eGFR(CYS) .
10aAged, 80 and over10aAnalysis of Variance10aCardiovascular Diseases10aChi-Square Distribution10aCreatinine10aCystatin C10aDiabetes Mellitus10aFemale10aGlomerular Filtration Rate10aHumans10aHypertension10aKidney Diseases10aMale10aPrevalence10aProportional Hazards Models10aRetrospective Studies10aRisk Factors10aUnited States1 aShastri, Shani1 aKatz, Ronit1 aRifkin, Dena, E1 aFried, Linda, F1 aOdden, Michelle, C1 aPeralta, Carmen, A1 aChonchol, Michel1 aSiscovick, David1 aShlipak, Michael, G1 aNewman, Anne, B1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/139508958nas a2202881 4500008004100000022001400041245014400055210006900199260001300268300001300281490000700294520091900301653001001220653001201230653001801242653001201260653001101272653001901283653003401302653001101336653001201347653000901359653003601368653000901404653002601413653002801439100002101467700002001488700001901508700002101527700002201548700001801570700001801588700002501606700001901631700002301650700002201673700003101695700001601726700002101742700002001763700001801783700001801801700002301819700001901842700001801861700002001879700001801899700002501917700002401942700001601966700002101982700002002003700002202023700001702045700001902062700002502081700002002106700002302126700001302149700002502162700001602187700002402203700001402227700002202241700001702263700001802280700002602298700002302324700002202347700002202369700001602391700002102407700002002428700001502448700002402463700002502487700001402512700002502526700002202551700002102573700002002594700001702614700001802631700002502649700002102674700002102695700002102716700002002737700002602757700001802783700002002801700001902821700001502840700002102855700001302876700003002889700002802919700002102947700002102968700002002989700002903009700002403038700002103062700001903083700002103102700002003123700001803143700002003161700002103181700001703202700002103219700002203240700002003262700001403282700002503296700002003321700001803341700001903359700002203378700002403400700002003424700001603444700002103460700001803481700001903499700001703518700002003535700001903555700001903574700002603593700002803619700002303647700002103670700002303691700002203714700002003736700001903756700002503775700002003800700002103820700002403841700002203865700001803887700002203905700002203927700002503949700001903974700002303993700002304016700002104039700002004060700002204080700002304102700002004125700002604145700002504171700002304196700002404219700001604243700002004259700001804279700002004297700002204317700002004339700002404359700002404383700002404407700002304431700002504454700001904479700002304498700001904521700001904540700002004559700002404579700002104603700002004624700001804644700002104662700002004683700002704703700002204730700001904752700002104771700002504792700002004817700002004837700001504857700002104872700002304893700002304916700002204939700001804961700002404979700002005003700001905023700002205042700001905064700002505083700002405108700001905132700002105151700002005172700002405192700002005216700001805236700001805254700002005272700002405292700001905316700002105335700003705356700002205393700002305415700002105438700001505459700001905474700002305493700001905516700002205535700002105557700002005578700002005598700002105618700002105639700002205660700001805682700002705700700002505727700002505752700002205777700002005799700002005819700002405839700002005863700002405883700002005907700002105927700001905948710007305967856003606040 2012 eng d a1546-171800aLarge-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.0 aLargescale association analyses identify new loci influencing gl c2012 Sep a991-10050 v443 aThrough genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
10aAdult10aAnimals10aBlood Glucose10aFasting10aFemale10aGene Frequency10aGenome-Wide Association Study10aHumans10aInsulin10aMale10aMetabolic Networks and Pathways10aMice10aOsmolar Concentration10aQuantitative Trait Loci1 aScott, Robert, A1 aLagou, Vasiliki1 aWelch, Ryan, P1 aWheeler, Eleanor1 aMontasser, May, E1 aLuan, Jian'an1 aMägi, Reedik1 aStrawbridge, Rona, J1 aRehnberg, Emil1 aGustafsson, Stefan1 aKanoni, Stavroula1 aRasmussen-Torvik, Laura, J1 aYengo, Loic1 aLecoeur, Cécile1 aShungin, Dmitry1 aSanna, Serena1 aSidore, Carlo1 aJohnson, Paul, C D1 aJukema, Wouter1 aJohnson, Toby1 aMahajan, Anubha1 aVerweij, Niek1 aThorleifsson, Gudmar1 aHottenga, Jouke-Jan1 aShah, Sonia1 aSmith, Albert, V1 aSennblad, Bengt1 aGieger, Christian1 aSalo, Perttu1 aPerola, Markus1 aTimpson, Nicholas, J1 aEvans, David, M1 aSt Pourcain, Beate1 aWu, Ying1 aAndrews, Jeanette, S1 aHui, Jennie1 aBielak, Lawrence, F1 aZhao, Wei1 aHorikoshi, Momoko1 aNavarro, Pau1 aIsaacs, Aaron1 aO'Connell, Jeffrey, R1 aStirrups, Kathleen1 aVitart, Veronique1 aHayward, Caroline1 aEsko, Tõnu1 aMihailov, Evelin1 aFraser, Ross, M1 aFall, Tove1 aVoight, Benjamin, F1 aRaychaudhuri, Soumya1 aChen, Han1 aLindgren, Cecilia, M1 aMorris, Andrew, P1 aRayner, Nigel, W1 aRobertson, Neil1 aRybin, Denis1 aLiu, Ching-Ti1 aBeckmann, Jacques, S1 aWillems, Sara, M1 aChines, Peter, S1 aJackson, Anne, U1 aKang, Hyun, Min1 aStringham, Heather, M1 aSong, Kijoung1 aTanaka, Toshiko1 aPeden, John, F1 aGoel, Anuj1 aHicks, Andrew, A1 aAn, Ping1 aMüller-Nurasyid, Martina1 aFranco-Cereceda, Anders1 aFolkersen, Lasse1 aMarullo, Letizia1 aJansen, Hanneke1 aOldehinkel, Albertine, J1 aBruinenberg, Marcel1 aPankow, James, S1 aNorth, Kari, E1 aForouhi, Nita, G1 aLoos, Ruth, J F1 aEdkins, Sarah1 aVarga, Tibor, V1 aHallmans, Göran1 aOksa, Heikki1 aAntonella, Mulas1 aNagaraja, Ramaiah1 aTrompet, Stella1 aFord, Ian1 aBakker, Stephan, J L1 aKong, Augustine1 aKumari, Meena1 aGigante, Bruna1 aHerder, Christian1 aMunroe, Patricia, B1 aCaulfield, Mark1 aAntti, Jula1 aMangino, Massimo1 aSmall, Kerrin1 aMiljkovic, Iva1 aLiu, Yongmei1 aAtalay, Mustafa1 aKiess, Wieland1 aJames, Alan, L1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aPalmer, Colin, N A1 aDoney, Alex, S F1 aWillemsen, Gonneke1 aSmit, Johannes, H1 aCampbell, Susan1 aPolasek, Ozren1 aBonnycastle, Lori, L1 aHercberg, Serge1 aDimitriou, Maria1 aBolton, Jennifer, L1 aFowkes, Gerard, R1 aKovacs, Peter1 aLindström, Jaana1 aZemunik, Tatijana1 aBandinelli, Stefania1 aWild, Sarah, H1 aBasart, Hanneke, V1 aRathmann, Wolfgang1 aGrallert, Harald1 aMaerz, Winfried1 aKleber, Marcus, E1 aBoehm, Bernhard, O1 aPeters, Annette1 aPramstaller, Peter, P1 aProvince, Michael, A1 aBorecki, Ingrid, B1 aHastie, Nicholas, D1 aRudan, Igor1 aCampbell, Harry1 aWatkins, Hugh1 aFarrall, Martin1 aStumvoll, Michael1 aFerrucci, Luigi1 aWaterworth, Dawn, M1 aBergman, Richard, N1 aCollins, Francis, S1 aTuomilehto, Jaakko1 aWatanabe, Richard, M1 aGeus, Eco, J C1 aPenninx, Brenda, W1 aHofman, Albert1 aOostra, Ben, A1 aPsaty, Bruce, M1 aVollenweider, Peter1 aWilson, James, F1 aWright, Alan, F1 aHovingh, Kees1 aMetspalu, Andres1 aUusitupa, Matti1 aMagnusson, Patrik, K E1 aKyvik, Kirsten, O1 aKaprio, Jaakko1 aPrice, Jackie, F1 aDedoussis, George, V1 aDeloukas, Panos1 aMeneton, Pierre1 aLind, Lars1 aBoehnke, Michael1 aShuldiner, Alan, R1 aDuijn, Cornelia, M1 aMorris, Andrew, D1 aToenjes, Anke1 aPeyser, Patricia, A1 aBeilby, John, P1 aKörner, Antje1 aKuusisto, Johanna1 aLaakso, Markku1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aLakka, Timo, A1 aRauramaa, Rainer1 aAdair, Linda, S1 aSmith, George Davey1 aSpector, Tim, D1 aIllig, Thomas1 ade Faire, Ulf1 aHamsten, Anders1 aGudnason, Vilmundur1 aKivimaki, Mika1 aHingorani, Aroon1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aBoomsma, Dorret, I1 aStefansson, Kari1 aHarst, Pim1 aDupuis, Josée1 aPedersen, Nancy, L1 aSattar, Naveed1 aHarris, Tamara, B1 aCucca, Francesco1 aRipatti, Samuli1 aSalomaa, Veikko1 aMohlke, Karen, L1 aBalkau, Beverley1 aFroguel, Philippe1 aPouta, Anneli1 aJarvelin, Marjo-Riitta1 aWareham, Nicholas, J1 aBouatia-Naji, Nabila1 aMcCarthy, Mark, I1 aFranks, Paul, W1 aMeigs, James, B1 aTeslovich, Tanya, M1 aFlorez, Jose, C1 aLangenberg, Claudia1 aIngelsson, Erik1 aProkopenko, Inga1 aBarroso, Inês1 aDIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium uhttps://chs-nhlbi.org/node/609102931nas a2200313 4500008004100000022001400041245013200055210006900187260000900256490000600265520193300271100001902204700002102223700002502244700001802269700001702287700002002304700002002324700002202344700001702366700002902383700001902412700002002431700002202451700002102473700002802494710005902522856003602581 2012 eng d a2044-605500aLarge-scale international validation of the ADO index in subjects with COPD: an individual subject data analysis of 10 cohorts.0 aLargescale international validation of the ADO index in subjects c20120 v23 aBACKGROUND: Little evidence on the validity of simple and widely applicable tools to predict mortality in patients with chronic obstructive pulmonary disease (COPD) exists.
OBJECTIVE: To conduct a large international study to validate the ADO index that uses age, dyspnoea and FEV(1) to predict 3-year mortality and to update it in order to make prediction of mortality in COPD patients as generalisable as possible.
DESIGN: Individual subject data analysis of 10 European and American cohorts (n=13 914).
SETTING: Population-based, primary, secondary and tertiary care.
PATIENTS: COPD GOLD stages I-IV.
MEASUREMENTS: We validated the original ADO index. We then obtained an updated ADO index in half of our cohorts to improve its predictive accuracy, which in turn was validated comprehensively in the remaining cohorts using discrimination, calibration and decision curve analysis and a number of sensitivity analyses.
RESULTS: 1350 (9.7%) of all subjects with COPD (60% male, mean age 61 years, mean FEV(1) 66% predicted) had died at 3 years. The original ADO index showed high discrimination but poor calibration (p<0.001 for difference between predicted and observed risk). The updated ADO index (scores from 0 to 14) preserved excellent discrimination (area under curve 0.81, 95% CI 0.80 to 0.82) but showed much improved calibration with predicted 3-year risks from 0.7% (95% CI 0.6% to 0.9%, score of 0) to 64.5% (61.2% to 67.7%, score of 14). The ADO index showed higher net benefit in subjects at low-to-moderate risk of 3-year mortality than FEV(1) alone.
INTERPRETATION: The updated 15-point ADO index accurately predicts 3-year mortality across the COPD severity spectrum and can be used to inform patients about their prognosis, clinical trial study design or benefit harm assessment of medical interventions.
1 aPuhan, Milo, A1 aHansel, Nadia, N1 aSobradillo, Patricia1 aEnright, Paul1 aLange, Peter1 aHickson, Demarc1 aMenezes, Ana, M1 aRiet, Gerben, ter1 aHeld, Ulrike1 aDomingo-Salvany, Antonia1 aMosenifar, Zab1 aAntó, Josep, M1 aMoons, Karel, G M1 aKessels, Alphons1 aGarcia-Aymerich, Judith1 aInternational COPD Cohorts Collaboration Working Group uhttps://chs-nhlbi.org/node/737804973nas a2200937 4500008004100000022001400041245006500055210006300120260001600183300001300199490000800212520237500220653000902595653001502604653002802619653002102647653001902668653001102687653001102698653001702709653000902726653001602735653002002751110004002771700003002811700001302841700001902854700002102873700002002894700002402914700002502938700001902963700001902982700002103001700002803022700002003050700002203070700002003092700002003112700002303132700001403155700002403169700001903193700002103212700002503233700001803258700002503276700002403301700002203325700001903347700001603366700002303382700003503405700002203440700002503462700002003487700002103507700002203528700001903550700002003569700003003589700001903619700001803638700001903656700002003675700002203695700002503717700001803742700002003760700002203780700002303802700002803825700002003853700002303873700002403896700001903920700001903939700002403958700001703982856003603999 2012 eng d a1538-359800aLipid-related markers and cardiovascular disease prediction.0 aLipidrelated markers and cardiovascular disease prediction c2012 Jun 20 a2499-5060 v3073 aCONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.
OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.
DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).
MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.
RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.
CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.
10aAged10aBiomarkers10aCardiovascular Diseases10aCholesterol, HDL10aCohort Studies10aFemale10aHumans10aLipoproteins10aMale10aMiddle Aged10aRisk Assessment1 aEmerging Risk Factors Collaboration1 aDi Angelantonio, Emanuele1 aGao, Pei1 aPennells, Lisa1 aKaptoge, Stephen1 aCaslake, Muriel1 aThompson, Alexander1 aButterworth, Adam, S1 aSarwar, Nadeem1 aWormser, David1 aSaleheen, Danish1 aBallantyne, Christie, M1 aPsaty, Bruce, M1 aSundström, Johan1 aRidker, Paul, M1 aNagel, Dorothea1 aGillum, Richard, F1 aFord, Ian1 aDucimetiere, Pierre1 aKiechl, Stefan1 aKoenig, Wolfgang1 aDullaart, Robin, P F1 aAssmann, Gerd1 aD'Agostino, Ralph, B1 aDagenais, Gilles, R1 aCooper, Jackie, A1 aKromhout, Daan1 aOnat, Altan1 aTipping, Robert, W1 aGómez-de-la-Cámara, Agustín1 aRosengren, Annika1 aSutherland, Susan, E1 aGallacher, John1 aFowkes, Gerry, R1 aCasiglia, Edoardo1 aHofman, Albert1 aSalomaa, Veikko1 aBarrett-Connor, Elizabeth1 aClarke, Robert1 aBrunner, Eric1 aJukema, Wouter1 aSimons, Leon, A1 aSandhu, Manjinder1 aWareham, Nicholas, J1 aKhaw, Kay-Tee1 aKauhanen, Jussi1 aSalonen, Jukka, T1 aHoward, William, J1 aNordestgaard, Børge, G1 aWood, Angela, M1 aThompson, Simon, G1 aBoekholdt, Matthijs1 aSattar, Naveed1 aPackard, Chris1 aGudnason, Vilmundur1 aDanesh, John uhttps://chs-nhlbi.org/node/139907748nas a2202497 4500008004100000022001400041245011400055210006900169260001600238300001000254490000700264520075000271653001601021653001801037653002501055653001601080653001501096653002301111653003201134653004001166653002601206653001101232653001701243653003401260653001101294653001301305653001401318653003601332653001301368100001901381700002101400700002301421700001601444700002101460700001901481700001901500700001701519700001901536700001901555700001601574700002301590700002801613700002401641700001701665700002401682700002001706700001801726700002101744700002601765700001801791700001901809700001801828700002501846700001901871700002501890700002501915700002501940700001801965700002101983700002402004700001802028700002002046700002402066700002002090700002502110700001802135700002402153700001702177700001702194700001802211700001902229700001802248700002702266700002502293700001802318700002402336700002002360700002302380700002402403700001902427700002002446700002002466700002102486700002302507700002102530700002202551700001902573700002602592700001402618700001902632700002402651700001602675700002202691700002102713700001902734700002002753700002602773700002302799700001902822700002402841700001802865700002102883700001802904700002102922700001602943700001602959700001702975700002102992700002203013700001703035700002003052700002303072700002703095700001903122700002403141700003003165700002303195700002203218700002203240700001803262700002003280700001703300700002003317700002003337700003103357700001903388700002103407700002003428700002303448700002403471700002003495700002103515700001903536700002103555700002003576700002303596700001903619700002203638700001603660700001703676700002103693700002003714700002203734700002303756700002003779700002003799700002103819700001903840700002703859700002303886700002103909700002603930700001603956700001903972700002103991700002104012700002604033700001404059700001804073700002004091700002204111700002304133700002204156700002404178700002304202700002204225700002004247700002504267700002304292700002104315700003404336700002304370700002104393700003004414700002004444700003104464700002204495700001604517700002504533700001904558700002104577700002304598700002104621700002004642700002304662700002404685700002204709700001704731700002104748700002204769700002104791700002504812700001904837700002004856700001804876700002404894700002004918700002104938700002704959700002804986700001705014700002805031700002305059700001905082700001705101700002405118700002105142700002405163710002705187856003605214 2012 eng d a1546-171800aMeta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.0 aMetaanalyses identify 13 loci associated with age at menopause a c2012 Jan 22 a260-80 v443 aTo newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
10aAge Factors10aDNA Helicases10aDNA Polymerase gamma10aDNA Primase10aDNA Repair10aDNA Repair Enzymes10aDNA-Directed DNA Polymerase10aEuropean Continental Ancestry Group10aExodeoxyribonucleases10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aImmunity10aMenopause10aPolymorphism, Single Nucleotide10aProteins1 aStolk, Lisette1 aPerry, John, R B1 aChasman, Daniel, I1 aHe, Chunyan1 aMangino, Massimo1 aSulem, Patrick1 aBarbalic, Maja1 aBroer, Linda1 aByrne, Enda, M1 aErnst, Florian1 aEsko, Tõnu1 aFranceschini, Nora1 aGudbjartsson, Daniel, F1 aHottenga, Jouke-Jan1 aKraft, Peter1 aMcArdle, Patrick, F1 aPorcu, Eleonora1 aShin, So-Youn1 aSmith, Albert, V1 avan Wingerden, Sophie1 aZhai, Guangju1 aZhuang, Wei, V1 aAlbrecht, Eva1 aAlizadeh, Behrooz, Z1 aAspelund, Thor1 aBandinelli, Stefania1 aLauc, Lovorka, Barac1 aBeckmann, Jacques, S1 aBoban, Mladen1 aBoerwinkle, Eric1 aBroekmans, Frank, J1 aBurri, Andrea1 aCampbell, Harry1 aChanock, Stephen, J1 aChen, Constance1 aCornelis, Marilyn, C1 aCorre, Tanguy1 aCoviello, Andrea, D1 aD'Adamo, Pio1 aDavies, Gail1 ade Faire, Ulf1 aGeus, Eco, J C1 aDeary, Ian, J1 aDedoussis, George, V Z1 aDeloukas, Panagiotis1 aEbrahim, Shah1 aEiriksdottir, Gudny1 aEmilsson, Valur1 aEriksson, Johan, G1 aFauser, Bart, C J M1 aFerreli, Liana1 aFerrucci, Luigi1 aFischer, Krista1 aFolsom, Aaron, R1 aGarcia, Melissa, E1 aGasparini, Paolo1 aGieger, Christian1 aGlazer, Nicole1 aGrobbee, Diederick, E1 aHall, Per1 aHaller, Toomas1 aHankinson, Susan, E1 aHass, Merli1 aHayward, Caroline1 aHeath, Andrew, C1 aHofman, Albert1 aIngelsson, Erik1 aJanssens, Cecile, J W1 aJohnson, Andrew, D1 aKarasik, David1 aKardia, Sharon, L R1 aKeyzer, Jules1 aKiel, Douglas, P1 aKolcic, Ivana1 aKutalik, Zoltán1 aLahti, Jari1 aLai, Sandra1 aLaisk, Triin1 aLaven, Joop, S E1 aLawlor, Debbie, A1 aLiu, Jianjun1 aLopez, Lorna, M1 aLouwers, Yvonne, V1 aMagnusson, Patrik, K E1 aMarongiu, Mara1 aMartin, Nicholas, G1 aKlaric, Irena, Martinovic1 aMasciullo, Corrado1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMelzer, David1 aMooser, Vincent1 aNavarro, Pau1 aNewman, Anne, B1 aNyholt, Dale, R1 aOnland-Moret, Charlotte, N1 aPalotie, Aarno1 aParé, Guillaume1 aParker, Alex, N1 aPedersen, Nancy, L1 aPeeters, Petra, H M1 aPistis, Giorgio1 aPlump, Andrew, S1 aPolasek, Ozren1 aPop, Victor, J M1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRehnberg, Emil1 aRotter, Jerome, I1 aRudan, Igor1 aSala, Cinzia1 aSalumets, Andres1 aScuteri, Angelo1 aSingleton, Andrew1 aSmith, Jennifer, A1 aSnieder, Harold1 aSoranzo, Nicole1 aStacey, Simon, N1 aStarr, John, M1 aStathopoulou, Maria, G1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStyrkarsdottir, Unnur1 aSun, Yan, V1 aTenesa, Albert1 aThorand, Barbara1 aToniolo, Daniela1 aTryggvadottir, Laufey1 aTsui, Kim1 aUlivi, Sheila1 avan Dam, Rob, M1 aSchouw, Yvonne, T1 avan Gils, Carla, H1 avan Nierop, Peter1 aVink, Jacqueline, M1 aVisscher, Peter, M1 aVoorhuis, Marlies1 aWaeber, Gérard1 aWallaschofski, Henri1 aWichmann, Erich, H1 aWiden, Elisabeth1 avan Gent, Colette, J M Wijnan1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZemunik, Tatijana1 aZgaga, Lina1 aZillikens, Carola, M1 aZygmunt, Marek1 aArnold, Alice, M1 aBoomsma, Dorret, I1 aBuring, Julie, E1 aCrisponi, Laura1 aDemerath, Ellen, W1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHu, Frank, B1 aHunter, David, J1 aLauner, Lenore, J1 aMetspalu, Andres1 aMontgomery, Grant, W1 aOostra, Ben, A1 aRidker, Paul, M1 aSanna, Serena1 aSchlessinger, David1 aSpector, Tim, D1 aStefansson, Kari1 aStreeten, Elizabeth, A1 aThorsteinsdottir, Unnur1 aUda, Manuela1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aMurray, Anna1 aMurabito, Joanne, M1 aVisser, Jenny, A1 aLunetta, Kathryn, L1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/136004917nas a2201453 4500008004100000022001400041245008200055210006900137260001600206300001000222490000700232520088500239653001501124653001001139653000901149653002201158653003701180653002401217653001001241653002101251653004001272653001101312653001701323653003801340653003401378653001101412653001101423653002001434653000901454653001601463653003601479653001701515653001601532100002401548700002401572700002501596700002201621700002401643700002101667700001901688700003001707700002201737700002201759700001901781700001901800700001801819700001901837700002201856700001801878700001801896700002201914700001701936700002001953700002301973700002301996700002202019700002102041700002602062700002202088700001702110700002202127700002202149700002302171700002202194700002202216700002302238700002202261700001902283700001702302700001902319700002002338700001902358700002102377700001702398700002402415700002402439700001202463700002602475700001902501700002002520700001902540700002002559700001702579700002302596700002302619700002202642700001402664700002202678700001702700700002102717700001802738700001902756700002002775700002102795700002102816700002002837700002202857700002002879700002202899700003002921700002002951700002202971700001802993700002803011700002603039700002203065700002203087700002003109700001703129700002303146700001903169700002203188700002603210700002203236700001903258700001903277700001803296700002303314700002303337700002403360700002403384700001903408856003603427 2012 eng d a1546-171800aMeta-analysis identifies six new susceptibility loci for atrial fibrillation.0 aMetaanalysis identifies six new susceptibility loci for atrial f c2012 Apr 29 a670-50 v443 aAtrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChild10aChild, Preschool10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aAlbert, Christine, M1 aGlazer, Nicole, L1 aRitchie, Marylyn, D1 aSmith, Albert, V1 aArking, Dan, E1 aMüller-Nurasyid, Martina1 aKrijthe, Bouwe, P1 aLubitz, Steven, A1 aBis, Joshua, C1 aChung, Mina, K1 aDörr, Marcus1 aOzaki, Kouichi1 aRoberts, Jason, D1 aSmith, Gustav1 aPfeufer, Arne1 aSinner, Moritz, F1 aLohman, Kurt1 aDing, Jingzhong1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aRienstra, Michiel1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aMagnani, Jared, W1 aWakili, Reza1 aClauss, Sebastian1 aRotter, Jerome, I1 aSteinbeck, Gerhard1 aLauner, Lenore, J1 aDavies, Robert, W1 aBorkovich, Matthew1 aHarris, Tamara, B1 aLin, Honghuang1 aVölker, Uwe1 aVölzke, Henry1 aMilan, David, J1 aHofman, Albert1 aBoerwinkle, Eric1 aChen, Lin, Y1 aSoliman, Elsayed, Z1 aVoight, Benjamin, F1 aLi, Guo1 aChakravarti, Aravinda1 aKubo, Michiaki1 aTedrow, Usha, B1 aRose, Lynda, M1 aRidker, Paul, M1 aConen, David1 aTsunoda, Tatsuhiko1 aFurukawa, Tetsushi1 aSotoodehnia, Nona1 aXu, Siyan1 aKamatani, Naoyuki1 aLevy, Daniel1 aNakamura, Yusuke1 aParvez, Babar1 aMahida, Saagar1 aFurie, Karen, L1 aRosand, Jonathan1 aMuhammad, Raafia1 aPsaty, Bruce, M1 aMeitinger, Thomas1 aPerz, Siegfried1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aKao, Linda, W H1 aKathiresan, Sekar1 aRoden, Dan, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aMcKnight, Barbara1 aSjögren, Marketa1 aNewman, Anne, B1 aLiu, Yongmei1 aGollob, Michael, H1 aMelander, Olle1 aTanaka, Toshihiro1 aStricker, Bruno, H Ch1 aFelix, Stephan, B1 aAlonso, Alvaro1 aDarbar, Dawood1 aBarnard, John1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aKääb, Stefan uhttps://chs-nhlbi.org/node/138303041nas a2200541 4500008004100000022001400041245007600055210006900131260000900200300001100209490000600220520147100226653002201697653002101719653002101740653004001761653003201801653001701833653001101850653003601861653001801897100002001915700002401935700002201959700002101981700002102002700002102023700002202044700002502066700002202091700002102113700001902134700002002153700002802173700002102201700001502222700002202237700002202259700002302281700002002304700002502324700002202349700002102371700002802392700002202420700002102442856003602463 2012 eng d a1932-620300aMulti-ethnic analysis of lipid-associated loci: the NHLBI CARe project.0 aMultiethnic analysis of lipidassociated loci the NHLBI CARe proj c2012 ae364730 v73 aBACKGROUND: Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.
METHODOLOGY/PRINCIPAL FINDINGS: We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed.
CONCLUSIONS/SIGNIFICANCE: We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.
10aAfrican Americans10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenetic Loci10aHumans10aPolymorphism, Single Nucleotide10aTriglycerides1 aMusunuru, Kiran1 aRomaine, Simon, P R1 aLettre, Guillaume1 aWilson, James, G1 aVolcik, Kelly, A1 aTsai, Michael, Y1 aTaylor, Herman, A1 aSchreiner, Pamela, J1 aRotter, Jerome, I1 aRich, Stephen, S1 aRedline, Susan1 aPsaty, Bruce, M1 aPapanicolaou, George, J1 aOrdovas, Jose, M1 aLiu, Kiang1 aKrauss, Ronald, M1 aGlazer, Nicole, L1 aGabriel, Stacey, B1 aFornage, Myriam1 aCupples, Adrienne, L1 aBuxbaum, Sarah, G1 aBoerwinkle, Eric1 aBallantyne, Christie, M1 aKathiresan, Sekar1 aRader, Daniel, J uhttps://chs-nhlbi.org/node/138802907nas a2200325 4500008004100000022001400041245010000055210006900155260000900224300001100233490000600244520199600250653000902246653002802255653002802283653001102311653001102322653000902333653001602342653001302358653002002371653002602391100002602417700002402443700002202467700001602489700002002505700002002525856003602545 2012 eng d a1932-620300aNocturia, sleep-disordered breathing, and cardiovascular morbidity in a community-based cohort.0 aNocturia sleepdisordered breathing and cardiovascular morbidity c2012 ae309690 v73 aBACKGROUND: Nocturia has been independently associated with cardiovascular morbidity and all-cause mortality, but such studies did not adjust for sleep-disordered breathing (SDB), which may have mediated such a relationship. Our aims were to determine whether an association between nocturia and cardiovascular morbidity exists that is independent of SDB. We also determined whether nocturia is independently associated with SDB.
METHODOLOGY/PRINCIPAL FINDINGS: In order to accomplish these aims we performed a cross-sectional analysis of the Sleep Heart Health Study that contained information regarding SDB, nocturia, and cardiovascular morbidity in a middle-age to elderly community-based population. In 6342 participants (age 63±11 [SD] years, 53% women), after adjusting for known confounders such as age, body mass index, diuretic use, diabetes mellitus, alpha-blocker use, nocturia was independently associated with SDB (measured as Apnea Hypopnea index >15 per hour; OR 1.3; 95%CI, 1.2-1.5). After adjusting for SDB and other known confounders, nocturia was independently associated with prevalent hypertension (OR 1.23; 95%CI 1.08-1.40; P = 0.002), cardiovascular disease (OR 1.26; 95%CI 1.05-1.52; P = 0.02) and stroke (OR 1.62; 95%CI 1.14-2.30; P = 0.007). Moreover, nocturia was also associated with adverse objective alterations of sleep as measured by polysomnography and self-reported excessive daytime sleepiness (P<0.05).
CONCLUSIONS/SIGNIFICANCE: Nocturia is independently associated with sleep-disordered breathing. After adjusting for SDB, there remained an association between nocturia and cardiovascular morbidity. Such results support screening for SDB in patients with nocturia, but the mechanisms underlying the relationship between nocturia and cardiovascular morbidity requires further study. MeSH terms: Nocturia, sleep-disordered breathing, obstructive sleep apnea, sleep apnea, polysomnography, hypertension.
10aAged10aCardiovascular Diseases10aCross-Sectional Studies10aFemale10aHumans10aMale10aMiddle Aged10aNocturia10aPolysomnography10aSleep Apnea Syndromes1 aParthasarathy, Sairam1 aFitzgerald, MaryPat1 aGoodwin, James, L1 aUnruh, Mark1 aGuerra, Stefano1 aQuan, Stuart, F uhttps://chs-nhlbi.org/node/155804310nas a2200901 4500008004100000022001400041245011000055210006900165260001300234300001100247490000600258520179200264653001002056653002202066653001902088653002402107653001102131653001702142653003402159653001102193653000902204653002702213653001602240653003602256100002002292700001702312700002102329700002202350700001902372700002002391700001202411700002202423700002102445700001902466700001902485700002402504700002402528700001702552700001402569700001502583700002402598700002302622700001902645700001902664700002402683700002202707700001202729700002402741700001702765700002202782700002602804700001702830700001702847700002002864700002902884700001902913700002302932700002002955700002102975700001902996700002003015700002203035700002403057700002403081700002503105700001803130700002403148700002803172700002003200700002303220700002003243700002103263700002203284700002203306700002203328700002203350856003603372 2012 eng d a1942-326800aNovel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.0 aNovel loci associated with PR interval in a genomewide associati c2012 Dec a639-460 v53 aBACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.
METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).
CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
10aAdult10aAfrican Americans10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide1 aButler, Anne, M1 aYin, Xiaoyan1 aEvans, Daniel, S1 aNalls, Michael, A1 aSmith, Erin, N1 aTanaka, Toshiko1 aLi, Guo1 aBuxbaum, Sarah, G1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBenjamin, Emelia, J1 aBerenson, Gerald, S1 aBis, Josh, C1 aChen, Wei1 aDeo, Rajat1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHsueh, Wen-Chi1 aKeating, Brendan, J1 aKerr, Kathleen, F1 aLi, Yun1 aLimacher, Marian, C1 aLiu, Yongmei1 aLubitz, Steven, A1 aMarciante, Kristin, D1 aMehra, Reena1 aMeng, Yan, A1 aNewman, Anne, B1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPalmer, Cameron, D1 aPsaty, Bruce, M1 aQuibrera, Miguel1 aRedline, Susan1 aReiner, Alex, P1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aSmith, Gustav1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aFerrucci, Luigi1 aMurray, Sarah, S1 aEvans, Michele, K1 aSotoodehnia, Nona1 aMagnani, Jared, W1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/608421848nas a2207177 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2012 eng d a1553-740400aNovel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.0 aNovel loci for adiponectin levels and their influence on type 2 c2012 ae10026070 v83 aCirculating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
10aAdiponectin10aAfrican Americans10aAsian Continental Ancestry Group10aCholesterol, HDL10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGene Expression10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlucose Tolerance Test10aHumans10aInsulin Resistance10aMale10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aDastani, Zari1 aHivert, Marie-France1 aTimpson, Nicholas1 aPerry, John, R B1 aYuan, Xin1 aScott, Robert, A1 aHenneman, Peter1 aHeid, Iris, M1 aKizer, Jorge, R1 aLyytikäinen, Leo-Pekka1 aFuchsberger, Christian1 aTanaka, Toshiko1 aMorris, Andrew, P1 aSmall, Kerrin1 aIsaacs, Aaron1 aBeekman, Marian1 aCoassin, Stefan1 aLohman, Kurt1 aQi, Lu1 aKanoni, Stavroula1 aPankow, James, S1 aUh, Hae-Won1 aWu, Ying1 aBidulescu, Aurelian1 aRasmussen-Torvik, Laura, J1 aGreenwood, Celia, M T1 aLadouceur, Martin1 aGrimsby, Jonna1 aManning, Alisa, K1 aLiu, Ching-Ti1 aKooner, Jaspal1 aMooser, Vincent, E1 aVollenweider, Peter1 aKapur, Karen, A1 aChambers, John1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aFrants, Rune1 aWillems-Vandijk, Ko1 aOostra, Ben, A1 aWillems, Sara, M1 aLamina, Claudia1 aWinkler, Thomas, W1 aPsaty, Bruce, M1 aTracy, Russell, P1 aBrody, Jennifer1 aChen, Ida1 aViikari, Jorma1 aKähönen, Mika1 aPramstaller, Peter, P1 aEvans, David, M1 aSt Pourcain, Beate1 aSattar, Naveed1 aWood, Andrew, R1 aBandinelli, Stefania1 aCarlson, Olga, D1 aEgan, Josephine, M1 aBöhringer, Stefan1 avan Heemst, Diana1 aKedenko, Lyudmyla1 aKristiansson, Kati1 aNuotio, Marja-Liisa1 aLoo, Britt-Marie1 aHarris, Tamara1 aGarcia, Melissa1 aKanaya, Alka1 aHaun, Margot1 aKlopp, Norman1 aWichmann, H-Erich1 aDeloukas, Panos1 aKatsareli, Efi1 aCouper, David, J1 aDuncan, Bruce, B1 aKloppenburg, Margreet1 aAdair, Linda, S1 aBorja, Judith, B1 aWilson, James, G1 aMusani, Solomon1 aGuo, Xiuqing1 aJohnson, Toby1 aSemple, Robert1 aTeslovich, Tanya, M1 aAllison, Matthew, A1 aRedline, Susan1 aBuxbaum, Sarah, G1 aMohlke, Karen, L1 aMeulenbelt, Ingrid1 aBallantyne, Christie, M1 aDedoussis, George, V1 aHu, Frank, B1 aLiu, Yongmei1 aPaulweber, Bernhard1 aSpector, Timothy, D1 aSlagboom, Eline1 aFerrucci, Luigi1 aJula, Antti1 aPerola, Markus1 aRaitakari, Olli1 aFlorez, Jose, C1 aSalomaa, Veikko1 aEriksson, Johan, G1 aFrayling, Timothy, M1 aHicks, Andrew, A1 aLehtimäki, Terho1 aSmith, George Davey1 aSiscovick, David, S1 aKronenberg, Florian1 aDuijn, Cornelia1 aLoos, Ruth, J F1 aWaterworth, Dawn, M1 aMeigs, James, B1 aDupuis, Josée1 aRichards, Brent1 aVoight, Benjamin, F1 aScott, Laura, J1 aSteinthorsdottir, Valgerdur1 aDina, Christian1 aWelch, Ryan, P1 aZeggini, Eleftheria1 aHuth, Cornelia1 aAulchenko, Yurii, S1 aThorleifsson, Gudmar1 aMcCulloch, Laura, J1 aFerreira, Teresa1 aGrallert, Harald1 aAmin, Najaf1 aWu, Guanming1 aWiller, Cristen, J1 aRaychaudhuri, Soumya1 aMcCarroll, Steve, A1 aHofmann, Oliver, M1 aSegrè, Ayellet, V1 aHoek, Mandy1 aNavarro, Pau1 aArdlie, Kristin1 aBalkau, Beverley1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBlagieva, Roza1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBoström, Kristina, Bengtsson1 aBravenboer, Bert1 aBumpstead, Suzannah1 aBurtt, Noel, P1 aCharpentier, Guillaume1 aChines, Peter, S1 aCornelis, Marilyn1 aCrawford, Gabe1 aDoney, Alex, S F1 aElliott, Katherine, S1 aElliott, Amanda, L1 aErdos, Michael, R1 aFox, Caroline, S1 aFranklin, Christopher, S1 aGanser, Martha1 aGieger, Christian1 aGrarup, Niels1 aGreen, Todd1 aGriffin, Simon1 aGroves, Christopher, J1 aGuiducci, Candace1 aHadjadj, Samy1 aHassanali, Neelam1 aHerder, Christian1 aIsomaa, Bo1 aJackson, Anne, U1 aJohnson, Paul, R V1 aJørgensen, Torben1 aKao, Wen, H L1 aKong, Augustine1 aKraft, Peter1 aKuusisto, Johanna1 aLauritzen, Torsten1 aLi, Man1 aLieverse, Aloysius1 aLindgren, Cecilia, M1 aLyssenko, Valeriya1 aMarre, Michel1 aMeitinger, Thomas1 aMidthjell, Kristian1 aMorken, Mario, A1 aNarisu, Narisu1 aNilsson, Peter1 aOwen, Katharine, R1 aPayne, Felicity1 aPetersen, Ann-Kristin1 aPlatou, Carl1 aProença, Christine1 aProkopenko, Inga1 aRathmann, Wolfgang1 aRayner, William1 aRobertson, Neil, R1 aRocheleau, Ghislain1 aRoden, Michael1 aSampson, Michael, J1 aSaxena, Richa1 aShields, Beverley, M1 aShrader, Peter1 aSigurdsson, Gunnar1 aSparsø, Thomas1 aStrassburger, Klaus1 aStringham, Heather, M1 aSun, Qi1 aSwift, Amy, J1 aThorand, Barbara1 aTichet, Jean1 aTuomi, Tiinamaija1 avan Dam, Rob, M1 avan Haeften, Timon, W1 avan Herpt, Thijs1 avan Vliet-Ostaptchouk, Jana, V1 aWalters, Bragi, G1 aWeedon, Michael, N1 aWijmenga, Cisca1 aWitteman, Jacqueline1 aBergman, Richard, N1 aCauchi, Stephane1 aCollins, Francis, S1 aGloyn, Anna, L1 aGyllensten, Ulf1 aHansen, Torben1 aHide, Winston, A1 aHitman, Graham, A1 aHofman, Albert1 aHunter, David, J1 aHveem, Kristian1 aLaakso, Markku1 aMorris, Andrew, D1 aPalmer, Colin, N A1 aRudan, Igor1 aSijbrands, Eric1 aStein, Lincoln, D1 aTuomilehto, Jaakko1 aUitterlinden, Andre1 aWalker, Mark1 aWatanabe, Richard, M1 aAbecasis, Goncalo, R1 aBoehm, Bernhard, O1 aCampbell, Harry1 aDaly, Mark, J1 aHattersley, Andrew, T1 aPedersen, Oluf1 aBarroso, Inês1 aGroop, Leif1 aSladek, Rob1 aThorsteinsdottir, Unnur1 aWilson, James, F1 aIllig, Thomas1 aFroguel, Philippe1 aDuijn, Cornelia, M1 aStefansson, Kari1 aAltshuler, David1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aSoranzo, Nicole1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aMägi, Reedik1 aRandall, Joshua1 aElliott, Paul1 aRybin, Denis1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aSong, Kijoung1 aGoel, Anuj1 aLajunen, Taina1 aDoney, Alex1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aTimpson, Nicholas, J1 aZabena, Carina1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aAriyurek, Yavuz1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBergmann, Sven1 aBochud, Murielle1 aBonnefond, Amélie1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGrundy, Scott1 aGwilliam, Rhian1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHillman, David, R1 aHingorani, Aroon, D1 aHui, Jennie1 aHung, Joe1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aMahley, Robert1 aMangino, Massimo1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, Braxton, D1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNeville, Matthew, J1 aOrrù, Marco1 aPakyz, Ruth1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurðsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTönjes, Anke1 aUitterlinden, André, G1 aDijk, Ko Willems1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWard, Kim, L1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aSilander, Kaisa1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aSerrano-Ríos, Manuel1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPramstaller, Peter Paul1 aWright, Alan, F1 aStumvoll, Michael1 aHamsten, Anders1 aBuchanan, Thomas, A1 aValle, Timo, T1 aRotter, Jerome, I1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aPeltonen, Leena1 aMooser, Vincent1 aSladek, Robert1 aMusunuru, Kiran1 aSmith, Albert, V1 aEdmondson, Andrew, C1 aStylianou, Ioannis, M1 aKoseki, Masahiro1 aPirruccello, James, P1 aChasman, Daniel, I1 aJohansen, Christopher, T1 aFouchier, Sigrid, W1 aPeloso, Gina, M1 aBarbalic, Maja1 aRicketts, Sally, L1 aBis, Joshua, C1 aFeitosa, Mary, F1 aOrho-Melander, Marju1 aMelander, Olle1 aLi, Xiaohui1 aLi, Mingyao1 aCho, Yoon Shin1 aGo, Min Jin1 aKim, Young, Jin1 aLee, Jong-Young1 aPark, Taesung1 aKim, Kyunga1 aSim, Xueling1 aOng, Rick Twee-Hee1 aCroteau-Chonka, Damien, C1 aLange, Leslie, A1 aSmith, Joshua, D1 aZiegler, Andreas1 aZhang, Weihua1 aZee, Robert, Y L1 aWhitfield, John, B1 aThompson, John, R1 aSurakka, Ida1 aSpector, Tim, D1 aSmit, Johannes, H1 aSinisalo, Juha1 aScott, James1 aSaharinen, Juha1 aSabatti, Chiara1 aRose, Lynda, M1 aRoberts, Robert1 aRieder, Mark1 aParker, Alex, N1 aParé, Guillaume1 aO'Donnell, Christopher, J1 aNieminen, Markku, S1 aNickerson, Deborah, A1 aMontgomery, Grant, W1 aMcArdle, Wendy1 aMasson, David1 aMartin, Nicholas, G1 aMarroni, Fabio1 aLucas, Gavin1 aLuben, Robert1 aLokki, Marja-Liisa1 aLettre, Guillaume1 aLauner, Lenore, J1 aLakatta, Edward, G1 aLaaksonen, Reijo1 aKyvik, Kirsten, O1 aKönig, Inke, R1 aKhaw, Kay-Tee1 aKaplan, Lee, M1 aJohansson, Asa1 aJanssens, Cecile, J W1 aIgl, Wilmar1 aHovingh, Kees1 aHengstenberg, Christian1 aHavulinna, Aki, S1 aHastie, Nicholas, D1 aHarris, Tamara, B1 aHaritunians, Talin1 aHall, Alistair, S1 aGroop, Leif, C1 aGonzalez, Elena1 aFreimer, Nelson, B1 aErdmann, Jeanette1 aEjebe, Kenechi, G1 aDöring, Angela1 aDominiczak, Anna, F1 aDemissie, Serkalem1 aDeloukas, Panagiotis1 ade Faire, Ulf1 aCrawford, Gabriel1 aChen, Yii-der, I1 aCaulfield, Mark, J1 aBoekholdt, Matthijs1 aAssimes, Themistocles, L1 aQuertermous, Thomas1 aSeielstad, Mark1 aWong, Tien, Y1 aTai, E-Shyong1 aFeranil, Alan, B1 aKuzawa, Christopher, W1 aTaylor, Herman, A1 aGabriel, Stacey, B1 aHolm, Hilma1 aGudnason, Vilmundur1 aKrauss, Ronald, M1 aOrdovas, Jose, M1 aMunroe, Patricia, B1 aKooner, Jaspal, S1 aTall, Alan, R1 aHegele, Robert, A1 aKastelein, John, J P1 aSchadt, Eric, E1 aStrachan, David, P1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aKathiresan, Sekar1 aDIAGRAM+ Consortium1 aMAGIC Consortium1 aGLGC Investigators1 aMuTHER Consortium1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal B Pgen Consortium1 aProcardis Consortium1 aMAGIC investigators1 aGLGC Consortium uhttps://chs-nhlbi.org/node/137802763nas a2200493 4500008004100000022001400041245010300055210006900158260001300227300001100240490000700251520140800258653003101666653001601697653000901713653002201722653001001744653002601754653002101780653001101801653002501812653001801837653001901855653001101874653001801885653000901903653002401912653001401936653001701950653003001967653002001997653001702017653002202034653001702056653001802073653002002091653001202111100002602123700002102149700002102170700002202191700002002213856003602233 2012 eng d a1468-283400aPredicting late-life disability and death by the rate of decline in physical performance measures.0 aPredicting latelife disability and death by the rate of decline c2012 Mar a155-610 v413 aBACKGROUND: the rate of performance decline may influence the risk of disability or death.
METHODS: for 4,182 Cardiovascular Health Study participants, we used multinomial Poisson log-linear models to assess the contribution of physical performance in 1998-99, and the rate of performance change between 1992-93 and 1998-99, to the risk of death or disability in 2005-06 in three domains: mobility, upper-extremity function (UEF) and activities of daily living (ADL). We evaluated performance in finger-tapping, grip strength, stride length, gait speed and chair stands separately and together for each outcome, adjusting for age, gender, race and years of disability in that outcome between 1992-93 and 1998-99.
RESULTS: participants' age averaged 79.4 in 1998-99; 1,901 died over 7 years. Compared with the lowest change quintile in stride length, the highest quintile had a 1.32 relative risk (RR) of ADL disability (95% CI: 1.16 -1.96) and a 1.27 RR of death (95% CI: 1.07 -1.51). The highest change quintile for grip strength increased the risk of ADL disability by 35% (95% CI: 1.13 -1.61) and death by 31% (95% CI: 1.16 -1.49), compared with the lowest quintile. The annual change in stride length and grip strength also predicted disability in mobility and UEF.
CONCLUSION: performance trajectories independently predict death and disability.
10aActivities of Daily Living10aAge Factors10aAged10aAged, 80 and over10aAging10aDisability Evaluation10aDisabled Persons10aFemale10aGeriatric Assessment10aHand Strength10aHealth Surveys10aHumans10aLinear Models10aMale10aMobility Limitation10aMortality10aMotor Skills10aPredictive Value of Tests10aRisk Assessment10aRisk Factors10aSurvival Analysis10aTime Factors10aUnited States10aUpper Extremity10aWalking1 aHirsch, Calvin, Hayes1 aBůzková, Petra1 aRobbins, John, A1 aPatel, Kushang, V1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/135702711nas a2200325 4500008004100000022001400041245008600055210006900141260001300210300001100223490000700234520179000241653001902031653002402050653001102074653002402085653002002109653001602129653002602145653001702171653001502188653001702203100002102220700002602241700002002267700001902287700002102306700002202327856003602349 2012 eng d a1365-286900aProbabilistic sleep architecture models in patients with and without sleep apnea.0 aProbabilistic sleep architecture models in patients with and wit c2012 Jun a330-410 v213 aSleep fragmentation of any cause is disruptive to the rejuvenating value of sleep. However, methods to quantify sleep architecture remain limited. We have previously shown that human sleep-wake stage distributions exhibit multi-exponential dynamics, which are fragmented by obstructive sleep apnea (OSA), suggesting that Markov models may be a useful method to quantify architecture in health and disease. Sleep stage data were obtained from two subsets of the Sleep Heart Health Study database: control subjects with no medications, no OSA, no medical co-morbidities and no sleepiness (n = 374); and subjects with severe OSA (n = 338). Sleep architecture was simplified into three stages: wake after sleep onset (WASO); non-rapid eye movement (NREM) sleep; and rapid eye movement (REM) sleep. The connectivity and transition rates among eight 'generator' states of a first-order continuous-time Markov model were inferred from the observed ('phenotypic') distributions: three exponentials each of NREM sleep and WASO; and two exponentials of REM sleep. Ultradian REM cycling was accomplished by imposing time-variation to REM state entry rates. Fragmentation in subjects with severe OSA involved faster transition probabilities as well as additional state transition paths within the model. The Markov models exhibit two important features of human sleep architecture: multi-exponential stage dynamics (accounting for observed bout distributions); and probabilistic transitions (an inherent source of variability). In addition, the model quantifies the fragmentation associated with severe OSA. Markov sleep models may prove important for quantifying sleep disruption to provide objective metrics to correlate with endpoints ranging from sleepiness to cardiovascular morbidity.
10aCohort Studies10aComputer Simulation10aHumans10aModels, Theoretical10aPolysomnography10aProbability10aSleep Apnea Syndromes10aSleep Stages10aSleep, REM10aTime Factors1 aBianchi, Matt, T1 aEiseman, Nathaniel, A1 aCash, Sydney, S1 aMietus, Joseph1 aPeng, Chung-Kang1 aThomas, Robert, J uhttps://chs-nhlbi.org/node/154202456nas a2200325 4500008004100000022001400041245011400055210006900169260001300238300001000251490000700261520152300268653002401791653001901815653001101834653001101845653001401856653002901870653001801899653003101917653000901948653001601957653001701973100002101990700002102011700002202032700002002054700002002074856003602094 2012 eng d a1531-824900aRisk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts.0 aRisk of intraparenchymal hemorrhage with magnetic resonance imag c2012 Apr a552-90 v713 aOBJECTIVE: To determine whether the burden of leukoaraiosis and the number of brain infarcts, defined by magnetic resonance imaging (MRI), are prospectively and independently associated with intraparenchymal hemorrhage (IPH) incidence in a pooled population-based study.
METHODS: Among 4,872 participants initially free of clinical stroke in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, we assessed white matter grade (range, 0-9), reflecting increasing leukoaraiosis, and brain infarcts using MRI. Over a median of 13 years of follow-up, 71 incident, spontaneous IPH events occurred.
RESULTS: After adjustment for other IPH risk factors, the hazard ratios (95% confidence intervals) across white matter grades 0 to 1, 2, 3, and 4 to 9 were 1.00, 1.68 (0.86-3.30), 3.52 (1.80-6.89), and 3.96 (1.90-8.27), respectively (p for trend <0.0001). These hazard ratios were weakened only modestly (p for trend = 0.0003) with adjustment for MRI-defined brain infarcts. The IPH hazard ratios for 0, 1, 2, or ≥3 MRI-defined brain infarcts were 1.00, 1.97 (1.10-3.54), 2.00 (0.83-4.78), and 3.12 (1.31-7.43) (p for trend = 0.002), but these were substantially attenuated when adjusted for white matter grade (p for trend = 0.049).
INTERPRETATION: Greater MRI-defined burden of leukoaraiosis is a risk factor for spontaneous IPH. Spontaneous IPH should be added to the growing list of potential poor outcomes in people with leukoaraiosis.
10aCerebral Infarction10aCohort Studies10aFemale10aHumans10aIncidence10aIntracranial Hemorrhages10aLeukoaraiosis10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aRisk Factors1 aFolsom, Aaron, R1 aYatsuya, Hiroshi1 aMosley, Thomas, H1 aPsaty, Bruce, M1 aLongstreth, W T uhttps://chs-nhlbi.org/node/138102660nas a2200469 4500008004100000022001400041245010500055210006900160260001300229300001200242490000700254520130100261653004401562653000901606653002201615653003401637653002501671653002801696653002701724653003801751653002201789653001101811653001101822653005101833653000901884653003601893653001401929653001901943653001601962100001601978700001501994700002002009700001602029700001802045700001402063700001802077700001402095700001402109700001602123700001502139856003602154 2012 eng d a1532-653500aA screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.0 ascreening study of drugdrug interactions in cerivastatin users a c2012 May a896-9040 v913 aAn analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8.
10aAdverse Drug Reaction Reporting Systems10aAged10aAged, 80 and over10aAryl Hydrocarbon Hydroxylases10aCase-Control Studies10aCytochrome P-450 CYP2C810aCytochrome P-450 CYP3A10aCytochrome P-450 CYP3A Inhibitors10aDrug Interactions10aFemale10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aPlatelet Aggregation Inhibitors10aPyridines10aRhabdomyolysis10aTiclopidine1 aFloyd, J, S1 aKaspera, R1 aMarciante, K, D1 aWeiss, N, S1 aHeckbert, S R1 aLumley, T1 aWiggins, K, L1 aTamraz, B1 aKwok, P-Y1 aTotah, R, A1 aPsaty, B M uhttps://chs-nhlbi.org/node/154902775nas a2200385 4500008004100000022001400041245009300055210006900148260001300217300001200230490000800242520174600250653001601996653000902012653001302021653002502034653001102059653002002070653002202090653001102112653001102123653000902134653001602143653002002159653001502179653002602194653001602220653002602236653000802262100001802270700002502288700001702313700002302330856003602353 2012 eng d a1931-354300aSleep-disordered breathing and caffeine consumption: results of a community-based study.0 aSleepdisordered breathing and caffeine consumption results of a c2012 Sep a631-6380 v1423 aBACKGROUND: Sleepiness is one of the most burdensome symptoms of sleep-disordered breathing (SDB). While caffeine is frequently used to avert sleepiness, the association between SDB and caffeine use has not been thoroughly explored. The current study examined whether SDB is associated with caffeine consumption and if factors such as sex, age, and daytime sleepiness explain or modify the association.
METHODS: Data from the Sleep Heart Health Study, a community-based study on the consequences of SDB, were used to characterize the association between SDB and caffeine intake. SDB was assessed with full-montage polysomnography. Caffeine use was quantified as the number of cans of soda or the cups of coffee or tea consumed daily. The Epworth Sleepiness Scale was used to assess daytime sleepiness. Multivariable negative binomial regression models were used to characterize the independent association between SDB and caffeine use.
RESULTS: Caffeinated soda, but not tea or coffee, intake was independently associated with SDB severity. Compared with participants without SDB, the relative ratios for caffeinated soda consumption in women with mild, moderate, and severe SDB were 1.20 (CI, 1.03-1.41), 1.46 (CI, 1.14-1.87), and 1.73 (CI, 1.23-2.42), respectively. For men, an association was only noted with severe SDB and caffeinated soda use. Age did not modify the SDB-caffeine association, and sleepiness could not explain the observed associations.
CONCLUSIONS: SDB is independently associated with caffeinated soda use in the general community. Identifying excessive caffeine used in SDB has potential significance given the cardiovascular effects of caffeine and untreated SDB.
10aAge Factors10aAged10aCaffeine10aCarbonated Beverages10aCoffee10aData Collection10aDrinking Behavior10aFemale10aHumans10aMale10aMiddle Aged10aPolysomnography10aPrevalence10aRetrospective Studies10aSex Factors10aSleep Apnea Syndromes10aTea1 aAurora, Nisha1 aCrainiceanu, Ciprian1 aCaffo, Brian1 aPunjabi, Naresh, M uhttps://chs-nhlbi.org/node/154002549nas a2200433 4500008004100000022001400041245013900055210006900194260001300263300001100276490000800287520129900295653000901594653002201603653002801625653001901653653004001672653001101712653001101723653001501734653000901749653002601758653003601784653000901820653000801829653001601837653001501853653001301868100003101881700002801912700002401940700002001964700002001984700001702004700001902021700002102040700001802061856003602079 2012 eng d a1872-621600aTelomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study.0 aTelomereassociated polymorphisms correlate with cardiovascular d c2012 May a275-810 v1333 aLeukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989-1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r(2)=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5-0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20-1.4 (CC vs. AA) (P-trend <0.01). For men there was no association, HR=1.0; 95% CI: 0.7-1.3 (CC vs. AC) and HR=1.7; 95% CI: 0.8-3.6 (CC vs. AA) (P-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aHumans10aLeukocytes10aMale10aPolymorphism, Genetic10aPolymorphism, Single Nucleotide10aRisk10aRNA10aSex Factors10aTelomerase10aTelomere1 aBurnett-Hartman, Andrea, N1 aFitzpatrick, Annette, L1 aKronmal, Richard, A1 aPsaty, Bruce, M1 aJenny, Nancy, S1 aBis, Josh, C1 aTracy, Russ, P1 aKimura, Masayuki1 aAviv, Abraham uhttps://chs-nhlbi.org/node/137502574nas a2200337 4500008004100000022001400041245011900055210006900174260001300243300001000256490000700266520159100273653000901864653002501873653001101898653001801909653001101927653001401938653003701952653001801989100002202007700002302029700001902052700002302071700002002094700002002114700002002134700002202154700002402176856003602200 2012 eng d a1096-002300aTransforming growth factor beta-1 and incidence of heart failure in older adults: the Cardiovascular Health Study.0 aTransforming growth factor beta1 and incidence of heart failure c2012 Nov a341-50 v603 aCONTEXT: Transforming growth factor-beta1 (TGF-B1) is a highly pleiotropic cytokine whose functions include a central role in the induction of fibrosis.
OBJECTIVE: To investigate the hypothesis that elevated plasma levels of TGF-B1 are positively associated with incident heart failure (HF).
PARTICIPANTS AND METHODS: The hypotheses were tested using a two-phase case-control study design, ancillary to the Cardiovascular Health Study - a longitudinal, population-based cohort study. Cases were defined as having an incident HF event after their 1992-1993 exam and controls were free of HF at follow-up. TGF-B1 was measured using plasma collected in 1992-1993 and data from 89 cases and 128 controls were used for analysis. The association between TGF-B1 and risk of HF was evaluated using the weighted likelihood method, and odds ratios (OR) for risk of HF were calculated for TGF-B1 as a continuous linear variable and across quartiles of TGF-B1.
RESULTS: The OR for HF was 1.88 (95% confidence intervals [CI] 1.26-2.81) for each nanogram increase in TGF-B1, and the OR for the highest quartile (compared to the lowest) of TGF-B1 was 5.79 (95% CI 1.65-20.34), after adjustment for age, sex, C-reactive protein, platelet count and digoxin use. Further adjustment with other covariates did not change the results.
CONCLUSIONS: Higher levels of plasma TGF-B1 were associated with an increased risk of incident heart failure among older adults. However, further study is needed in larger samples to confirm these findings.
10aAged10aCase-Control Studies10aHealth10aHeart Failure10aHumans10aIncidence10aTransforming Growth Factor beta110aUnited States1 aGlazer, Nicole, L1 aMacy, Elizabeth, M1 aLumley, Thomas1 aSmith, Nicholas, L1 aReiner, Alex, P1 aPsaty, Bruce, M1 aKing, George, L1 aTracy, Russell, P1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/140303691nas a2200649 4500008004100000022001400041245014200055210006900197260001300266300001100279490000800290520184900298653001202147653001202159653001602171653002002187653001002207653002302217653000902240653002502249653001102274653002002285653002202305653001802327653001302345653001102358653002502369653000902394653000902403653001302412653001402425653003602439653000902475653001702484653001602501100002802517700001802545700002202563700002102585700002302606700002402629700002202653700001802675700002302693700002002716700002302736700002102759700002202780700002102802700001902823700002802842700002502870700002402895700002402919710006202943856003603005 2012 eng d a1943-263100aUltraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms.0 aUltraconserved elements in the human genome association and tran c2012 Sep a253-660 v1923 aUltraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.
10aAlleles10aAnimals10aBody Height10aBody Mass Index10aChild10aConserved Sequence10aDogs10aEvolution, Molecular10aFemale10aGenetic Fitness10aGenetic Variation10aGenome, Human10aGenotype10aHumans10aInheritance Patterns10aMale10aMice10aPedigree10aPhenotype10aPolymorphism, Single Nucleotide10aRats10aReproduction10aYoung Adult1 aChiang, Charleston, W K1 aLiu, Ching-Ti1 aLettre, Guillaume1 aLange, Leslie, A1 aJorgensen, Neal, W1 aKeating, Brendan, J1 aVedantam, Sailaja1 aNock, Nora, L1 aFranceschini, Nora1 aReiner, Alex, P1 aDemerath, Ellen, W1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aWilson, James, G1 aNorth, Kari, E1 aPapanicolaou, George, J1 aCupples, Adrienne, L1 aMurabito, Joanne, M1 aHirschhorn, Joel, N1 aGenetic Investigation of ANthropometric Traits Consortium uhttps://chs-nhlbi.org/node/154402699nas a2200637 4500008004100000022001400041024001700055245009000072210006900162260001300231300001200244490000700256520098700263653003901250653001501289653001901304653001501323653001701338653002601355653004001381653001101421653002001432653001101452653003801463653000901501653000901510653001601519653001501535653004301550653003101593653001501624100001801639700002001657700001801677700001501695700001801710700001701728700001301745700001701758700001601775700001601791700001701807700001901824700002001843700001801863700001801881700001601899700001501915700001901930700001501949700001501964700001601979700001501995700001502010856003602025 2013 eng d a1366-5804 aCollaborator00aAdhesion molecules, endothelin-1 and lung function in seven population-based cohorts.0 aAdhesion molecules endothelin1 and lung function in seven popula c2013 May a196-2030 v183 aCONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown.
OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables.
METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets.
RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative.
CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.
10aAfrican Continental Ancestry Group10aBiomarkers10aCohort Studies10aE-Selectin10aEndothelin-110aEndothelium, Vascular10aEuropean Continental Ancestry Group10aFemale10aGene Expression10aHumans10aIntercellular Adhesion Molecule-110aLung10aMale10aMiddle Aged10aP-Selectin10aPulmonary Disease, Chronic Obstructive10aRespiratory Function Tests10aSpirometry1 aOelsner, E, C1 aPottinger, T, D1 aBurkart, K, M1 aAllison, M1 aBuxbaum, S, G1 aHansel, N, N1 aKumar, R1 aLarkin, E, K1 aLange, L, A1 aLoehr, L, R1 aLondon, S, J1 aO'Connor, G, T1 aPapanicolaou, G1 aPetrini, M, F1 aRabinowitz, D1 aRaghavan, S1 aRedline, S1 aThyagarajan, B1 aTracy, R P1 aWilk, J, B1 aWhite, W, B1 aRich, S, S1 aBarr, R, G uhttps://chs-nhlbi.org/node/608103504nas a2200505 4500008004100000022001400041245021500055210006900270260001300339300000900352490000600361520189100367653003902258653002002297653004002317653001102357653003402368653001102402653000902413653001602422653003502438653003602473653002402509653003002533653001702563653001502580100001302595700001902608700002002627700001702647700002202664700001802686700002202704700002202726700003002748700003002778700002202808700001402830700002302844700002802867700002002895700002102915710002602936856003602962 2013 eng d a1942-326800aAssociation of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies.0 aAssociation of genomewide variation with highly sensitive cardia c2013 Feb a82-80 v63 aBACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.
METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).
CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.
10aAfrican Continental Ancestry Group10aAtherosclerosis10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNuclear Receptor Coactivator 210aPolymorphism, Single Nucleotide10aProspective Studies10aResidence Characteristics10aRisk Factors10aTroponin T1 aYu, Bing1 aBarbalic, Maja1 aBrautbar, Ariel1 aNambi, Vijay1 aHoogeveen, Ron, C1 aTang, Weihong1 aMosley, Thomas, H1 aRotter, Jerome, I1 adeFilippi, Christopher, R1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aRice, Ken1 aHeckbert, Susan, R1 aBallantyne, Christie, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/585703088nas a2200697 4500008004100000022001400041245006500055210006300120260001300183300001200196490000700208520134600215653002201561653001001583653001901593653001601612653001301628653002401641653001101665653001401676653003001690653002601720653002701746653001801773100001301791700001901804700001701823700001401840700001701854700001801871700001401889700001701903700001401920700001701934700001401951700001601965700001601981700001501997700001502012700001402027700001602041700001702057700001602074700001602090700002202106700002102128700001802149700001302167700001602180700002002196700001602216700001402232700001102246700001902257700001702276700001602293700001502309700001502324700001502339856003602354 2013 eng d a1574-464700aAssociation of heat shock proteins with all-cause mortality.0 aAssociation of heat shock proteins with allcause mortality c2013 Aug a1367-760 v353 aExperimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.
10aAged, 80 and over10aAging10aCause of Death10aForecasting10aGenotype10aHeat-Shock Proteins10aHumans10aLongevity10aPromoter Regions, Genetic10aRetrospective Studies10aTranscription, Genetic10aUnited States1 aBroer, L1 aDemerath, E, W1 aGarcia, M, E1 aHomuth, G1 aKaplan, R, C1 aLunetta, K, L1 aTanaka, T1 aTranah, G, J1 aWalter, S1 aArnold, A, M1 aAtzmon, G1 aHarris, T B1 aHoffmann, W1 aKarasik, D1 aKiel, D, P1 aKocher, T1 aLauner, L J1 aLohman, K, K1 aRotter, J I1 aTiemeier, H1 aUitterlinden, A G1 aWallaschofski, H1 aBandinelli, S1 aDörr, M1 aFerrucci, L1 aFranceschini, N1 aGudnason, V1 aHofman, A1 aLiu, Y1 aMurabito, J, M1 aNewman, A, B1 aOostra, B A1 aPsaty, B M1 aSmith, A V1 aDuijn, C M uhttps://chs-nhlbi.org/node/606102959nas a2200529 4500008004100000022001400041245015700055210006900212260001600281300001200297490000600309520144300315653001601758653000901774653002201783653002501805653002401830653001501854653000901869653001101878653001101889653001401900653001801914653002501932653000901957653002301966653001801989653003202007653002402039653002002063653001702083653001702100653001802117100002202135700002502157700002402182700002302206700002202229700001902251700001802270700002002288700002002308700001902328700002202347700002402369856003602393 2013 eng d a2047-998000aAssociations of plasma phospholipid and dietary alpha linolenic acid with incident atrial fibrillation in older adults: the Cardiovascular Health Study.0 aAssociations of plasma phospholipid and dietary alpha linolenic c2013 Jan 31 ae0038140 v23 aBACKGROUND: Few studies have examined the relationship of α-linolenic acid (ALA 18:3n-3), an intermediate-chain essential n-3 polyunsaturated fatty acid derived from plants and vegetable oils, with incident atrial fibrillation (AF).
METHODS AND RESULTS: The study population included participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 or older, free of prevalent coronary heart disease and atrial fibrillation. We assessed the associations of plasma phospholipid and dietary ALA with incident AF using Cox regression. The biomarker analysis comprised a total of 2899 participants, and the dietary analysis comprised 4337 participants. We found no association of plasma phospholipid ALA and incident AF. Comparing each of the second, third, and fourth quartiles to the lowest quartile, the hazard ratios for AF were 1.11 (95% CI, 0.90 to 1.37), 1.09 (95% CI, 0.88 to 1.35), and 0.92 (95% CI, 0.74 to 1.15), after adjustment for age, sex, race, clinic, education, smoking, alcohol, body mass index, waist circumference, diabetes, heart failure, stroke, treated hypertension, and physical activity (P trend=0.48). When dietary ALA was considered the exposure of interest, results were similar.
CONCLUSIONS: Results from this prospective cohort study of older adults indicate no association of plasma phospholipid or dietary ALA and incident AF.
10aAge Factors10aAged10aAged, 80 and over10aalpha-Linolenic Acid10aAtrial Fibrillation10aBiomarkers10aDiet10aFemale10aHumans10aIncidence10aLinear Models10aLongitudinal Studies10aMale10aNutritional Status10aPhospholipids10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aTime Factors10aUnited States1 aFretts, Amanda, M1 aMozaffarian, Dariush1 aSiscovick, David, S1 aHeckbert, Susan, R1 aMcKnight, Barbara1 aKing, Irena, B1 aRimm, Eric, B1 aPsaty, Bruce, M1 aSacks, Frank, M1 aSong, Xiaoling1 aSpiegelman, Donna1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/584603298nas a2200397 4500008004100000022001400041245008200055210006900137260001600206300001000222490000800232520217800240653000902418653002402427653002002451653001902471653002402490653001102514653001102525653000902536653002402545653002702569653002402596653002002620100002302640700002202663700002102685700002302706700002402729700002202753700002002775700002202795700002402817700002302841856003602864 2013 eng d a1539-370400aAtrial ectopy as a predictor of incident atrial fibrillation: a cohort study.0 aAtrial ectopy as a predictor of incident atrial fibrillation a c c2013 Dec 03 a721-80 v1593 aBACKGROUND: Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable.
OBJECTIVE: To investigate whether PAC count improves model performance for AF risk.
DESIGN: Prospective cohort study.
SETTING: 4 U.S. communities.
PATIENTS: A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990.
MEASUREMENTS: The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model.
RESULTS: In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2% [CI, 12.8% to 33.6%]; P < 0.001), and integrated discrimination improvement (5.6% [CI, 4.2% to 7.0%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90% for PAC counts more than 32 beats/h.
LIMITATION: This study does not establish a causal link between PACs and AF.
CONCLUSION: The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk.
PRIMARY FUNDING SOURCE: American Heart Association, Joseph Drown Foundation, and National Institutes of Health.
10aAged10aAtrial Fibrillation10aAtrial Function10aCause of Death10aElectrocardiography10aFemale10aHumans10aMale10aModels, Statistical10aMyocardial Contraction10aProspective Studies10aRisk Assessment1 aDewland, Thomas, A1 aVittinghoff, Eric1 aMandyam, Mala, C1 aHeckbert, Susan, R1 aSiscovick, David, S1 aStein, Phyllis, K1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/616602861nas a2200409 4500008004100000022001400041245007600055210006900131260001600200300001100216490000700227520170000234653001601934653000901950653002201959653002401981653002402005653001602029653001102045653001102056653001402067653002502081653004602106653000902152653003002161100002102191700002202212700002002234700002002254700002402274700001902298700002102317700002802338700002602366700002302392856003602415 2013 eng d a1526-632X00aAtrial fibrillation and cognitive decline: a longitudinal cohort study.0 aAtrial fibrillation and cognitive decline a longitudinal cohort c2013 Jul 09 a119-250 v813 aOBJECTIVE: We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation.
METHODS: We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times.
RESULTS: Analyses included 5,150 participants, of whom 552 (10.7%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95% confidence interval [CI]: -7.0, -5.9) for participants without a history of atrial fibrillation, but was -10.3 points (95% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95% CI: -5.3, -2.5).
CONCLUSIONS: In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation.
10aAge Factors10aAged10aAged, 80 and over10aAtrial Fibrillation10aCognition Disorders10aComorbidity10aFemale10aHumans10aIncidence10aLongitudinal Studies10aLuria-Nebraska Neuropsychological Battery10aMale10aPredictive Value of Tests1 aThacker, Evan, L1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aLongstreth, W T1 aSitlani, Colleen, M1 aDublin, Sascha1 aArnold, Alice, M1 aFitzpatrick, Annette, L1 aGottesman, Rebecca, F1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/600203502nas a2200481 4500008004100000022001400041245014100055210006900196260001600265300001000281490000800291520213900299653000902438653002402447653002802471653002702499653001502526653001802541653001102559653001102570653001402581653000902595653001602604653003202620653002002652653001702672653001602689653001802705100001702723700002202740700002102762700001902783700001802802700002302820700002002843700002402863700001902887700001702906700002102923700002102944700001902965856003602984 2013 eng d a2168-611400aAtrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study.0 aAtrial fibrillation and the risk of sudden cardiac death the ath c2013 Jan 14 a29-350 v1733 aBACKGROUND: It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.
METHODS: In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2% women; and 26.6% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, ≥65 years; 58.2% women; and 15.4% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.
RESULTS: In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively.
CONCLUSIONS: Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.
10aAged10aAtrial Fibrillation10aCardiovascular Diseases10aDeath, Sudden, Cardiac10aDemography10aEthnic Groups10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aSex Factors10aUnited States1 aChen, Lin, Y1 aSotoodehnia, Nona1 aBůzková, Petra1 aLopez, Faye, L1 aYee, Laura, M1 aHeckbert, Susan, R1 aPrineas, Ronald1 aSoliman, Elsayed, Z1 aAdabag, Selcuk1 aKonety, Suma1 aFolsom, Aaron, R1 aSiscovick, David1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/585003560nas a2200709 4500008004100000022001400041245008800055210006900143260000900212300001100221490000600232520160600238653001001844653001201854653002101866653001901887653003401906653001001940653001101950653001901961653001301980653001301993653001002006653001102016653000902027653004402036653003602080653001602116653001602132653002702148100002002175700001302195700002402208700002302232700001902255700002002274700001702294700002302311700002502334700002002359700002402379700002202403700002202425700001902447700002202466700001702488700001702505700001902522700002002541700002002561700002102581700002602602700002402628700002102652700002402673700002302697700002102720700003002741700002202771700002102793856003602814 2013 eng d a1932-620300aBest practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium.0 aBest practices and joint calling of the HumanExome BeadChip the c2013 ae680950 v83 aGenotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.
10aAging10aAlleles10aCluster Analysis10aCohort Studies10aContinental Population Groups10aExome10aFemale10aGene Frequency10aGenomics10aGenotype10aHeart10aHumans10aMale10aOligonucleotide Array Sequence Analysis10aPolymorphism, Single Nucleotide10aSample Size10aSelf Report10aSequence Analysis, DNA1 aGrove, Megan, L1 aYu, Bing1 aCochran, Barbara, J1 aHaritunians, Talin1 aBis, Joshua, C1 aTaylor, Kent, D1 aHansen, Mark1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aFornage, Myriam1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aKathiresan, Sekar1 aKraaij, Robert1 aLauner, Lenore, J1 aLevy, Daniel1 aLiu, Yongmei1 aMosley, Thomas1 aPeloso, Gina, M1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRivadeneira, Fernando1 aSiscovick, David, S1 aSmith, Albert, V1 aUitterlinden, Andre1 aDuijn, Cornelia, M1 aWilson, James, G1 aO'Donnell, Christopher, J1 aRotter, Jerome, I1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/606703435nas a2200469 4500008004100000022001400041245007300055210006900128260001600197300001100213490000800224520218200232653000902414653002402423653001302447653001102460653002002471653001102491653002502502653000902527653002902536653001402565653003202579653001702611100002202628700001802650700002002668700001702688700002002705700001702725700001702742700001902759700002102778700002302799700001802822700001402840700002002854700002002874700001702894700001802911856003602929 2013 eng d a1535-497000aBidirectional relationship between cognitive function and pneumonia.0 aBidirectional relationship between cognitive function and pneumo c2013 Sep 01 a586-920 v1883 aRATIONALE: Relationships between chronic health conditions and acute infections remain poorly understood. Preclinical studies suggest crosstalk between nervous and immune systems.
OBJECTIVES: To determine bidirectional relationships between cognition and pneumonia.
METHODS: We conducted longitudinal analyses of a population-based cohort over 10 years. We determined whether changes in cognition increase risk of pneumonia hospitalization by trajectory analyses and joint modeling. We then determined whether pneumonia hospitalization increased risk of subsequent dementia using a Cox model with pneumonia as a time-varying covariate.
MEASUREMENTS AND MAIN RESULTS: Of the 5,888 participants, 639 (10.9%) were hospitalized with pneumonia at least once. Most participants had normal cognition before pneumonia. Three cognition trajectories were identified: no, minimal, and severe rapid decline. A greater proportion of participants hospitalized with pneumonia were on trajectories of minimal or severe decline before occurrence of pneumonia compared with those never hospitalized with pneumonia (proportion with no, minimal, and severe decline were 67.1%, 22.8%, and 10.0% vs. 76.0%, 19.3%, and 4.6% for participants with and without pneumonia, respectively; P < 0.001). Small subclinical changes in cognition increased risk of pneumonia, even in those with normal cognition and physical function before pneumonia (β = -0.02; P < 0.001). Participants with pneumonia were subsequently at an increased risk of dementia (hazard ratio, 2.24 [95% confidence interval, 1.62-3.11]; P = 0.01). Associations were independent of demographics, health behaviors, other chronic conditions, and physical function. Bidirectional relationship did not vary based on severity of disease, and similar associations were noted for those with severe sepsis and other infections.
CONCLUSIONS: A bidirectional relationship exists between pneumonia and cognition and may explain how a single episode of infection in well-appearing older individuals accelerates decline in chronic health conditions and loss of functional independence.
10aAged10aCognition Disorders10aDementia10aFemale10aHospitalization10aHumans10aLongitudinal Studies10aMale10aNeuropsychological Tests10aPneumonia10aProportional Hazards Models10aRisk Factors1 aShah, Faraaz, Ali1 aPike, Francis1 aAlvarez, Karina1 aAngus, Derek1 aNewman, Anne, B1 aLopez, Oscar1 aTate, Judith1 aKapur, Vishesh1 aWilsdon, Anthony1 aKrishnan, Jerry, A1 aHansel, Nadia1 aAu, David1 aAvdalovic, Mark1 aFan, Vincent, S1 aBarr, Graham1 aYende, Sachin uhttps://chs-nhlbi.org/node/628502921nas a2200433 4500008004100000022001400041245012800055210006900183260001300252300001200265490000700277520170100284653000901985653001901994653001902013653001502032653001302047653002402060653001102084653003102095653001102126653001702137653002002154653002502174653000902199653001002208653003302218653001202251100002002263700001602283700002102299700002402320700002002344700002002364700002002384700002402404700002302428856003602451 2013 eng d a1941-722500aBlood pressure components and decline in kidney function in community-living older adults: the Cardiovascular Health Study.0 aBlood pressure components and decline in kidney function in comm c2013 Aug a1037-440 v263 aBACKGROUND: Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.
METHODS: We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.
RESULTS: Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (-0.19, -0.08, P < 0.001) and 0.15-ml/min/year faster decline (-0.21, -0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, -0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.
CONCLUSIONS: Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.
10aAged10aBlood Pressure10aCohort Studies10aCystatin C10aDiastole10aDisease Progression10aFemale10aGlomerular Filtration Rate10aHumans10aHypertension10aLogistic Models10aLongitudinal Studies10aMale10aPulse10aRenal Insufficiency, Chronic10aSystole1 aRifkin, Dena, E1 aKatz, Ronit1 aChonchol, Michel1 aShlipak, Michael, G1 aSarnak, Mark, J1 aFried, Linda, F1 aNewman, Anne, B1 aSiscovick, David, S1 aPeralta, Carmen, A uhttps://chs-nhlbi.org/node/599902991nas a2200397 4500008004100000022001400041245015600055210006900211260001300280300001100293490000700304520185300311653000902164653001902173653001902192653001102211653001102222653001402233653002502247653000902272653001402281653002602295653000902321653001102330653001802341100002702359700002102386700002602407700001902433700002602452700001802478700002102496700002002517700002002537856003602557 2013 eng d a1941-722500aBlood pressure variability and the risk of all-cause mortality, incident myocardial infarction, and incident stroke in the cardiovascular health study.0 aBlood pressure variability and the risk of allcause mortality in c2013 Oct a1210-70 v263 aBACKGROUND: Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time.
METHODS: The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant's 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time.
RESULTS: Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05-1.21) and of incident MI (HR = 1.20; 95%CI = 1.06-1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89-1.21).
CONCLUSIONS: Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.
10aAged10aBlood Pressure10aCohort Studies10aFemale10aHumans10aIncidence10aLongitudinal Studies10aMale10aMortality10aMyocardial Infarction10aRisk10aStroke10aUnited States1 aSuchy-Dicey, Astrid, M1 aWallace, Erin, R1 aMitchell, S, V Elkind1 aAguilar, Maria1 aGottesman, Rebecca, F1 aRice, Kenneth1 aKronmal, Richard1 aPsaty, Bruce, M1 aLongstreth, W T uhttps://chs-nhlbi.org/node/600100896nas a2200289 4500008004100000022001400041245012600055210006900181260001300250300001000263490000700273653001000280653001900290653002500309653003400334653001800368653001100386653001400397653003300411653002600444653003000470653001100500653001800511100002000529700002100549856003600570 2013 eng d a1531-548700aThe Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium as a model of collaborative science.0 aCohorts for Heart and Aging Research in Genomic Epidemiology CHA c2013 May a346-80 v2410aAging10aCohort Studies10aCooperative Behavior10aGenome-Wide Association Study10aHeart Failure10aHumans10aIncidence10aMulticenter Studies as Topic10aMyocardial Infarction10aResearch Support as Topic10aStroke10aUnited States1 aPsaty, Bruce, M1 aSitlani, Colleen uhttps://chs-nhlbi.org/node/603003625nas a2200673 4500008004100000022001400041245014300055210006900198260001300267300001300280490000700293520182500300653002802125653003502153653002202188653001102210653002602221653001702247653001102264100002202275700001902297700002202316700001902338700001802357700001702375700001602392700002002408700001602428700001602444700001802460700001502478700001402493700001602507700001302523700001502536700001602551700001602567700001802583700001602601700001502617700001702632700002002649700001502669700001502684700001702699700001602716700001602732700001702748700001802765700001502783700001402798700001802812700001402830700002202844700001802866700001602884700001502900856003602915 2013 eng d a1432-042800aCommon carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.0 aCommon carotid intimamedia thickness does not add to Framingham c2013 Jul a1494-5020 v563 aAIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes.
METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added.
RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women.
CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.
10aCardiovascular Diseases10aCarotid Intima-Media Thickness10aDiabetes Mellitus10aHumans10aMyocardial Infarction10aRisk Factors10aStroke1 aRuijter, H, M den1 aPeters, S, A E1 aGroenewegen, K, A1 aAnderson, T, J1 aBritton, A, R1 aDekker, J, M1 aEngstrom, G1 aEijkemans, M, J1 aEvans, G, W1 ade Graaf, J1 aGrobbee, D, E1 aHedblad, B1 aHofman, A1 aHolewijn, S1 aIkeda, A1 aKavousi, M1 aKitagawa, K1 aKitamura, A1 aKoffijberg, H1 aIkram, M, A1 aLonn, E, M1 aLorenz, M, W1 aMathiesen, E, B1 aNijpels, G1 aOkazaki, S1 aO'Leary, D H1 aPolak, J, F1 aPrice, J, F1 aRobertson, C1 aRembold, C, M1 aRosvall, M1 aRundek, T1 aSalonen, J, T1 aSitzer, M1 aStehouwer, C, D A1 aWitteman, J C1 aMoons, K, G1 aBots, M, L uhttps://chs-nhlbi.org/node/675102610nas a2200481 4500008004100000022001400041245010100055210006900156260001300225300001200238490000700250520122800257653002201485653000901507653002201516653001801538653002001556653001901576653004001595653003201635653001101667653001901678653003201697653001501729653001101744653001201755653002701767653000901794653003601803100002401839700001901863700001901882700002201901700001901923700002001942700002201962700002101984700002502005700002002030700002402050700001802074856003602092 2013 eng d a1558-930700aCommon FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults.0 aCommon FABP4 genetic variants and plasma levels of fatty acid bi c2013 Nov a1169-750 v483 aWe examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p ≤ 0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p = 0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency = 16 %; p = 0.001) and African Americans (frequency = 8 %; p = 0.04). The haplotype combined a SNP in the first intron with one in the 3'untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.
10aAfrican Americans10aAged10aAged, 80 and over10aBlood Glucose10aBody Mass Index10aCohort Studies10aEuropean Continental Ancestry Group10aFatty Acid-Binding Proteins10aFemale10aGene Frequency10aGenetic Association Studies10aHaplotypes10aHumans10aInsulin10aLinkage Disequilibrium10aMale10aPolymorphism, Single Nucleotide1 aMukamal, Kenneth, J1 aWilk, Jemma, B1 aBiggs, Mary, L1 aJensen, Majken, K1 aIx, Joachim, H1 aKizer, Jorge, R1 aTracy, Russell, P1 aZieman, Susan, J1 aMozaffarian, Dariush1 aPsaty, Bruce, M1 aSiscovick, David, S1 aDjoussé, Luc uhttps://chs-nhlbi.org/node/608004481nas a2200937 4500008004100000022001400041245012400055210006900179260001300248300001100261490000700272520180500279653002802084653001002112653001702122653003802139653001302177653001702190653001102207653002602218653001702244100002602261700002102287700002502308700001702333700002002350700002302370700002202393700001402415700002302429700002502452700001902477700001502496700002102511700002002532700001902552700002202571700001902593700002202612700002002634700002002654700001902674700002102693700001502714700002302729700002202752700001902774700002102793700003102814700002202845700001702867700001902884700002202903700002702925700003002952700002002982700002003002700002603022700001903048700001703067700002403084700002403108700001803132700001903150700002403169700002003193700002403213700001803237700003003255700002403285700001803309700002803327700002203355700001803377700002403395700002003419700002303439700002203462700002303484856003603507 2013 eng d a1938-320700aCommon genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.0 aCommon genetic loci influencing plasma homocysteine concentratio c2013 Sep a668-760 v983 aBACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD.
OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.
DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls.
RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49).
CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.
10aCoronary Artery Disease10aGenes10aGenetic Loci10aGenetic Predisposition to Disease10aGenotype10aHomocysteine10aHumans10aPolymorphism, Genetic10aRisk Factors1 avan Meurs, Joyce, B J1 aParé, Guillaume1 aSchwartz, Stephen, M1 aHazra, Aditi1 aTanaka, Toshiko1 aVermeulen, Sita, H1 aCotlarciuc, Ioana1 aYuan, Xin1 aMälarstig, Anders1 aBandinelli, Stefania1 aBis, Joshua, C1 aBlom, Henk1 aBrown, Morris, J1 aChen, Constance1 aDer Chen, Yii-1 aClarke, Robert, J1 aDehghan, Abbas1 aErdmann, Jeanette1 aFerrucci, Luigi1 aHamsten, Anders1 aHofman, Albert1 aHunter, David, J1 aGoel, Anuj1 aJohnson, Andrew, D1 aKathiresan, Sekar1 aKampman, Ellen1 aKiel, Douglas, P1 aKiemeney, Lambertus, A L M1 aChambers, John, C1 aKraft, Peter1 aLindemans, Jan1 aMcKnight, Barbara1 aNelson, Christopher, P1 aO'Donnell, Christopher, J1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRose, Lynda, M1 aSeedorf, Udo1 aSiscovick, David, S1 aSchunkert, Heribert1 aSelhub, Jacob1 aUeland, Per, M1 aVollenweider, Peter1 aWaeber, Gérard1 aWaterworth, Dawn, M1 aWatkins, Hugh1 aWitteman, Jacqueline, C M1 aHeijer, Martin, den1 aJacques, Paul1 aUitterlinden, André, G1 aKooner, Jaspal, S1 aRader, Dan, J1 aReilly, Muredach, P1 aMooser, Vincent1 aChasman, Daniel, I1 aSamani, Nilesh, J1 aAhmadi, Kourosh, R uhttps://chs-nhlbi.org/node/628404753nas a2201057 4500008004100000022001400041245017100055210006900226260001300295300001000308490000700318520203200325653001002357653002202367653000902389653002502398653001602423653002402439653001102463653002202474653003402496653001302530653001502543653001102558653000902569653002702578653001602605653003602621653000902657653001802666100001102684700001602695700001602711700001602727700001602743700001702759700001702776700001802793700001002811700002102821700001602842700001402858700002102872700001402893700001602907700001802923700001902941700001302960700001502973700001202988700001903000700001803019700001603037700001603053700001403069700001803083700001303101700001603114700001503130700001903145700001103164700001703175700001803192700001303210700001703223700001703240700001703257700001403274700001603288700001703304700001503321700001803336700001703354700001903371700001603390700002003406700001803426700001703444700002003461700001703481700001803498700001903516700002103535700001703556700001603573700001303589700002003602700001903622700001803641856003603659 2013 eng d a1556-387100aCommon genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.0 aCommon genetic variation near the connexin43 gene is associated c2013 Mar a401-80 v103 aBACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.
OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.
METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)).
RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.
CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.
10aAdult10aAfrican Americans10aAged10aArrhythmias, Cardiac10aConnexin 4310aElectrocardiography10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHeart Rate10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRest10aUnited States1 aDeo, R1 aNalls, M, A1 aAvery, C, L1 aSmith, J, G1 aEvans, D, S1 aKeller, M, F1 aButler, A, M1 aBuxbaum, S, G1 aLi, G1 aQuibrera, Miguel1 aSmith, E, N1 aTanaka, T1 aAkylbekova, E, L1 aAlonso, A1 aArking, D E1 aBenjamin, E J1 aBerenson, G, S1 aBis, J C1 aChen, L, Y1 aChen, W1 aCummings, S, R1 aEllinor, P, T1 aEvans, M, K1 aFerrucci, L1 aFox, E, R1 aHeckbert, S R1 aHeiss, G1 aHsueh, W, C1 aKerr, K, F1 aLimacher, M, C1 aLiu, Y1 aLubitz, S, A1 aMagnani, J, W1 aMehra, R1 aMarcus, G, M1 aMurray, S, S1 aNewman, A, B1 aNjajou, O1 aNorth, K, E1 aPaltoo, D, N1 aPsaty, B M1 aRedline, S, S1 aReiner, A, P1 aRobinson, J, G1 aRotter, J I1 aSamdarshi, T, E1 aSchnabel, R B1 aSchork, N, J1 aSingleton, A, B1 aSiscovick, D1 aSoliman, E, Z1 aSotoodehnia, N1 aSrinivasan, S, R1 aTaylor, H, A1 aTrevisan, M1 aZhang, Z1 aZonderman, A, B1 aNewton-Cheh, C1 aWhitsel, E, A uhttps://chs-nhlbi.org/node/606310597nas a2203385 4500008004100000022001400041245009500055210006900150260001300219300001200232490000700244520112400251653002501375653002101400653002101421653002801442653001101470653003601481653001701517653001801534100001201552700002301564700002201587700002201609700001301631700002001644700002301664700002201687700001801709700001401727700002601741700001601767700002501783700003101808700002001839700001901859700002601878700002401904700002001928700001601948700002101964700002101985700002002006700002402026700002002050700002302070700002202093700002102115700002102136700001802157700002102175700001902196700001802215700002102233700002302254700002202277700001602299700001802315700002802333700002702361700002102388700002102409700002202430700003002452700001902482700002602501700002302527700001902550700002602569700001802595700001802613700002202631700001602653700002002669700001802689700001302707700002502720700001702745700002002762700002402782700002502806700002802831700002402859700002102883700002202904700001702926700001302943700001802956700001802974700001902992700001903011700002103030700002403051700002503075700002103100700002103121700002203142700002103164700002103185700002003206700001803226700002403244700003203268700001903300700002203319700002103341700002303362700002703385700002103412700002803433700002203461700002003483700002103503700001603524700001703540700001803557700002303575700002203598700002503620700001803645700001403663700001803677700002203695700001803717700002403735700002203759700001703781700002203798700002003820700002003840700002203860700002303882700002503905700002303930700002203953700001903975700002503994700002404019700002304043700001604066700001904082700002504101700002204126700001804148700002104166700002404187700002004211700002604231700001604257700001904273700001904292700002204311700001804333700002004351700002504371700002304396700001804419700002004437700002804457700002004485700002204505700002504527700002004552700001904572700002304591700001904614700002104633700002404654700001904678700002004697700002404717700002904741700002504770700002204795700002104817700002304838700002304861700002304884700002504907700001804932700002004950700002004970700002604990700002205016700002205038700002405060700002305084700001705107700002205124700001805146700002105164700002005185700002005205700002305225700002205248700001905270700002405289700002005313700002005333700002205353700002105375700002405396700001905420700001805439700002405457700002405481700002005505700002005525700002205545700002705567700001605594700002005610700001905630700002305649700001905672700002205691700002405713700002205737700001505759700002205774700002205796700001905818700001905837700001505856700002505871700002405896700002005920700002205940700002305962700002005985700002106005700002006026700002206046700002406068700002106092700002306113700001706136700002606153700002106179700002006200700002406220700002106244700002106265700002006286700002706306700002006333700002406353700002106377700002306398700002106421700002006442700002106462700002306483700002206506700001906528700002306547700002006570700002306590700002406613700002006637700002506657700002306682700003006705700002106735700002106756700002106777700002306798700002806821700002306849700002206872700002006894700002006914700002506934700002506959700002106984700002107005700002007026700002107046700002007067700002507087700001807112700002307130700002207153856003607175 2013 eng d a1546-171800aCommon variants associated with plasma triglycerides and risk for coronary artery disease.0 aCommon variants associated with plasma triglycerides and risk fo c2013 Nov a1345-520 v453 aTriglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
10aBiological Transport10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors10aTriglycerides1 aDo, Ron1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aGao, Chi1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 aKesäniemi, Antero1 aKivimaki, Mika1 aKooner, Jaspal, S1 aKoudstaal, Peter, J1 aKrauss, Ronald, M1 aKuh, Diana1 aKuusisto, Johanna1 aKyvik, Kirsten, O1 aLaakso, Markku1 aLakka, Timo, A1 aLind, Lars1 aLindgren, Cecilia, M1 aMartin, Nicholas, G1 aMärz, Winfried1 aMcCarthy, Mark, I1 aMcKenzie, Colin, A1 aMeneton, Pierre1 aMetspalu, Andres1 aMoilanen, Leena1 aMorris, Andrew, D1 aMunroe, Patricia, B1 aNjølstad, Inger1 aPedersen, Nancy, L1 aPower, Chris1 aPramstaller, Peter, P1 aPrice, Jackie, F1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRauramaa, Rainer1 aSaleheen, Danish1 aSalomaa, Veikko1 aSanghera, Dharambir, K1 aSaramies, Jouko1 aSchwarz, Peter, E H1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aSiegbahn, Agneta1 aSpector, Tim, D1 aStefansson, Kari1 aStrachan, David, P1 aTayo, Bamidele, O1 aTremoli, Elena1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aDuijn, Cornelia, M1 aVollenweider, Peter1 aWallentin, Lars1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWolffenbuttel, Bruce, H R1 aAltshuler, David1 aOrdovas, Jose, M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aDaly, Mark, J1 aNeale, Benjamin, M1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/801407440nas a2202173 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2013 eng d a1533-345000aCommon variants in Mendelian kidney disease genes and their association with renal function.0 aCommon variants in Mendelian kidney disease genes and their asso c2013 Dec a2105-170 v243 aMany common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aHumans10aKidney10aMendelian Randomization Analysis10aPhenotype10aPolymorphism, Single Nucleotide10aRenal Insufficiency, Chronic1 aParsa, Afshin1 aFuchsberger, Christian1 aKöttgen, Anna1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 ade Andrade, Mariza1 aChasman, Daniel, I1 aTeumer, Alexander1 aEndlich, Karlhans1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aKim, Young, J1 aTaliun, Daniel1 aLi, Man1 aFeitosa, Mary1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aGlazer, Nicole1 aIsaacs, Aaron1 aRao, Madhumathi1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aCouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aHofer, Edith1 aHu, Frank1 aDemirkan, Ayse1 aOostra, Ben, A1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aGiulianini, Franco1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aZgaga, Lina1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aStengel, Bénédicte1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMitchell, Paul1 aCiullo, Marina1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline1 aHayward, Caroline1 aRidker, Paul, M1 aBochud, Murielle1 aHeid, Iris, M1 aSiscovick, David, S1 aFox, Caroline, S1 aKao, Linda1 aBöger, Carsten, A uhttps://chs-nhlbi.org/node/628803326nas a2200409 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520214100238653001502379653001502394653003102409653001102440653002802451653002602479653002402505653003302529653000902562653002002571100002402591700002502615700001902640700002102659700001602680700002702696700002702723700002002750700001902770700001802789700002102807700002302828710002902851856003602880 2013 eng d a1533-440600aCystatin C versus creatinine in determining risk based on kidney function.0 aCystatin C versus creatinine in determining risk based on kidney c2013 Sep 05 a932-430 v3693 aBACKGROUND: Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined.
METHODS: We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C.
RESULTS: In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR.
CONCLUSIONS: The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.).
10aCreatinine10aCystatin C10aGlomerular Filtration Rate10aHumans10aKidney Failure, Chronic10aKidney Function Tests10aReference Standards10aRenal Insufficiency, Chronic10aRisk10aRisk Assessment1 aShlipak, Michael, G1 aMatsushita, Kunihiro1 aArnlöv, Johan1 aInker, Lesley, A1 aKatz, Ronit1 aPolkinghorne, Kevan, R1 aRothenbacher, Dietrich1 aSarnak, Mark, J1 aAstor, Brad, C1 aCoresh, Josef1 aLevey, Andrew, S1 aGansevoort, Ron, T1 aCKD Prognosis Consortium uhttps://chs-nhlbi.org/node/737710661nas a2203397 4500008004100000022001400041245006700055210006600122260001300188300001400201490000700215520110800222653003901330653003701369653002101406653002101427653002801448653004001476653003801516653003401554653001301588653001101601653001101612653001801623100002301641700002201664700002201686700002001708700002301728700002201751700001801773700001401791700002601805700001601831700002501847700003101872700002001903700001901923700002601942700001201968700002401980700002002004700001602024700002102040700002102061700002002082700002402102700002002126700002302146700002202169700002102191700002102212700001802233700002102251700001902272700001802291700002102309700002302330700002202353700001602375700001802391700002802409700002702437700002102464700002102485700002202506700003002528700001902558700002602577700002302603700001902626700002602645700001802671700001802689700002202707700001602729700002002745700001802765700001302783700002502796700001702821700002002838700002402858700002502882700002802907700002402935700002102959700002202980700001703002700001303019700001803032700001803050700001903068700001903087700002103106700002403127700002503151700002103176700002103197700002203218700002103240700002103261700002003282700001803302700002403320700003203344700001903376700002203395700002103417700002303438700002703461700002103488700002803509700002203537700002003559700002103579700001603600700001703616700001803633700002303651700002203674700002503696700001803721700001403739700001803753700002203771700001803793700002403811700002203835700001703857700002203874700002003896700002003916700002203936700002303958700002503981700002304006700002204029700001904051700002504070700002404095700002304119700001604142700001904158700002504177700002204202700001804224700002104242700002404263700002004287700002604307700001604333700001904349700001904368700002204387700001804409700002004427700002504447700002304472700001804495700002004513700002804533700002004561700002204581700002504603700002004628700001904648700002304667700001904690700002104709700002404730700001904754700002004773700002404793700002904817700002504846700002204871700002104893700002304914700002304937700002304960700002504983700001805008700002005026700002005046700002605066700002205092700002205114700002405136700002305160700001705183700002205200700001805222700002105240700002005261700002005281700002305301700002205324700001905346700002405365700002005389700002005409700002205429700002105451700002405472700001905496700001805515700002405533700002405557700002005581700002005601700002205621700002705643700001605670700002005686700001905706700002305725700001905748700002205767700002405789700002205813700001505835700002205850700002205872700001905894700001905913700001505932700002505947700002405972700002005996700002206016700002306038700002006061700002106081700002006102700002206122700002406144700002106168700002306189700001706212700002606229700002106255700002006276700002406296700002106320700002106341700002006362700002706382700002006409700002406429700002106453700002306474700002106497700002006518700002106538700002306559700002206582700001906604700002306623700002006646700002306666700002406689700002006713700002506733700002306758700003006781700002106811700002106832700002306853700002806876700002306904700002206927700002006949700002006969700002506989700002507014700002107039700002107060700002007081700002207101700002107123700002007144700002507164710003807189856003607227 2013 eng d a1546-171800aDiscovery and refinement of loci associated with lipid levels.0 aDiscovery and refinement of loci associated with lipid levels c2013 Nov a1274-12830 v453 aLevels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
10aAfrican Continental Ancestry Group10aAsian Continental Ancestry Group10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLipids10aTriglycerides1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDo, Ron1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 aKesäniemi, Antero1 aKivimaki, Mika1 aKooner, Jaspal, S1 aKoudstaal, Peter, J1 aKrauss, Ronald, M1 aKuh, Diana1 aKuusisto, Johanna1 aKyvik, Kirsten, O1 aLaakso, Markku1 aLakka, Timo, A1 aLind, Lars1 aLindgren, Cecilia, M1 aMartin, Nicholas, G1 aMärz, Winfried1 aMcCarthy, Mark, I1 aMcKenzie, Colin, A1 aMeneton, Pierre1 aMetspalu, Andres1 aMoilanen, Leena1 aMorris, Andrew, D1 aMunroe, Patricia, B1 aNjølstad, Inger1 aPedersen, Nancy, L1 aPower, Chris1 aPramstaller, Peter, P1 aPrice, Jackie, F1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRauramaa, Rainer1 aSaleheen, Danish1 aSalomaa, Veikko1 aSanghera, Dharambir, K1 aSaramies, Jouko1 aSchwarz, Peter, E H1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aSiegbahn, Agneta1 aSpector, Tim, D1 aStefansson, Kari1 aStrachan, David, P1 aTayo, Bamidele, O1 aTremoli, Elena1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aDuijn, Cornelia, M1 aVollenweider, Peter1 aWallentin, Lars1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWolffenbuttel, Bruce, H R1 aOrdovas, Jose, M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aKathiresan, Sekar1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aGlobal Lipids Genetics Consortium uhttps://chs-nhlbi.org/node/615403734nas a2200745 4500008004100000022001400041245012200055210006900177260001600246300000600262490000700268520160700275653001501882653001001897653002201907653000901929653005001938653002001988653004002008653001102048653003802059653001102097653000902108653002202117653001602139653001202155653003602167653001302203653001702216653001202233653001602245100002502261700001902286700001502305700002102320700002202341700002202363700002002385700001802405700002002423700002202443700001602465700002802481700002102509700002002530700002102550700002402571700001902595700002202614700001502636700003002651700002402681700002402705700002202729700002502751700002102776700001802797700002302815700002302838700002202861700002702883700002302910700001902933856003602952 2013 eng d a1471-235000aEffects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study.0 aEffects of smoking on the genetic risk of obesity the population c2013 Jan 11 a60 v143 aBACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.
METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.
RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08).
CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.
CLINICAL TRIAL REGISTRATION: NCT00000611.
10aAdolescent10aAdult10aAfrican Americans10aAged10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Mass Index10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aHumans10aMale10aMembrane Proteins10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins10aRisk Factors10aSmoking10aYoung Adult1 aFesinmeyer, Megan, D1 aNorth, Kari, E1 aLim, Unhee1 aBůzková, Petra1 aCrawford, Dana, C1 aHaessler, Jeffrey1 aGross, Myron, D1 aFowke, Jay, H1 aGoodloe, Robert1 aLove, Shelley-Ann1 aGraff, Misa1 aCarlson, Christopher, S1 aKuller, Lewis, H1 aMatise, Tara, C1 aHong, Ching-Ping1 aHenderson, Brian, E1 aAllen, Melissa1 aRohde, Rebecca, R1 aMayo, Ping1 aSchnetz-Boutaud, Nathalie1 aMonroe, Kristine, R1 aRitchie, Marylyn, D1 aPrentice, Ross, L1 aKolonel, Lawrence, N1 aManson, JoAnn, E1 aPankow, James1 aHindorff, Lucia, A1 aFranceschini, Nora1 aWilkens, Lynne, R1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/606504096nas a2200901 4500008004100000022001400041245007000055210006900125260001500194300001100209490000700220520164400227653001001871653002201881653000901903653002201912653002001934653001101954653001701965653003801982653001802020653003402038653001302072653001102085653002702096653000902123653001602132653001202148653003602160653001602196100001502212700002502227700001502252700002302267700001902290700001902309700002802328700002102356700002102377700002002398700001702418700002102435700002102456700002502477700002002502700001702522700001602539700002002555700002502575700002102600700001602621700002102637700001602658700001902674700001802693700001902711700001702730700002602747700002002773700002202793700002102815700002002836700002402856700001502880700002002895700001602915700003002931700002202961700002102983700002403004700002003028700002303048700002203071700002703093700001903120700001903139856003603158 2013 eng d a1537-660500aFine Mapping and Identification of BMI Loci in African Americans.0 aFine Mapping and Identification of BMI Loci in African Americans c2013 Oct 3 a661-710 v933 aGenome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.
10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aBody Mass Index10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aYoung Adult1 aGong, Jian1 aSchumacher, Fredrick1 aLim, Unhee1 aHindorff, Lucia, A1 aHaessler, Jeff1 aBuyske, Steven1 aCarlson, Christopher, S1 aRosse, Stephanie1 aBůzková, Petra1 aFornage, Myriam1 aGross, Myron1 aPankratz, Nathan1 aPankow, James, S1 aSchreiner, Pamela, J1 aCooper, Richard1 aEhret, Georg1 aGu, Charles1 aHouston, Denise1 aIrvin, Marguerite, R1 aJackson, Rebecca1 aKuller, Lew1 aHenderson, Brian1 aCheng, Iona1 aWilkens, Lynne1 aLeppert, Mark1 aLewis, Cora, E1 aLi, Rongling1 aNguyen, Khanh-Dung, H1 aGoodloe, Robert1 aFarber-Eger, Eric1 aBoston, Jonathan1 aDilks, Holli, H1 aRitchie, Marylyn, D1 aFowke, Jay1 aPooler, Loreall1 aGraff, Misa1 aFernandez-Rhodes, Lindsay1 aCochrane, Barbara1 aBoerwinkle, Eric1 aKooperberg, Charles1 aMatise, Tara, C1 aLe Marchand, Loïc1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aNorth, Kari, E1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/662603887nas a2200601 4500008004100000022001400041245013100055210006900186260001300255300001300268490000700281520205500288653002202343653002002365653002002385653003002405653004002435653001902475653003802494653002202532653003402554653002302588653001102611653002802622653001102650653001702661653002702678653003602705100002802741700002002769700001902789700002702808700002502835700001902860700002802879700001902907700002302926700002402949700002102973700002202994700002203016700002203038700002103060700001803081700001603099700001903115700002303134700002203157700002303179700002703202710002003229856003603249 2013 eng d a1545-788500aGeneralization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.0 aGeneralization and dilution of association results from European c2013 Sep ae10016610 v113 aThe vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
10aAfrican Americans10aAsian Americans10aBody Mass Index10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHispanic Americans10aHumans10aIndians, North American10aLipids10aMetagenomics10aOceanic Ancestry Group10aPolymorphism, Single Nucleotide1 aCarlson, Christopher, S1 aMatise, Tara, C1 aNorth, Kari, E1 aHaiman, Christopher, A1 aFesinmeyer, Megan, D1 aBuyske, Steven1 aSchumacher, Fredrick, R1 aPeters, Ulrike1 aFranceschini, Nora1 aRitchie, Marylyn, D1 aDuggan, David, J1 aSpencer, Kylee, L1 aDumitrescu, Logan1 aEaton, Charles, B1 aThomas, Fridtjof1 aYoung, Alicia1 aCarty, Cara1 aHeiss, Gerardo1 aLe Marchand, Loïc1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aKooperberg, Charles, L1 aPAGE Consortium uhttps://chs-nhlbi.org/node/628902941nas a2200517 4500008004100000022001400041245009800055210006900153260001300222300001100235490000700246520147300253653000901726653002101735653001501756653002501771653004001796653002401836653003201860653001701892653003801909653002201947653001101969653001401980653000901994653001602003653001402019653003602033653000902069100002002078700002302098700002102121700001902142700002402161700002002185700002202205700002202227700002802249700001702277700001802294700001902312700001902331700001702350700002002367856003602387 2013 eng d a1533-712X00aGenetic analysis of a population heavy drinking phenotype identifies risk variants in whites.0 aGenetic analysis of a population heavy drinking phenotype identi c2013 Apr a206-100 v333 aGenetic association studies thus far have used detailed diagnoses of alcoholism to identify loci associated with risk. This proof-of-concept analysis examined whether population data of lifetime heaviest alcohol consumption may be used to identify genetic loci that modulate risk. We conducted a genetic association study in European Americans between variants in approximately 2100 genes and alcohol consumption as part of the Candidate gene Association Resource project. We defined cases as individuals with a history of drinking 5 or more drinks per day almost every day of the week and controls as current light drinkers (1-5 drinks per week). We cross-validated identified single nucleotide polymorphisms in a meta-analysis of 2 cohorts of unrelated individuals--Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)--and in a separate cohort of related individuals--Framingham Heart Study (FHS). The most significant variant in the meta-analysis of ARIC and CHS was rs6933598 in methylenetetrahydrofolate dehydrogenase (P = 7.46 × 10(-05)) with a P value in FHS of 0.042. The top variants in FHS were rs12249562 in cubulin (P = 3.03 × 10(-05)) and rs9839267 near cholecystokinin (P = 3.05 × 10(-05)) with a P value of 0.019 for rs9839267 in CHS. We have here shown feasibility in evaluating lifetime incidence of heavy alcohol drinking from population-based studies for the purpose of conducting genetic association analyses.
10aAged10aAlcohol Drinking10aAlcoholism10aCase-Control Studies10aEuropean Continental Ancestry Group10aFeasibility Studies10aGenetic Association Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aHumans10aIncidence10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aRisk1 aHamidovic, Ajna1 aGoodloe, Robert, J1 aYoung, Taylor, R1 aStyn, Mindi, A1 aMukamal, Kenneth, J1 aChoquet, Helene1 aKasberger, Jay, L1 aBuxbaum, Sarah, G1 aPapanicolaou, George, J1 aWhite, Wendy1 aVolcik, Kelly1 aSpring, Bonnie1 aHitsman, Brian1 aLevy, Daniel1 aJorgenson, Eric uhttps://chs-nhlbi.org/node/162004387nas a2201021 4500008004100000022001400041245005800055210005700113260000900170300001100179490000600190520154700196653000901743653002201752653001501774653003101789653004001820653001101860653001701871653003401888653001301922653001101935653000901946653003101955653002101986653001602007653002002023653002002043100001702063700002302080700001802103700002502121700001602146700002202162700001402184700002602198700002102224700001902245700001802264700002402282700002202306700001902328700002202347700002002369700002702389700001902416700002602435700002802461700002302489700001902512700002402531700002202555700002302577700002202600700001602622700001902638700002002657700002702677700002002704700002202724700002102746700002402767700001202791700002302803700002202826700001702848700002002865700002002885700002402905700002502929700001402954700002002968700002102988700002703009700002103036700002303057700002203080700002203102700001903124700002403143700002803167700002403195700001903219700001803238710004503256710002803301856003603329 2013 eng d a1932-620300aGenetic loci for retinal arteriolar microcirculation.0 aGenetic loci for retinal arteriolar microcirculation c2013 ae658040 v83 aNarrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
10aAged10aAged, 80 and over10aArterioles10aChromosomes, Human, Pair 510aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMEF2 Transcription Factors10aMicrocirculation10aMiddle Aged10aModels, Genetic10aRetinal Vessels1 aSim, Xueling1 aJensen, Richard, A1 aIkram, Kamran1 aCotch, Mary, Frances1 aLi, Xiaohui1 aMacgregor, Stuart1 aXie, Jing1 aSmith, Albert, Vernon1 aBoerwinkle, Eric1 aMitchell, Paul1 aKlein, Ronald1 aKlein, Barbara, E K1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 ade Jong, Paulus, T V M1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aJonasson, Fridbert1 aLauner, Lenore, J1 aAttia, John1 aBaird, Paul, N1 aHarrap, Stephen1 aHolliday, Elizabeth, G1 aInouye, Michael1 aRochtchina, Elena1 aScott, Rodney, J1 aViswanathan, Ananth1 aLi, Guo1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aKuo, Jane, Z1 aTaylor, Kent, D1 aHewitt, Alex, W1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aSun, Cong1 aYoung, Terri, L1 aMackey, David, A1 avan Zuydam, Natalie, R1 aDoney, Alex, S F1 aPalmer, Colin, N A1 aMorris, Andrew, D1 aRotter, Jerome, I1 aTai, Shyong, E1 aGudnason, Vilmundur1 aVingerling, Johannes, R1 aSiscovick, David, S1 aWang, Jie, Jin1 aWong, Tien, Y1 aWellcome Trust Case Control Consortium 21 aGlobal BPgen Consortium uhttps://chs-nhlbi.org/node/602703914nas a2200673 4500008004100000022001400041245016900055210006900224260001300293300001100306490000700317520191200324653001202236653002002248653001802268653001902286653001702305653003802322653003402360653001102394653002702405653001702432653001202449653001402461653003602475653001702511100002502528700001902553700002402572700001502596700002302611700002202634700002002656700002102676700002002697700002102717700003002738700001402768700001802782700001702800700002802817700002202845700002102867700002102888700002002909700002102929700002502950700002302975700002502998700002403023700002403047700002203071700002303093700001903116700002703135700002303162700001903185856003603204 2013 eng d a1930-739X00aGenetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study.0 aGenetic risk factors for BMI and obesity in an ethnically divers c2013 Apr a835-460 v213 aOBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.
DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI.
RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.
CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.
10aAlleles10aBody Mass Index10aEthnic Groups10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMetagenomics10aObesity10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors1 aFesinmeyer, Megan, D1 aNorth, Kari, E1 aRitchie, Marylyn, D1 aLim, Unhee1 aFranceschini, Nora1 aWilkens, Lynne, R1 aGross, Myron, D1 aBůzková, Petra1 aGlenn, Kimberly1 aQuibrera, Miguel1 aFernandez-Rhodes, Lindsay1 aLi, Qiong1 aFowke, Jay, H1 aLi, Rongling1 aCarlson, Christopher, S1 aPrentice, Ross, L1 aKuller, Lewis, H1 aManson, JoAnn, E1 aMatise, Tara, C1 aCole, Shelley, A1 aChen, Christina, T L1 aHoward, Barbara, V1 aKolonel, Laurence, N1 aHenderson, Brian, E1 aMonroe, Kristine, R1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aBuyske, Steven1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/663103932nas a2200769 4500008004100000022001400041245020400055210006900259260001600328300000700344490000700351520160000358653004101958653001001999653002202009653000902031653001202040653003702052653001802089653003002107653004002137653001102177653001902188653001702207653003402224653001302258653002302271653001102294653002802305653001202333653000902345653001602354653003602370653004202406100002502448700002002473700001902493700002802512700002102540700002302561700002202584700002002606700002202626700003102648700002302679700002102702700002502723700001502748700002102763700002402784700002102808700002002829700002602849700001702875700001502892700002202907700002302929700002302952700001902975700002002994700002203014700002303036700002703059700001903086700002103105856003603126 2013 eng d a1471-235000aGenetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.0 aGenetic variants associated with fasting glucose and insulin con c2013 Sep 25 a980 v143 aBACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.
METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.
RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.
CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.
10aAdaptor Proteins, Signal Transducing10aAdult10aAfrican Americans10aAged10aAlleles10aAsian Continental Ancestry Group10aBlood Glucose10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aGenomics10aHispanic Americans10aHumans10aIndians, North American10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factor 7-Like 2 Protein1 aFesinmeyer, Megan, D1 aMeigs, James, B1 aNorth, Kari, E1 aSchumacher, Fredrick, R1 aBůzková, Petra1 aFranceschini, Nora1 aHaessler, Jeffrey1 aGoodloe, Robert1 aSpencer, Kylee, L1 aVoruganti, Venkata, Saroja1 aHoward, Barbara, V1 aJackson, Rebecca1 aKolonel, Laurence, N1 aLiu, Simin1 aManson, JoAnn, E1 aMonroe, Kristine, R1 aMukamal, Kenneth1 aDilks, Holli, H1 aPendergrass, Sarah, A1 aNato, Andrew1 aWan, Peggy1 aWilkens, Lynne, R1 aLe Marchand, Loïc1 aAmbite, Jose, Luis1 aBuyske, Steven1 aFlorez, Jose, C1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aHaiman, Christopher, A1 aPeters, Ulrike1 aPankow, James, S uhttps://chs-nhlbi.org/node/629002899nas a2200361 4500008004100000022001400041245012800055210006900183260001300252300001100265490000700276520184400283653002802127653001802155653003002173653001202203653001102215653001302226653001102239653000902250653003602259100002202295700002002317700001802337700002002355700002102375700001802396700002402414700002002438700001902458700002402477856003602501 2013 eng d a1935-554800aGenetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.0 aGenetically elevated fetuinA levels fasting glucose levels and r c2013 Oct a3121-70 v363 aOBJECTIVE: Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes.
RESEARCH DESIGN AND METHODS: Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993.
RESULTS: Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant.
CONCLUSIONS: Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.
10aalpha-2-HS-Glycoprotein10aBlood Glucose10aDiabetes Mellitus, Type 210aFasting10aFemale10aGenotype10aHumans10aMale10aPolymorphism, Single Nucleotide1 aJensen, Majken, K1 aBartz, Traci, M1 aDjoussé, Luc1 aKizer, Jorge, R1 aZieman, Susan, J1 aRimm, Eric, B1 aSiscovick, David, S1 aPsaty, Bruce, M1 aIx, Joachim, H1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/599504091nas a2200793 4500008004100000022001400041245011400055210006900169260001600238300001200254490000700266520179600273653001002069653002202079653000902101653002502110653002402135653002802159653004002187653001102227653004402238653003202282653002202314653003402336653001302370653001102383653000902394653001602403653001502419653003602434653001602470100002502486700002002511700001802531700001902549700001902568700002002587700001802607700002202625700002102647700002002668700002602688700002102714700001802735700002402753700002102777700002102798700003002819700002202849700002002871700001802891700002202909700002402931700002202955700002102977700002202998700002103020700002103041700002103062700002203083700002403105700002003129700002003149700002403169700002203193700002003215710002603235856003603261 2013 eng d a1460-208300aGenome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia.0 aGenomewide and genecentric analyses of circulating myeloperoxida c2013 Aug 15 a3381-930 v223 aIncreased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
10aAdult10aAfrican Americans10aAged10aCase-Control Studies10aComplement Factor H10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aGene Expression Regulation, Enzymologic10aGenetic Association Studies10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPeroxidase10aPolymorphism, Single Nucleotide10aYoung Adult1 aReiner, Alexander, P1 aHartiala, Jaana1 aZeller, Tanja1 aBis, Joshua, C1 aDupuis, Josée1 aFornage, Myriam1 aBaumert, Jens1 aKleber, Marcus, E1 aWild, Philipp, S1 aBaldus, Stephan1 aBielinski, Suzette, J1 aFontes, João, D1 aIllig, Thomas1 aKeating, Brendan, J1 aLange, Leslie, A1 aOjeda, Francisco1 aMüller-Nurasyid, Martina1 aMunzel, Thomas, F1 aPsaty, Bruce, M1 aRice, Kenneth1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aTang, W, H Wilson1 aThorand, Barbara1 aErdmann, Jeanette1 aJacobs, David, R1 aWilson, James, G1 aKoenig, Wolfgang1 aTracy, Russell, P1 aBlankenberg, Stefan1 aMärz, Winfried1 aGross, Myron, D1 aBenjamin, Emelia, J1 aHazen, Stanley, L1 aAllayee, Hooman1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/628209406nas a2203037 4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520104700257653002501304653004001329653001901369653001701388653003401405653001201439653000901451653001101460653001301471653003601484653002401520653001401544100001901558700001801577700002201595700002201617700001801639700002501657700002001682700002201702700002601724700001901750700001601769700002001785700002301805700002101828700002101849700001501870700002301885700002601908700002101934700002101955700002001976700001201996700002202008700002202030700002202052700001602074700001902090700001902109700002102128700001402149700002202163700002002185700001502205700001702220700002202237700002102259700001902280700001902299700002102318700001902339700002502358700001902383700001902402700002202421700001902443700002002462700001702482700002102499700001902520700002202539700002202561700002002583700001802603700002302621700002702644700001802671700002002689700001702709700002002726700002202746700002102768700002902789700002202818700002202840700002102862700002302883700002102906700001802927700002002945700002302965700002402988700002503012700001903037700002103056700002203077700002403099700002203123700002103145700001503166700001703181700001803198700002203216700002003238700002403258700002003282700002003302700002103322700001703343700001803360700002103378700002103399700002203420700001603442700002103458700001903479700002403498700002503522700001803547700001603565700001903581700002103600700002103621700002703642700001403669700002103683700002503704700002303729700001803752700002503770700002103795700002003816700001603836700002403852700001803876700002603894700002203920700001703942700001703959700002403976700002104000700002204021700001804043700002804061700002304089700001904112700002304131700002204154700001704176700001904193700002204212700001804234700001904252700001704271700002104288700002404309700001904333700001504352700001704367700001904384700002604403700002804429700001904457700002804476700002104504700002204525700002504547700002004572700002304592700001904615700001904634700002504653700002404678700002104702700002204723700001604745700001904761700002004780700001804800700002004818700001704838700002004855700002004875700001904895700002804914700002704942700002204969700002204991700001905013700002505032700002205057700001805079700002005097700001605117700001605133700001805149700002105167700002005188700001505208700001905223700001705242700002905259700001905288700002405307700001805331700002205349700002305371700002005394700002105414700002405435700001905459700002005478700001605498700002505514700002105539700002005560700002305580700002305603700002005626700002205646700001805668700003005686700002205716700002005738700002605758700002005784700002005804700002005824700001805844700001805862700003005880700001805910700001905928700002305947700001805970700002005988700002006008700002106028700002306049700002006072700002006092700001906112700002106131700002006152700002106172700002206193710002706215710002606242710002306268710002006291710002106311856003606332 2013 eng d a1546-171800aGenome-wide association analyses identify 18 new loci associated with serum urate concentrations.0 aGenomewide association analyses identify 18 new loci associated c2013 Feb a145-540 v453 aElevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
10aAnalysis of Variance10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aGlucose10aGout10aHumans10aInhibins10aPolymorphism, Single Nucleotide10aSignal Transduction10aUric Acid1 aKöttgen, Anna1 aAlbrecht, Eva1 aTeumer, Alexander1 aVitart, Veronique1 aKrumsiek, Jan1 aHundertmark, Claudia1 aPistis, Giorgio1 aRuggiero, Daniela1 aO'Seaghdha, Conall, M1 aHaller, Toomas1 aYang, Qiong1 aTanaka, Toshiko1 aJohnson, Andrew, D1 aKutalik, Zoltán1 aSmith, Albert, V1 aShi, Julia1 aStruchalin, Maksim1 aMiddelberg, Rita, P S1 aBrown, Morris, J1 aGaffo, Angelo, L1 aPirastu, Nicola1 aLi, Guo1 aHayward, Caroline1 aZemunik, Tatijana1 aHuffman, Jennifer1 aYengo, Loic1 aZhao, Jing Hua1 aDemirkan, Ayse1 aFeitosa, Mary, F1 aLiu, Xuan1 aMalerba, Giovanni1 aLopez, Lorna, M1 aHarst, Pim1 aLi, Xinzhong1 aKleber, Marcus, E1 aHicks, Andrew, A1 aNolte, Ilja, M1 aJohansson, Asa1 aMurgia, Federico1 aWild, Sarah, H1 aBakker, Stephan, J L1 aPeden, John, F1 aDehghan, Abbas1 aSteri, Maristella1 aTenesa, Albert1 aLagou, Vasiliki1 aSalo, Perttu1 aMangino, Massimo1 aRose, Lynda, M1 aLehtimäki, Terho1 aWoodward, Owen, M1 aOkada, Yukinori1 aTin, Adrienne1 aMüller, Christian1 aOldmeadow, Christopher1 aPutku, Margus1 aCzamara, Darina1 aKraft, Peter1 aFrogheri, Laura1 aThun, Gian, Andri1 aGrotevendt, Anne1 aGislason, Gauti, Kjartan1 aHarris, Tamara, B1 aLauner, Lenore, J1 aMcArdle, Patrick1 aShuldiner, Alan, R1 aBoerwinkle, Eric1 aCoresh, Josef1 aSchmidt, Helena1 aSchallert, Michael1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aKubo, Michiaki1 aNakamura, Yusuke1 aTanaka, Toshihiro1 aMunroe, Patricia, B1 aSamani, Nilesh, J1 aJacobs, David, R1 aLiu, Kiang1 aD'Adamo, Pio1 aUlivi, Sheila1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aVollenweider, Peter1 aWaeber, Gérard1 aCampbell, Susan1 aDevuyst, Olivier1 aNavarro, Pau1 aKolcic, Ivana1 aHastie, Nicholas1 aBalkau, Beverley1 aFroguel, Philippe1 aEsko, Tõnu1 aSalumets, Andres1 aKhaw, Kay, Tee1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aIsaacs, Aaron1 aKraja, Aldi1 aZhang, Qunyuan1 aWild, Philipp, S1 aScott, Rodney, J1 aHolliday, Elizabeth, G1 aOrg, Elin1 aViigimaa, Margus1 aBandinelli, Stefania1 aMetter, Jeffrey, E1 aLupo, Antonio1 aTrabetti, Elisabetta1 aSorice, Rossella1 aDöring, Angela1 aLattka, Eva1 aStrauch, Konstantin1 aTheis, Fabian1 aWaldenberger, Melanie1 aWichmann, H-Erich1 aDavies, Gail1 aGow, Alan, J1 aBruinenberg, Marcel1 aStolk, Ronald, P1 aKooner, Jaspal, S1 aZhang, Weihua1 aWinkelmann, Bernhard, R1 aBoehm, Bernhard, O1 aLucae, Susanne1 aPenninx, Brenda, W1 aSmit, Johannes, H1 aCurhan, Gary1 aMudgal, Poorva1 aPlenge, Robert, M1 aPortas, Laura1 aPersico, Ivana1 aKirin, Mirna1 aWilson, James, F1 aLeach, Irene, Mateo1 aGilst, Wiek, H1 aGoel, Anuj1 aOngen, Halit1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aImboden, Medea1 avon Eckardstein, Arnold1 aCucca, Francesco1 aNagaraja, Ramaiah1 aPiras, Maria, Grazia1 aNauck, Matthias1 aSchurmann, Claudia1 aBudde, Kathrin1 aErnst, Florian1 aFarrington, Susan, M1 aTheodoratou, Evropi1 aProkopenko, Inga1 aStumvoll, Michael1 aJula, Antti1 aPerola, Markus1 aSalomaa, Veikko1 aShin, So-Youn1 aSpector, Tim, D1 aSala, Cinzia1 aRidker, Paul, M1 aKähönen, Mika1 aViikari, Jorma1 aHengstenberg, Christian1 aNelson, Christopher, P1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aSingleton, Andrew, B1 aKamatani, Naoyuki1 aZeller, Tanja1 aBurnier, Michel1 aAttia, John1 aLaan, Maris1 aKlopp, Norman1 aHillege, Hans, L1 aKloiber, Stefan1 aChoi, Hyon1 aPirastu, Mario1 aTore, Silvia1 aProbst-Hensch, Nicole, M1 aVölzke, Henry1 aGudnason, Vilmundur1 aParsa, Afshin1 aSchmidt, Reinhold1 aWhitfield, John, B1 aFornage, Myriam1 aGasparini, Paolo1 aSiscovick, David, S1 aPolasek, Ozren1 aCampbell, Harry1 aRudan, Igor1 aBouatia-Naji, Nabila1 aMetspalu, Andres1 aLoos, Ruth, J F1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aFerrucci, Luigi1 aGambaro, Giovanni1 aDeary, Ian, J1 aWolffenbuttel, Bruce, H R1 aChambers, John, C1 aMärz, Winfried1 aPramstaller, Peter, P1 aSnieder, Harold1 aGyllensten, Ulf1 aWright, Alan, F1 aNavis, Gerjan1 aWatkins, Hugh1 aWitteman, Jacqueline, C M1 aSanna, Serena1 aSchipf, Sabine1 aDunlop, Malcolm, G1 aTönjes, Anke1 aRipatti, Samuli1 aSoranzo, Nicole1 aToniolo, Daniela1 aChasman, Daniel, I1 aRaitakari, Olli1 aKao, Linda, W H1 aCiullo, Marina1 aFox, Caroline, S1 aCaulfield, Mark1 aBochud, Murielle1 aGieger, Christian1 aLifeLines Cohort Study1 aCARDIoGRAM consortium1 aDIAGRAM Consortium1 aICBP Consortium1 aMAGIC Consortium uhttps://chs-nhlbi.org/node/607506047nas a2201393 4500008004100000022001400041245010400055210006900159260000900228300001300237490000600250520209200256653001402348653003902362653002602401653004002427653001102467653001702478653003402495653001102529653000902540653001202549653003602561653002002597100001802617700001902635700002002654700001802674700002302692700001902715700002402734700002102758700002202779700001502801700002802816700002502844700001602869700002202885700002202907700002302929700001802952700001202970700002802982700001803010700001503028700002403043700002403067700002803091700001903119700001703138700002503155700001603180700002203196700001903218700002003237700002303257700002203280700002803302700001703330700002003347700002303367700001503390700001703405700002003422700002103442700001803463700002203481700002303503700002303526700003103549700002203580700002003602700001703622700002803639700001403667700002403681700002403705700002203729700002103751700001803772700001403790700003203804700002503836700002403861700001703885700002403902700002103926700002103947700002803968700002203996700002004018700002104038700002104059700002704080700002204107700002304129700002104152700002404173700001704197700002404214700002304238700002204261700002104283700002504304700002304329700002204352700001904374700002204393700002104415700002804436700002304464700001804487700002204505700002504527700002504552700001904577700002104596856003604617 2013 eng d a1553-740400aGenome-wide association of body fat distribution in African ancestry populations suggests new loci.0 aGenomewide association of body fat distribution in African ances c2013 ae10036810 v93 aCentral obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
10aAdiposity10aAfrican Continental Ancestry Group10aBody Fat Distribution10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aObesity10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aLiu, Ching-Ti1 aMonda, Keri, L1 aTaylor, Kira, C1 aLange, Leslie1 aDemerath, Ellen, W1 aPalmas, Walter1 aWojczynski, Mary, K1 aEllis, Jaclyn, C1 aVitolins, Mara, Z1 aLiu, Simin1 aPapanicolaou, George, J1 aIrvin, Marguerite, R1 aXue, Luting1 aGriffin, Paula, J1 aNalls, Michael, A1 aAdeyemo, Adebowale1 aLiu, Jiankang1 aLi, Guo1 aRuiz-Narvaez, Edward, A1 aChen, Wei-Min1 aChen, Fang1 aHenderson, Brian, E1 aMillikan, Robert, C1 aAmbrosone, Christine, B1 aStrom, Sara, S1 aGuo, Xiuqing1 aAndrews, Jeanette, S1 aSun, Yan, V1 aMosley, Thomas, H1 aYanek, Lisa, R1 aShriner, Daniel1 aHaritunians, Talin1 aRotter, Jerome, I1 aSpeliotes, Elizabeth, K1 aSmith, Megan1 aRosenberg, Lynn1 aMychaleckyj, Josyf1 aNayak, Uma1 aSpruill, Ida1 aGarvey, Timothy1 aPettaway, Curtis1 aNyante, Sarah1 aBandera, Elisa, V1 aBritton, Angela, F1 aZonderman, Alan, B1 aRasmussen-Torvik, Laura, J1 aChen, Yii-Der Ida1 aDing, Jingzhong1 aLohman, Kurt1 aKritchevsky, Stephen, B1 aZhao, Wei1 aPeyser, Patricia, A1 aKardia, Sharon, L R1 aKabagambe, Edmond1 aBroeckel, Ulrich1 aChen, Guanjie1 aZhou, Jie1 aWassertheil-Smoller, Sylvia1 aNeuhouser, Marian, L1 aRampersaud, Evadnie1 aPsaty, Bruce1 aKooperberg, Charles1 aManson, JoAnn, E1 aKuller, Lewis, H1 aOchs-Balcom, Heather, M1 aJohnson, Karen, C1 aSucheston, Lara1 aOrdovas, Jose, M1 aPalmer, Julie, R1 aHaiman, Christopher, A1 aMcKnight, Barbara1 aHoward, Barbara, V1 aBecker, Diane, M1 aBielak, Lawrence, F1 aLiu, Yongmei1 aAllison, Matthew, A1 aGrant, Struan, F A1 aBurke, Gregory, L1 aPatel, Sanjay, R1 aSchreiner, Pamela, J1 aBorecki, Ingrid, B1 aEvans, Michele, K1 aTaylor, Herman1 aSale, Michèle, M1 aHoward, Virginia1 aCarlson, Christopher, S1 aRotimi, Charles, N1 aCushman, Mary1 aHarris, Tamara, B1 aReiner, Alexander, P1 aCupples, Adrienne, L1 aNorth, Kari, E1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/628704061nas a2200781 4500008004100000022001400041245015900055210006900214260001300283300001200296490000700308520179500315653000902110653001002119653002502129653001902154653001102173653003402184653001102218653000902229653002702238653001602265653003602281653002402317653001702341653002702358100001802385700002202403700002302425700001802448700002902466700001202495700002102507700002202528700002102550700002302571700002402594700002002618700001702638700001802655700001602673700002502689700001902714700002302733700002802756700001802784700002102802700001802823700001902841700002602860700002202886700002102908700002802929700002202957700001902979700002102998700001903019700002203038700002103060700002203081700003203103700001803135700002603153700002003179700002103199700002303220856003603243 2013 eng d a1098-227200aA genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.0 agenomewide association study for venous thromboembolism the exte c2013 Jul a512-5210 v373 aVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
10aAged10aAging10aCase-Control Studies10aCohort Studies10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aVenous Thromboembolism1 aTang, Weihong1 aTeichert, Martina1 aChasman, Daniel, I1 aHeit, John, A1 aMorange, Pierre-Emmanuel1 aLi, Guo1 aPankratz, Nathan1 aLeebeek, Frank, W1 aParé, Guillaume1 ade Andrade, Mariza1 aTzourio, Christophe1 aPsaty, Bruce, M1 aBasu, Saonli1 aRuiter, Rikje1 aRose, Lynda1 aArmasu, Sebastian, M1 aLumley, Thomas1 aHeckbert, Susan, R1 aUitterlinden, André, G1 aLathrop, Mark1 aRice, Kenneth, M1 aCushman, Mary1 aHofman, Albert1 aLambert, Jean-Charles1 aGlazer, Nicole, L1 aPankow, James, S1 aWitteman, Jacqueline, C1 aAmouyel, Philippe1 aBis, Joshua, C1 aBovill, Edwin, G1 aKong, Xiaoxiao1 aTracy, Russell, P1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aTrégouët, David-Alexandre1 aLoth, Daan, W1 aStricker, Bruno, H Ch1 aRidker, Paul, M1 aFolsom, Aaron, R1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/602904169nas a2200709 4500008004100000022001400041245026000055210006900315260001300384300001100397490000600408520202600414653001002440653000902450653003102459653001902490653002102509653003002530653003302560653001102593653001702604653003402621653001302655653001102668653002702679653001602706653000902722653001602731653001502747653001802762653003602780653001802816100001802834700002402852700002102876700001702897700002002914700001902934700002502953700001802978700002102996700002203017700002303039700001903062700002003081700002203101700002103123700002103144700002703165700001803192700002503210700002103235700002303256700002103279700001703300700002103317700002003338700002003358700002003378700002503398856003603423 2013 eng d a1942-326800aGenome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu0 aGenomewide association study identifies novel loci associated wi c2013 Apr a171-830 v63 aBACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.
10aAdult10aAged10aChromosomes, Human, Pair 210aCohort Studies10aCoronary Disease10aDiabetes Mellitus, Type 210aFatty Acids, Monounsaturated10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aLinkage Disequilibrium10aLipogenesis10aMale10aMiddle Aged10aOleic Acid10aPalmitic Acid10aPolymorphism, Single Nucleotide10aStearic Acids1 aH Y Wu, Jason1 aLemaitre, Rozenn, N1 aManichaikul, Ani1 aGuan, Weihua1 aTanaka, Toshiko1 aFoy, Millennia1 aKabagambe, Edmond, K1 aDjoussé, Luc1 aSiscovick, David1 aFretts, Amanda, M1 aJohnson, Catherine1 aKing, Irena, B1 aPsaty, Bruce, M1 aMcKnight, Barbara1 aRich, Stephen, S1 aChen, Yii-der, I1 aNettleton, Jennifer, A1 aTang, Weihong1 aBandinelli, Stefania1 aJacobs, David, R1 aBrowning, Brian, L1 aLaurie, Cathy, C1 aGu, Xiangjun1 aTsai, Michael, Y1 aSteffen, Lyn, M1 aFerrucci, Luigi1 aFornage, Myriam1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/588004246nas a2200769 4500008004100000022001400041245015300055210006900208260001300277300001000290490000600300520206100306653002202367653000902389653001902398653001302417653002102430653004002451653001102491653003402502653001302536653001002549653001102559653000902570653001602579653001402595653003602609653001202645100001802657700002302675700001902698700001902717700001302736700002402749700002302773700002102796700002202817700001902839700002002858700002102878700002302899700002502922700002202947700002302969700001602992700002103008700001903029700001303048700001803061700002503079700002003104700002903124700002103153700002403174700002203198700002403220700001903244700001803263700002203281700002203303700002203325700002003347700002303367700002303390700002703413856003603440 2013 eng d a1942-326800aGenome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study.0 aGenomewide association study of cardiac structure and systolic f c2013 Feb a37-460 v63 aBACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.
METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.
CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
10aAfrican Americans10aAged10aCohort Studies10aDiastole10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aMusani, Solomon, K1 aBarbalic, Maja1 aLin, Honghuang1 aYu, Bing1 aOgunyankin, Kofo, O1 aSmith, Nicholas, L1 aKutlar, Abdullah1 aGlazer, Nicole, L1 aPost, Wendy, S1 aPaltoo, Dina, N1 aDries, Daniel, L1 aFarlow, Deborah, N1 aDuarte, Christine, W1 aKardia, Sharon, L1 aMeyers, Kristin, J1 aSun, Yan, V1 aArnett, Donna, K1 aPatki, Amit, A1 aSha, Jin1 aCui, Xiangqui1 aSamdarshi, Tandaw, E1 aPenman, Alan, D1 aBibbins-Domingo, Kirsten1 aBůzková, Petra1 aBenjamin, Emelia, J1 aBluemke, David, A1 aMorrison, Alanna, C1 aHeiss, Gerardo1 aCarr, Jeffrey1 aTracy, Russell, P1 aMosley, Thomas, H1 aTaylor, Herman, A1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aCappola, Thomas, P1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/663205039nas a2201297 4500008004100000022001400041245006000055210005600115260001600171300001100187490000700198520149400205653000901699653002201708653003101730653001501761653001101776653003801787653003401825653001101859653000901870653001601879653003601895100001501931700001901946700001601965700002501981700002202006700002502028700001602053700001802069700001802087700002002105700001702125700002302142700002202165700002202187700001602209700002302225700001202248700002502260700002402285700002202309700002002331700002302351700002002374700001702394700002402411700002202435700001902457700001702476700001902493700002102512700002202533700001702555700001802572700002002590700002202610700002202632700001902654700002302673700002002696700002002716700002002736700002402756700001902780700001802799700001902817700002602836700002102862700001702883700002002900700002302920700001802943700002102961700002402982700001703006700001903023700001903042700002003061700002303081700002103104700001703125700001803142700002003160700001903180700002303199700002503222700002103247700002303268700002803291700001903319700002103338700002003359700002303379700002103402700001903423700002303442700002403465700002303489700002003512700002303532700001903555700002203574700002403596700002203620700002003642700002203662700002103684856003603705 2013 eng d a1873-240200aA genome-wide association study of depressive symptoms.0 agenomewide association study of depressive symptoms c2013 Apr 01 a667-780 v733 aBACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
10aAged10aAged, 80 and over10aChromosomes, Human, Pair 510aDepression10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aHek, Karin1 aDemirkan, Ayse1 aLahti, Jari1 aTerracciano, Antonio1 aTeumer, Alexander1 aCornelis, Marilyn, C1 aAmin, Najaf1 aBakshis, Erin1 aBaumert, Jens1 aDing, Jingzhong1 aLiu, Yongmei1 aMarciante, Kristin1 aMeirelles, Osorio1 aNalls, Michael, A1 aSun, Yan, V1 aVogelzangs, Nicole1 aYu, Lei1 aBandinelli, Stefania1 aBenjamin, Emelia, J1 aBennett, David, A1 aBoomsma, Dorret1 aCannas, Alessandra1 aCoker, Laura, H1 ade Geus, Eco1 aDe Jager, Philip, L1 aDiez-Roux, Ana, V1 aPurcell, Shaun1 aHu, Frank, B1 aRimma, Eric, B1 aHunter, David, J1 aJensen, Majken, K1 aCurhan, Gary1 aRice, Kenneth1 aPenman, Alan, D1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aEmeny, Rebecca1 aEriksson, Johan, G1 aEvans, Denis, A1 aFerrucci, Luigi1 aFornage, Myriam1 aGudnason, Vilmundur1 aHofman, Albert1 aIllig, Thomas1 aKardia, Sharon1 aKelly-Hayes, Margaret1 aKoenen, Karestan1 aKraft, Peter1 aKuningas, Maris1 aMassaro, Joseph, M1 aMelzer, David1 aMulas, Antonella1 aMulder, Cornelis, L1 aMurray, Anna1 aOostra, Ben, A1 aPalotie, Aarno1 aPenninx, Brenda1 aPetersmann, Astrid1 aPilling, Luke, C1 aPsaty, Bruce1 aRawal, Rajesh1 aReiman, Eric, M1 aSchulz, Andrea1 aShulman, Joshua, M1 aSingleton, Andrew, B1 aSmith, Albert, V1 aSutin, Angelina, R1 aUitterlinden, André, G1 aVölzke, Henry1 aWiden, Elisabeth1 aYaffe, Kristine1 aZonderman, Alan, B1 aCucca, Francesco1 aHarris, Tamara1 aLadwig, Karl-Heinz1 aLlewellyn, David, J1 aRäikkönen, Katri1 aTanaka, Toshiko1 aDuijn, Cornelia, M1 aGrabe, Hans, J1 aLauner, Lenore, J1 aLunetta, Kathryn, L1 aMosley, Thomas, H1 aNewman, Anne, B1 aTiemeier, Henning1 aMurabito, Joanne uhttps://chs-nhlbi.org/node/607004181nas a2201057 4500008004100000022001400041245010300055210006900158260001600227300001200243490000700255520120000262653002501462653001101487653001901498653003401517653001101551653002501562653003601587653003401623653002801657653000901685100002101694700001801715700001601733700002301749700002001772700002301792700001601815700002101831700002101852700001901873700002601892700001901918700001901937700002301956700001901979700001801998700001902016700001902035700002102054700001802075700002002093700002502113700002102138700002202159700002402181700001902205700001902224700001902243700001702262700001902279700002102298700001202319700002202331700002302353700001702376700001802393700002002411700002002431700002602451700001702477700002102494700002302515700002102538700002002559700002402579700002302603700002002626700002402646700001702670700002102687700002402708700002102732700002502753700002402778700002002802700001602822700002002838700002102858700002502879700002802904700002002932700002802952700002102980700002403001700002103025700001703046710002403063856003603087 2013 eng d a1460-208300aA genome-wide association study of early menopause and the combined impact of identified variants.0 agenomewide association study of early menopause and the combined c2013 Apr 01 a1465-720 v223 aEarly menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
10aCase-Control Studies10aFemale10aGene Frequency10aGenome-Wide Association Study10aHumans10aMenopause, Premature10aPolymorphism, Single Nucleotide10aPrimary Ovarian Insufficiency10aQuantitative Trait Loci10aRisk1 aPerry, John, R B1 aCorre, Tanguy1 aEsko, Tõnu1 aChasman, Daniel, I1 aFischer, Krista1 aFranceschini, Nora1 aHe, Chunyan1 aKutalik, Zoltán1 aMangino, Massimo1 aRose, Lynda, M1 aSmith, Albert, Vernon1 aStolk, Lisette1 aSulem, Patrick1 aWeedon, Michael, N1 aZhuang, Wei, V1 aArnold, Alice1 aAshworth, Alan1 aBergmann, Sven1 aBuring, Julie, E1 aBurri, Andrea1 aChen, Constance1 aCornelis, Marilyn, C1 aCouper, David, J1 aGoodarzi, Mark, O1 aGudnason, Vilmundur1 aHarris, Tamara1 aHofman, Albert1 aJones, Michael1 aKraft, Peter1 aLauner, Lenore1 aLaven, Joop, S E1 aLi, Guo1 aMcKnight, Barbara1 aMasciullo, Corrado1 aMilani, Lili1 aOrr, Nicholas1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aSala, Cinzia1 aSalumets, Andres1 aSchoemaker, Minouk1 aTraglia, Michela1 aWaeber, Gérard1 aChanock, Stephen, J1 aDemerath, Ellen, W1 aGarcia, Melissa1 aHankinson, Susan, E1 aHu, Frank, B1 aHunter, David, J1 aLunetta, Kathryn, L1 aMetspalu, Andres1 aMontgomery, Grant, W1 aMurabito, Joanne, M1 aNewman, Anne, B1 aOng, Ken, K1 aSpector, Tim, D1 aStefansson, Kari1 aSwerdlow, Anthony, J1 aThorsteinsdottir, Unnur1 avan Dam, Rob, M1 aUitterlinden, André, G1 aVisser, Jenny, A1 aVollenweider, Peter1 aToniolo, Daniela1 aMurray, Anna1 aReproGen Consortium uhttps://chs-nhlbi.org/node/615304413nas a2200889 4500008004100000022001400041245008200055210006900137260000900206300001100215490000600226520194300232653000902175653002202184653001102206653003402217653001302251653002502264653001102289653001702300653000902317653003602326653002302362653002102385100002302406700001702429700001602446700002502462700001802487700002702505700002402532700002202556700002302578700002402601700002202625700002602647700002102673700001702694700002002711700001702731700001902748700001902767700001602786700001802802700002202820700001902842700002202861700002002883700001702903700001902920700002702939700002602966700002802992700001803020700001903038700002003057700001703077700002003094700001903114700001403133700002203147700003003169700001903199700002203218700001703240700002303257700002403280700001803304700002403322700002203346700001503368700002503383700001803408710003903426710002203465856003603487 2013 eng d a1932-620300aGenome-wide association study of retinopathy in individuals without diabetes.0 aGenomewide association study of retinopathy in individuals witho c2013 ae542320 v83 aBACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.
RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.
CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
10aAged10aAged, 80 and over10aFemale10aGenome-Wide Association Study10aGenotype10aHistone Deacetylases10aHumans10aHypertension10aMale10aPolymorphism, Single Nucleotide10aRepressor Proteins10aRetinal Diseases1 aJensen, Richard, A1 aSim, Xueling1 aLi, Xiaohui1 aCotch, Mary, Frances1 aIkram, Kamran1 aHolliday, Elizabeth, G1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore, J1 aSmith, Albert, Vernon1 aBoerwinkle, Eric1 aCheung, Ning1 aHewitt, Alex, W1 aLiew, Gerald1 aMitchell, Paul1 aWang, Jie, Jin1 aAttia, John1 aScott, Rodney1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aTaylor, Kent1 aHofman, Albert1 ade Jong, Paulus, T V M1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aTay, Wan-Ting1 aTeo, Yik, Ying1 aSeielstad, Mark1 aLiu, Jianjun1 aCheng, Ching-Yu1 aSaw, Seang-Mei1 aAung, Tin1 aGanesh, Santhi, K1 aO'Donnell, Christopher, J1 aNalls, Mike, A1 aWiggins, Kerri, L1 aKuo, Jane, Z1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aKlein, Ronald1 aSiscovick, David, S1 aRotter, Jerome, I1 aTai, Shong1 aVingerling, Johannes1 aWong, Tien, Y1 aBlue Mountains Eye Study GWAS Team1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/607212626nas a2204177 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2013 eng d a1546-171800aGenome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.0 aGenomewide metaanalysis identifies 11 new loci for anthropometri c2013 May a501-120 v453 aApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
10aAnthropometry10aBody Height10aBody Mass Index10aCase-Control Studies10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMeta-Analysis as Topic10aObesity10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aWaist-Hip Ratio1 aBerndt, Sonja, I1 aGustafsson, Stefan1 aMägi, Reedik1 aGanna, Andrea1 aWheeler, Eleanor1 aFeitosa, Mary, F1 aJustice, Anne, E1 aMonda, Keri, L1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aEsko, Tõnu1 aFall, Tove1 aFerreira, Teresa1 aGentilini, Davide1 aJackson, Anne, U1 aLuan, Jian'an1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWiller, Cristen, J1 aWinkler, Thomas, W1 aWood, Andrew, R1 aWorkalemahu, Tsegaselassie1 aHu, Yi-Juan1 aLee, Sang, Hong1 aLiang, Liming1 aLin, Dan-Yu1 aMin, Josine, L1 aNeale, Benjamin, M1 aThorleifsson, Gudmar1 aYang, Jian1 aAlbrecht, Eva1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aHeijer, Martin, den1 aEklund, Niina1 aFischer, Krista1 aGoel, Anuj1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aJarick, Ivonne1 aJohansson, Asa1 aJohnson, Toby1 aKanoni, Stavroula1 aKleber, Marcus, E1 aKönig, Inke, R1 aKristiansson, Kati1 aKutalik, Zoltán1 aLamina, Claudia1 aLecoeur, Cécile1 aLi, Guo1 aMangino, Massimo1 aMcArdle, Wendy, L1 aMedina-Gómez, Carolina1 aMüller-Nurasyid, Martina1 aNgwa, Julius, S1 aNolte, Ilja, M1 aPaternoster, Lavinia1 aPechlivanis, Sonali1 aPerola, Markus1 aPeters, Marjolein, J1 aPreuss, Michael1 aRose, Lynda, M1 aShi, Jianxin1 aShungin, Dmitry1 aSmith, Albert, Vernon1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTeumer, Alexander1 aTrip, Mieke, D1 aTyrer, Jonathan1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aWaite, Lindsay, L1 aZhao, Jing Hua1 aAbsher, Devin1 aAsselbergs, Folkert, W1 aAtalay, Mustafa1 aAttwood, Antony, P1 aBalmforth, Anthony, J1 aBasart, Hanneke1 aBeilby, John1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBruinenberg, Marcel1 aCampbell, Harry1 aChasman, Daniel, I1 aChines, Peter, S1 aCollins, Francis, S1 aConnell, John, M1 aCookson, William, O1 ade Faire, Ulf1 ade Vegt, Femmie1 aDei, Mariano1 aDimitriou, Maria1 aEdkins, Sarah1 aEstrada, Karol1 aEvans, David, M1 aFarrall, Martin1 aFerrario, Marco, M1 aFerrieres, Jean1 aFranke, Lude1 aFrau, Francesca1 aGejman, Pablo, V1 aGrallert, Harald1 aGrönberg, Henrik1 aGudnason, Vilmundur1 aHall, Alistair, S1 aHall, Per1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHeath, Andrew, C1 aHebebrand, Johannes1 aHomuth, Georg1 aHu, Frank, B1 aHunt, Sarah, E1 aHyppönen, Elina1 aIribarren, Carlos1 aJacobs, Kevin, B1 aJansson, John-Olov1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKee, Frank1 aKhaw, Kay-Tee1 aKivimaki, Mika1 aKoenig, Wolfgang1 aKraja, Aldi, T1 aKumari, Meena1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaitinen, Jaana, H1 aLakka, Timo, A1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLind, Lars1 aLindström, Jaana1 aLiu, Jianjun1 aLiuzzi, Antonio1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aMadden, Pamela, A1 aMagnusson, Patrik, K1 aManunta, Paolo1 aMarek, Diana1 aMärz, Winfried1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMihailov, Evelin1 aMilani, Lili1 aMontgomery, Grant, W1 aMooser, Vincent1 aMühleisen, Thomas, W1 aMunroe, Patricia, B1 aMusk, Arthur, W1 aNarisu, Narisu1 aNavis, Gerjan1 aNicholson, George1 aNohr, Ellen, A1 aOng, Ken, K1 aOostra, Ben, A1 aPalmer, Colin, N A1 aPalotie, Aarno1 aPeden, John, F1 aPedersen, Nancy1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aProkopenko, Inga1 aPütter, Carolin1 aRadhakrishnan, Aparna1 aRaitakari, Olli1 aRendon, Augusto1 aRivadeneira, Fernando1 aRudan, Igor1 aSaaristo, Timo, E1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSanna, Serena1 aSaramies, Jouko1 aSchipf, Sabine1 aSchreiber, Stefan1 aSchunkert, Heribert1 aShin, So-Youn1 aSignorini, Stefano1 aSinisalo, Juha1 aSkrobek, Boris1 aSoranzo, Nicole1 aStančáková, Alena1 aStark, Klaus1 aStephens, Jonathan, C1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStumvoll, Michael1 aSwift, Amy, J1 aTheodoraki, Eirini, V1 aThorand, Barbara1 aTrégouët, David-Alexandre1 aTremoli, Elena1 avan der Klauw, Melanie, M1 avan Meurs, Joyce, B J1 aVermeulen, Sita, H1 aViikari, Jorma1 aVirtamo, Jarmo1 aVitart, Veronique1 aWaeber, Gérard1 aWang, Zhaoming1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWinkelmann, Bernhard, R1 aWitteman, Jacqueline, C M1 aWolffenbuttel, Bruce, H R1 aWong, Andrew1 aWright, Alan, F1 aZillikens, Carola, M1 aAmouyel, Philippe1 aBoehm, Bernhard, O1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCupples, Adrienne, L1 aCusi, Daniele1 aDedoussis, George, V1 aErdmann, Jeanette1 aEriksson, Johan, G1 aFranks, Paul, W1 aFroguel, Philippe1 aGieger, Christian1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHingorani, Aroon1 aHinney, Anke1 aHofman, Albert1 aHovingh, Kees, G1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aJöckel, Karl-Heinz1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKiemeney, Lambertus, A1 aKuh, Diana1 aLaakso, Markku1 aLehtimäki, Terho1 aLevinson, Douglas, F1 aMartin, Nicholas, G1 aMetspalu, Andres1 aMorris, Andrew, D1 aNieminen, Markku, S1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aOuwehand, Willem, H1 aPalmer, Lyle, J1 aPenninx, Brenda1 aPower, Chris1 aProvince, Michael, A1 aPsaty, Bruce, M1 aQi, Lu1 aRauramaa, Rainer1 aRidker, Paul, M1 aRipatti, Samuli1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSnieder, Harold1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aTönjes, Anke1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aHarst, Pim1 aVollenweider, Peter1 aWallaschofski, Henri1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWichmann, H-Erich1 aWilson, James, F1 aAbecasis, Goncalo, R1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunian, Talin1 aHeid, Iris, M1 aHunter, David1 aKaplan, Robert, C1 aKarpe, Fredrik1 aMoffatt, Miriam, F1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPawitan, Yudi1 aSchadt, Eric, E1 aSchlessinger, David1 aSteinthorsdottir, Valgerdur1 aStrachan, David, P1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aVisscher, Peter, M1 aDi Blasio, Anna, Maria1 aHirschhorn, Joel, N1 aLindgren, Cecilia, M1 aMorris, Andrew, P1 aMeyre, David1 aScherag, Andre1 aMcCarthy, Mark, I1 aSpeliotes, Elizabeth, K1 aNorth, Kari, E1 aLoos, Ruth, J F1 aIngelsson, Erik uhttps://chs-nhlbi.org/node/615204041nas a2200805 4500008004100000022001400041245010600055210006900161260001300230300001000243490000800253520176400261653001002025653001302035653003202048653003202080653001902112653001102131653003402142653003802176653001102214653002702225653000902252653000902261653002202270653001602292653003602308653004302344100002102387700002002408700002202428700001602450700001802466700001902484700001602503700002102519700001802540700001702558700002402575700002302599700002002622700001202642700001802654700002302672700001902695700002402714700002102738700001902759700001902778700002202797700002202819700001802841700003202859700002402891700002302915700002002938700002002958700002102978700001502999700001903014700002003033700001803053700002003071700002103091700002303112700002003135700002003155700002403175856003603199 2013 eng d a1432-120300aGenome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.0 aGenomewide study identifies two loci associated with lung functi c2013 Jan a79-900 v1323 aAccelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
10aAdult10aAnkyrins10aChromosomes, Human, Pair 1010aChromosomes, Human, Pair 1410aCohort Studies10aFemale10aGenome-Wide Association Study10aHepatocyte Nuclear Factor 3-alpha10aHumans10aLinkage Disequilibrium10aLung10aMale10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aPulmonary Disease, Chronic Obstructive1 aHansel, Nadia, N1 aRuczinski, Ingo1 aRafaels, Nicholas1 aSin, Don, D1 aDaley, Denise1 aMalinina, Alla1 aHuang, Lili1 aSandford, Andrew1 aMurray, Tanda1 aKim, Yoonhee1 aVergara, Candelaria1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aLi, Guo1 aElliott, Mark1 aAminuddin, Farzian1 aDupuis, Josée1 aO'Connor, George, T1 aDoheny, Kimberly1 aScott, Alan, F1 aBoezen, Marike1 aPostma, Dirkje, S1 aSmolonska, Joanna1 aZanen, Pieter1 aHoesein, Firdaus, A Mohamed1 ade Koning, Harry, J1 aCrystal, Ronald, G1 aTanaka, Toshiko1 aFerrucci, Luigi1 aSilverman, Edwin1 aWan, Emily1 aVestbo, Jorgen1 aLomas, David, A1 aConnett, John1 aWise, Robert, A1 aNeptune, Enid, R1 aMathias, Rasika, A1 aParé, Peter, D1 aBeaty, Terri, H1 aBarnes, Kathleen, C uhttps://chs-nhlbi.org/node/606802853nas a2200409 4500008004100000022001400041245013800055210006900193260001300262300001000275490000700285520166900292653002201961653000901983653001601992653002402008653004002032653001102072653001102083653001402094653000902108653001602117653002602133653003202159653002402191653002002215653001702235653001602252653001702268653001802285100002202303700002102325700002002346700002002366700002102386856003602407 2013 eng d a1532-851100aHeight and risk of incident intraparenchymal hemorrhage: Atherosclerosis Risk in Communities and Cardiovascular Health study cohorts.0 aHeight and risk of incident intraparenchymal hemorrhage Atherosc c2013 May a323-80 v223 aBACKGROUND: Height is inversely associated with incident coronary disease and total stroke, but few studies have examined the association between height and intraparenchymal hemorrhage (IPH). We hypothesized that height would be inversely associated with incident IPH in the combined cohorts of the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study.
METHODS: Data on Caucasian and African American participants were used to estimate the association of height at baseline with incident IPH verified by clinician review of medical records and imaging reports. Sex-specific Cox proportional hazards regression models were used to calculate hazard ratios.
RESULTS: A total of 20,983 participants initially free of stroke (11,788 women and 9195 men) were followed for an average of 15.9 years (standard deviation [SD] 5.1 years). Incident IPH occurred in 115 women and 73 men. Sex, but not age, race, study, or blood pressure, modified the association (P = .03). After adjustment for risk factors (age, systolic blood pressure, triglycerides, low-density lipoprotein cholesterol, fibrinogen, and race), among women, height was significantly inversely associated with incident IPH (hazard ratio [HR] per SD [6.3 cm] was 0.81; 95% confidence interval [CI] 0.66-0.99; P = .04). The HR for tertile 3 vs 1 in women was 0.63 (95% CI 0.37-1.08). Among men, height was not linearly associated with incident IPH (HR per SD [6.7 cm] was 1.09; 95% CI 0.84-1.40; P = .52).
CONCLUSIONS: This large prospective study provides evidence that shorter height may be a risk factor for incident IPH in women.
10aAfrican Americans10aAged10aBody Height10aCerebral Hemorrhage10aEuropean Continental Ancestry Group10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aMultivariate Analysis10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aSex Factors10aTime Factors10aUnited States1 aSmith, Lindsay, G1 aYatsuya, Hiroshi1 aPsaty, Bruce, M1 aLongstreth, W T1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/135804700nas a2200961 4500008004100000022001400041245019200055210006900247260001300316300001100329490000800340520188800348653001802236653001102254653001702265653001102282653001202293653001402305653000902319653003602328653001902364653002502383100001702408700002002425700002002445700002402465700001802489700002102507700002302528700002102551700002202572700002202594700002402616700002102640700001902661700001902680700002102699700002002720700002602740700002502766700001802791700001902809700002402828700002002852700002102872700002302893700001702916700002202933700002502955700002202980700001703002700002503019700002903044700002803073700002803101700001903129700002703148700001903175700001503194700002203209700001903231700002103250700002103271700002303292700002503315700002503340700002003365700001703385700002003402700002003422700002003442700002803462700002503490700002103515700002203536700002403558700003003582700002003612700002003632700002303652700002703675856003603702 2013 eng d a1541-610000aHigher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies.0 aHigher magnesium intake is associated with lower fasting glucose c2013 Mar a345-530 v1433 aFavorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.
10aBlood Glucose10aFemale10aGenetic Loci10aHumans10aInsulin10aMagnesium10aMale10aPolymorphism, Single Nucleotide10aTrace Elements10aTRPM Cation Channels1 aHruby, Adela1 aNgwa, Julius, S1 aRenstrom, Frida1 aWojczynski, Mary, K1 aGanna, Andrea1 aHallmans, Göran1 aHouston, Denise, K1 aJacques, Paul, F1 aKanoni, Stavroula1 aLehtimäki, Terho1 aLemaitre, Rozenn, N1 aManichaikul, Ani1 aNorth, Kari, E1 aNtalla, Ioanna1 aSonestedt, Emily1 aTanaka, Toshiko1 avan Rooij, Frank, J A1 aBandinelli, Stefania1 aDjoussé, Luc1 aGrigoriou, Efi1 aJohansson, Ingegerd1 aLohman, Kurt, K1 aPankow, James, S1 aRaitakari, Olli, T1 aRiserus, Ulf1 aYannakoulia, Mary1 aZillikens, Carola, M1 aHassanali, Neelam1 aLiu, Yongmei1 aMozaffarian, Dariush1 aPapoutsakis, Constantina1 aSyvänen, Ann-Christine1 aUitterlinden, André, G1 aViikari, Jorma1 aGroves, Christopher, J1 aHofman, Albert1 aLind, Lars1 aMcCarthy, Mark, I1 aMikkilä, Vera1 aMukamal, Kenneth1 aFranco, Oscar, H1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aDedoussis, George, V1 aFerrucci, Luigi1 aHu, Frank, B1 aIngelsson, Erik1 aKähönen, Mika1 aKao, Linda, W H1 aKritchevsky, Stephen, B1 aOrho-Melander, Marju1 aProkopenko, Inga1 aRotter, Jerome, I1 aSiscovick, David, S1 aWitteman, Jacqueline, C M1 aFranks, Paul, W1 aMeigs, James, B1 aMcKeown, Nicola, M1 aNettleton, Jennifer, A uhttps://chs-nhlbi.org/node/587911009nas a2203553 4500008004100000022001400041245011100055210006900166260001300235300001100248490000700259520106100266653001201327653002501339653001901364653001701383653003401400653002801434653001501462653001101477653003601488653003601524653002801560100002201588700002201610700001601632700002701648700001901675700002001694700001901714700002301733700001601756700002501772700002101797700001801818700001801836700001501854700001901869700001901888700002001907700001601927700001901943700002101962700002301983700002502006700002502031700001802056700001502074700002202089700002402111700001602135700002102151700002102172700001802193700001802211700002302229700002102252700002302273700002202296700002002318700002202338700002502360700002302385700002002408700001702428700002002445700002502465700002202490700001902512700002102531700001802552700002502570700002102595700002202616700002202638700002102660700003102681700001302712700002302725700001602748700001602764700001802780700002502798700001902823700001902842700002502861700002102886700002502907700002002932700001902952700002502971700001802996700002403014700002103038700001603059700001903075700002003094700001803114700001803132700002203150700002003172700002703192700001903219700002203238700002403260700002203284700002803306700002203334700002303356700002103379700001903400700002203419700002803441700002403469700002203493700001903515700002103534700001903555700001603574700002003590700001803610700002303628700002203651700001703673700001803690700001703708700001803725700002303743700002403766700002103790700001703811700002103828700002403849700002103873700002603894700002503920700002403945700002203969700002503991700002204016700002304038700002504061700002404086700003004110700001704140700001604157700002604173700003004199700001604229700002004245700002004265700001904285700001804304700002604322700002004348700002004368700001904388700002504407700001704432700001804449700002104467700002004488700001904508700002004527700002504547700002104572700002004593700002004613700001804633700002604651700002304677700002804700700002404728700002004752700002304772700002004795700001904815700002304834700002104857700003004878700001704908700001704925700002004942700001904962700002304981700002305004700002305027700002305050700001705073700002105090700002205111700002105133700002005154700001905174700002405193700001505217700001505232700002405247700001905271700002305290700002405313700002205337700002205359700002905381700001705410700002305427700002005450700002905470700002505499700002105524700002305545700002105568700002505589700002205614700001705636700001805653700002005671700002005691700001905711700002105730700002505751700001605776700002005792700001905812700001705831700002305848700002105871700002205892700001505914700002705929700001605956700002005972700002705992700003006019700002206049700001706071700002206088700002206110700002606132700002506158700001806183700002406201700001906225700002106244700001106265700002306276700001806299700001906317700002006336700001606356700002006372700002006392700002206412700002306434700001906457700002206476700002106498700002306519700002406542700002806566700002206594700002806616700001906644700001906663700002406682700002006706700002106726700001906747700002106766700002306787700002006810700001706830700002206847700002206869700001806891700002206909700002906931700002406960700002606984700002107010700001907031700002507050700002407075700002107099700002507120700002407145700002007169700002007189700002007209700002207229700002007251710002807271710002607299710002307325710002407348710002207372710002507394856003607419 2013 eng d a1546-171800aIdentification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.0 aIdentification of heart rateassociated loci and their effects on c2013 Jun a621-310 v453 aElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
10aAnimals10aArrhythmias, Cardiac10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHeart Rate10aHumans10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aHoed, Marcel, den1 aEijgelsheim, Mark1 aEsko, Tõnu1 aBrundel, Bianca, J J M1 aPeal, David, S1 aEvans, David, M1 aNolte, Ilja, M1 aSegrè, Ayellet, V1 aHolm, Hilma1 aHandsaker, Robert, E1 aWestra, Harm-Jan1 aJohnson, Toby1 aIsaacs, Aaron1 aYang, Jian1 aLundby, Alicia1 aZhao, Jing Hua1 aKim, Young, Jin1 aGo, Min Jin1 aAlmgren, Peter1 aBochud, Murielle1 aBoucher, Gabrielle1 aCornelis, Marilyn, C1 aGudbjartsson, Daniel1 aHadley, David1 aHarst, Pim1 aHayward, Caroline1 aHeijer, Martin, den1 aIgl, Wilmar1 aJackson, Anne, U1 aKutalik, Zoltán1 aLuan, Jian'an1 aKemp, John, P1 aKristiansson, Kati1 aLadenvall, Claes1 aLorentzon, Mattias1 aMontasser, May, E1 aNjajou, Omer, T1 aO'Reilly, Paul, F1 aPadmanabhan, Sandosh1 aSt Pourcain, Beate1 aRankinen, Tuomo1 aSalo, Perttu1 aTanaka, Toshiko1 aTimpson, Nicholas, J1 aVitart, Veronique1 aWaite, Lindsay1 aWheeler, William1 aZhang, Weihua1 aDraisma, Harmen, H M1 aFeitosa, Mary, F1 aKerr, Kathleen, F1 aLind, Penelope, A1 aMihailov, Evelin1 aOnland-Moret, Charlotte, N1 aSong, Ci1 aWeedon, Michael, N1 aXie, Weijia1 aYengo, Loic1 aAbsher, Devin1 aAlbert, Christine, M1 aAlonso, Alvaro1 aArking, Dan, E1 ade Bakker, Paul, I W1 aBalkau, Beverley1 aBarlassina, Cristina1 aBenaglio, Paola1 aBis, Joshua, C1 aBouatia-Naji, Nabila1 aBrage, Søren1 aChanock, Stephen, J1 aChines, Peter, S1 aChung, Mina1 aDarbar, Dawood1 aDina, Christian1 aDörr, Marcus1 aElliott, Paul1 aFelix, Stephan, B1 aFischer, Krista1 aFuchsberger, Christian1 aGeus, Eco, J C1 aGoyette, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aHofman, Albert1 aHolewijn, Suzanne1 aHoogstra-Berends, Femke1 aHottenga, Jouke-Jan1 aJensen, Majken, K1 aJohansson, Asa1 aJunttila, Juhani1 aKääb, Stefan1 aKanon, Bart1 aKetkar, Shamika1 aKhaw, Kay-Tee1 aKnowles, Joshua, W1 aKooner, Angrad, S1 aKors, Jan, A1 aKumari, Meena1 aMilani, Lili1 aLaiho, Päivi1 aLakatta, Edward, G1 aLangenberg, Claudia1 aLeusink, Maarten1 aLiu, Yongmei1 aLuben, Robert, N1 aLunetta, Kathryn, L1 aLynch, Stacey, N1 aMarkus, Marcello, R P1 aMarques-Vidal, Pedro1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcCarroll, Steven, A1 aMedland, Sarah, E1 aMiller, Kathryn, A1 aMontgomery, Grant, W1 aMorrison, Alanna, C1 aMüller-Nurasyid, Martina1 aNavarro, Pau1 aNelis, Mari1 aO'Connell, Jeffrey, R1 aO'Donnell, Christopher, J1 aOng, Ken, K1 aNewman, Anne, B1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aRao, Dabeeru, C1 aRing, Susan, M1 aRossin, Elizabeth, J1 aRudan, Diana1 aSanna, Serena1 aScott, Robert, A1 aSehmi, Jaban, S1 aSharp, Stephen1 aShin, Jordan, T1 aSingleton, Andrew, B1 aSmith, Albert, V1 aSoranzo, Nicole1 aSpector, Tim, D1 aStewart, Chip1 aStringham, Heather, M1 aTarasov, Kirill, V1 aUitterlinden, André, G1 aVandenput, Liesbeth1 aHwang, Shih-Jen1 aWhitfield, John, B1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aWong, Andrew1 aWong, Quenna1 aJamshidi, Yalda1 aZitting, Paavo1 aBoer, Jolanda, M A1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aEkelund, Ulf1 aForouhi, Nita, G1 aFroguel, Philippe1 aHingorani, Aroon1 aIngelsson, Erik1 aKivimaki, Mika1 aKronmal, Richard, A1 aKuh, Diana1 aLind, Lars1 aMartin, Nicholas, G1 aOostra, Ben, A1 aPedersen, Nancy, L1 aQuertermous, Thomas1 aRotter, Jerome, I1 aSchouw, Yvonne, T1 aVerschuren, W, M Monique1 aWalker, Mark1 aAlbanes, Demetrius1 aArnar, David, O1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBoehnke, Michael1 ade Boer, Rudolf, A1 aBouchard, Claude1 aCaulfield, W, L Mark1 aChambers, John, C1 aCurhan, Gary1 aCusi, Daniele1 aEriksson, Johan1 aFerrucci, Luigi1 aGilst, Wiek, H1 aGlorioso, Nicola1 ade Graaf, Jacqueline1 aGroop, Leif1 aGyllensten, Ulf1 aHsueh, Wen-Chi1 aHu, Frank, B1 aHuikuri, Heikki, V1 aHunter, David, J1 aIribarren, Carlos1 aIsomaa, Bo1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKiemeney, Lambertus, A1 avan der Klauw, Melanie, M1 aKooner, Jaspal, S1 aKraft, Peter1 aIacoviello, Licia1 aLehtimäki, Terho1 aLokki, Marja-Liisa, L1 aMitchell, Braxton, D1 aNavis, Gerjan1 aNieminen, Markku, S1 aOhlsson, Claes1 aPoulter, Neil, R1 aQi, Lu1 aRaitakari, Olli, T1 aRimm, Eric, B1 aRioux, John, D1 aRizzi, Federica1 aRudan, Igor1 aSalomaa, Veikko1 aSever, Peter, S1 aShields, Denis, C1 aShuldiner, Alan, R1 aSinisalo, Juha1 aStanton, Alice, V1 aStolk, Ronald, P1 aStrachan, David, P1 aTardif, Jean-Claude1 aThorsteinsdottir, Unnur1 aTuomilehto, Jaako1 avan Veldhuisen, Dirk, J1 aVirtamo, Jarmo1 aViikari, Jorma1 aVollenweider, Peter1 aWaeber, Gérard1 aWiden, Elisabeth1 aCho, Yoon Shin1 aOlsen, Jesper, V1 aVisscher, Peter, M1 aWiller, Cristen1 aFranke, Lude1 aErdmann, Jeanette1 aThompson, John, R1 aPfeufer, Arne1 aSotoodehnia, Nona1 aNewton-Cheh, Christopher1 aEllinor, Patrick, T1 aStricker, Bruno, H Ch1 aMetspalu, Andres1 aPerola, Markus1 aBeckmann, Jacques, S1 aSmith, George Davey1 aStefansson, Kari1 aWareham, Nicholas, J1 aMunroe, Patricia, B1 aSibon, Ody, C M1 aMilan, David, J1 aSnieder, Harold1 aSamani, Nilesh, J1 aLoos, Ruth, J F1 aGlobal BPgen Consortium1 aCARDIoGRAM consortium1 aPR GWAS Consortium1 aQRS GWAS Consortium1 aQT-IGC consortium1 aCHARGE-AF Consortium uhttps://chs-nhlbi.org/node/801503572nas a2200745 4500008004100000022001400041245011600055210006900171260001300240300001100253490000700264520148800271653001501759653001001774653000901784653002201793653001001815653002001825653001901845653002801864653004001892653001101932653003201943653001901975653001101994653000902005653001602014653001202030653003602042653001302078653001802091653001602109100002202125700002502147700001502172700001802187700002102205700002202226700002202248700002402270700002402294700002202318700001602340700002102356700002102377700002302398700002102421700002502442700001902467700002402486700001902510700002002529700002002549700002302569700002802592700001902620700002102639700002302660700002002683700002202703700002702725700001902752700001902771856003602790 2013 eng d a1939-327X00aThe influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study.0 ainfluence of obesityrelated single nucleotide polymorphisms on B c2013 May a1763-70 v623 aEvidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAging10aBody Mass Index10aCohort Studies10aCross-Sectional Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aHealth Surveys10aHumans10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins10aUnited States10aYoung Adult1 aGraff, Mariaelisa1 aGordon-Larsen, Penny1 aLim, Unhee1 aFowke, Jay, H1 aLove, Shelly-Ann1 aFesinmeyer, Megan1 aWilkens, Lynne, R1 aVertilus, Shawyntee1 aRitchie, Marilyn, D1 aPrentice, Ross, L1 aPankow, Jim1 aMonroe, Kristine1 aManson, JoAnn, E1 aLe Marchand, Loïc1 aKuller, Lewis, H1 aKolonel, Laurence, N1 aHong, Ching, P1 aHenderson, Brian, E1 aHaessler, Jeff1 aGross, Myron, D1 aGoodloe, Robert1 aFranceschini, Nora1 aCarlson, Christopher, S1 aBuyske, Steven1 aBůzková, Petra1 aHindorff, Lucia, A1 aMatise, Tara, C1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aPeters, Ulrike1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/663004392nas a2200841 4500008004100000022001400041245013900055210006900194260000900263300001100272490000600283520190900289653002202198653002402220653003802244653003402282653001302316653001102329653003902340653002502379653002602404653003602430653001302466653001702479653002902496100002702525700002102552700002302573700003202596700002302628700001702651700001902668700001402687700001902701700002102720700002102741700002302762700002402785700002402809700001902833700002002852700002002872700002302892700002402915700001902939700001602958700001702974700001902991700002203010700002203032700001903054700002003073700002203093700002203115700002103137700001703158700001703175700001903192700002803211700002403239700001603263700002803279700002603307700001903333700002103352700001803373700002503391700001803416700001603434700001903450710004503469856003603514 2013 eng d a1932-620300aInsights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.0 aInsights into the genetic architecture of early stage agerelated c2013 ae538300 v83 aGenetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
10aApolipoproteins E10aComplement Factor H10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aKruppel-Like Transcription Factors10aMacular Degeneration10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aProteins10aRisk Factors10aZinc Finger Protein Gli31 aHolliday, Elizabeth, G1 aSmith, Albert, V1 aCornes, Belinda, K1 aBuitendijk, Gabriëlle, H S1 aJensen, Richard, A1 aSim, Xueling1 aAspelund, Thor1 aAung, Tin1 aBaird, Paul, N1 aBoerwinkle, Eric1 aCheng, Ching, Yu1 aDuijn, Cornelia, M1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aHarris, Tamara1 aHewitt, Alex, W1 aInouye, Michael1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore1 aLi, Xiaohui1 aLiew, Gerald1 aLumley, Thomas1 aMcElduff, Patrick1 aMcKnight, Barbara1 aMitchell, Paul1 aPsaty, Bruce, M1 aRochtchina, Elena1 aRotter, Jerome, I1 aScott, Rodney, J1 aTay, Wanting1 aTaylor, Kent1 aTeo, Yik, Ying1 aUitterlinden, André, G1 aViswanathan, Ananth1 aXie, Sophia1 aVingerling, Johannes, R1 aKlaver, Caroline, C W1 aTai, Shyong, E1 aSiscovick, David1 aKlein, Ronald1 aCotch, Mary, Frances1 aWong, Tien, Y1 aAttia, John1 aWang, Jie, Jin1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/587503673nas a2200601 4500008004100000022001400041245015800055210006900213260000900282300000700291490000700298520191500305653001102220653002602231653001802257653003402275653001102309653001102320653000902331653003602340653002202376100002002398700001902418700002202437700002102459700002102480700002002501700002402521700002202545700002102567700002102588700002202609700002402631700001902655700002302674700002202697700002102719700002102740700001602761700002202777700002602799700002102825700002302846700002402869700002302893700002402916700002202940700001902962700001902981700002003000710001503020856003603035 2013 eng d a1471-215600aInvestigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study.0 aInvestigation of genebysex interactions for lipid traits in dive c2013 a330 v143 aBACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.
RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.
CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.
10aFemale10aGenetic Heterogeneity10aGenome, Human10aGenome-Wide Association Study10aHumans10aLipids10aMale10aPolymorphism, Single Nucleotide10aPopulation Groups1 aTaylor, Kira, C1 aCarty, Cara, L1 aDumitrescu, Logan1 aBůzková, Petra1 aCole, Shelley, A1 aHindorff, Lucia1 aSchumacher, Fred, R1 aWilkens, Lynne, R1 aShohet, Ralph, V1 aQuibrera, Miguel1 aJohnson, Karen, C1 aHenderson, Brian, E1 aHaessler, Jeff1 aFranceschini, Nora1 aEaton, Charles, B1 aDuggan, David, J1 aCochran, Barbara1 aCheng, Iona1 aCarlson, Chris, S1 aBrown-Gentry, Kristin1 aAnderson, Garnet1 aAmbite, Jose, Luis1 aHaiman, Christopher1 aLe Marchand, Loïc1 aKooperberg, Charles1 aCrawford, Dana, C1 aBuyske, Steven1 aNorth, Kari, E1 aFornage, Myriam1 aPAGE Study uhttps://chs-nhlbi.org/node/662705259nas a2201129 4500008004100000022001400041245007400055210006900129260001300198300001000211490000700221520208800228653002702316653001502343653001002358653000902368653002202377653002202399653001902421653001902440653001102459653001102470653001702481653003802498653002202536653003402558653001102592653000902603653001602612653003602628653001102664653001602675100002702691700002202718700001902740700002502759700002002784700002002804700002102824700001702845700002102862700002502883700001902908700002002927700002002947700001902967700001802986700001803004700002003022700001903042700002003061700002203081700002403103700002003127700002403147700002003171700001903191700002803210700002303238700002203261700002703283700002803310700002503338700002103363700002003384700002103404700002603425700001703451700002103468700002503489700002003514700001903534700002003553700001903573700002203592700001603614700002703630700002103657700002003678700001903698700002003717700002103737700001603758700001903774700002203793700001603815700001903831700002003850700002003870700002003890710002703910710004503937710005103982710001504033710004504048856003604093 2013 eng d a1531-824900aIschemic stroke is associated with the ABO locus: the EuroCLOT study.0 aIschemic stroke is associated with the ABO locus the EuroCLOT st c2013 Jan a16-310 v733 aOBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).
RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).
INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
10aABO Blood-Group System10aAdolescent10aAdult10aAged10aAged, 80 and over10aBlood Coagulation10aBrain Ischemia10aCohort Studies10aEurope10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aStroke10aYoung Adult1 aWilliams, Frances, M K1 aCarter, Angela, M1 aHysi, Pirro, G1 aSurdulescu, Gabriela1 aHodgkiss, Dylan1 aSoranzo, Nicole1 aTraylor, Matthew1 aBevan, Steve1 aDichgans, Martin1 aRothwell, Peter, M W1 aSudlow, Cathie1 aFarrall, Martin1 aSilander, Kaisa1 aKaunisto, Mari1 aWagner, Peter1 aSaarela, Olli1 aKuulasmaa, Kari1 aVirtamo, Jarmo1 aSalomaa, Veikko1 aAmouyel, Philippe1 aArveiler, Dominique1 aFerrieres, Jean1 aWiklund, Per-Gunnar1 aIkram, Arfan, M1 aHofman, Albert1 aBoncoraglio, Giorgio, B1 aParati, Eugenio, A1 aHelgadottir, Anna1 aGretarsdottir, Solveig1 aThorsteinsdottir, Unnur1 aThorleifsson, Gudmar1 aStefansson, Kari1 aSeshadri, Sudha1 aDeStefano, Anita1 aGschwendtner, Andreas1 aPsaty, Bruce1 aLongstreth, Will1 aMitchell, Braxton, D1 aCheng, Yu-Ching1 aClarke, Robert1 aFerrario, Marco1 aBis, Joshua, C1 aLevi, Christopher1 aAttia, John1 aHolliday, Elizabeth, G1 aScott, Rodney, J1 aFornage, Myriam1 aSharma, Pankaj1 aFurie, Karen, L1 aRosand, Jonathan1 aNalls, Mike1 aMeschia, James1 aMosely, Thomas, H1 aEvans, Alun1 aPalotie, Aarno1 aMarkus, Hugh, S1 aGrant, Peter, J1 aSpector, Tim, D1 aEuroCLOT Investigators1 aWellcome Trust Case Control Consortium 21 aMOnica Risk, Genetics, Archiving and Monograph1 aMetaStroke1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/610809008nas a2202809 4500008004100000022001400041245010800055210006900163260001300232300001000245490000700255520108900262653002201351653002001373653002501393653001901418653001701437653003801454653003401492653001101526653002701537653001201564653003601576100001901612700001801631700002001649700002001669700002101689700002101710700001901731700002601750700002401776700002401800700001801824700002201842700002501864700001801889700001201907700001701919700001701936700001801953700002201971700001601993700002402009700001902033700002402052700002202076700002502098700002202123700002102145700002002166700002102186700001602207700002202223700002202245700001802267700001802285700001802303700001502321700002102336700002802357700002402385700002002409700003202429700002002461700002202481700002102503700001302524700002302537700002902560700002002589700001702609700002302626700001902649700002202668700002402690700002302714700002202737700002302759700002302782700002402805700002202829700001702851700002402868700001802892700002102910700002102931700002302952700002202975700001702997700001803014700001603032700002103048700002103069700001703090700002403107700002603131700002003157700002603177700001803203700002803221700001503249700002003264700002203284700001603306700002003322700002903342700002203371700001803393700002503411700002203436700002703458700002303485700002903508700002103537700002803558700002603586700002203612700002503634700003103659700002803690700002203718700002003740700002103760700002303781700002103804700001903825700003203844700002803876700002303904700002003927700001903947700002203966700002403988700002704012700002804039700001904067700002104086700002304107700001904130700002204149700001504171700001904186700002104205700002104226700001904247700001804266700002304284700001904307700001404326700001904340700001404359700002304373700002104396700002604417700002204443700002004465700001904485700002004504700002804524700001704552700002104569700001804590700002104608700002104629700002204650700002104672700002304693700002404716700002204740700001904762700002404781700002304805700002004828700001804848700002204866700001804888700002004906700002704926700002204953700002304975700001504998700001405013700002005027700001705047700001905064700002005083700002205103700002505125700002405150700002105174700002405195700001905219700002505238700002305263700001505286700002205301700002405323700002205347700002705369700002005396700002105416700001905437700002405456700002405480700002005504700001905524700002305543700002505566700002205591700002505613700002405638700002505662700002305687700001905710700002105729700001905750700001505769700002005784700002305804700002005827700001805847700002305865700002405888700002805912700002405940700002005964700002405984700002006008700001906028700002706047710002106074710002106095710002606116710002006142856003606162 2013 eng d a1546-171800aA meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.0 ametaanalysis identifies new loci associated with body mass index c2013 Jun a690-60 v453 aGenome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
10aAfrican Americans10aBody Mass Index10aCase-Control Studies10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aObesity10aPolymorphism, Single Nucleotide1 aMonda, Keri, L1 aChen, Gary, K1 aTaylor, Kira, C1 aPalmer, Cameron1 aEdwards, Todd, L1 aLange, Leslie, A1 aC Y Ng, Maggie1 aAdeyemo, Adebowale, A1 aAllison, Matthew, A1 aBielak, Lawrence, F1 aChen, Guanjie1 aGraff, Mariaelisa1 aIrvin, Marguerite, R1 aRhie, Suhn, K1 aLi, Guo1 aLiu, Yongmei1 aLiu, Youfang1 aLu, Yingchang1 aNalls, Michael, A1 aSun, Yan, V1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aAldrich, Melinda, C1 aAdemola, Adeyinka1 aAmos, Christopher, I1 aBandera, Elisa, V1 aBock, Cathryn, H1 aBritton, Angela1 aBroeckel, Ulrich1 aCai, Quiyin1 aCaporaso, Neil, E1 aCarlson, Chris, S1 aCarpten, John1 aCasey, Graham1 aChen, Wei-Min1 aChen, Fang1 aChen, Yii-der, I1 aChiang, Charleston, W K1 aCoetzee, Gerhard, A1 aDemerath, Ellen1 aDeming-Halverson, Sandra, L1 aDriver, Ryan, W1 aDubbert, Patricia1 aFeitosa, Mary, F1 aFeng, Ye1 aFreedman, Barry, I1 aGillanders, Elizabeth, M1 aGottesman, Omri1 aGuo, Xiuqing1 aHaritunians, Talin1 aHarris, Tamara1 aHarris, Curtis, C1 aHennis, Anselm, J M1 aHernandez, Dena, G1 aMcNeill, Lorna, H1 aHoward, Timothy, D1 aHoward, Barbara, V1 aHoward, Virginia, J1 aJohnson, Karen, C1 aKang, Sun, J1 aKeating, Brendan, J1 aKolb, Suzanne1 aKuller, Lewis, H1 aKutlar, Abdullah1 aLangefeld, Carl, D1 aLettre, Guillaume1 aLohman, Kurt1 aLotay, Vaneet1 aLyon, Helen1 aManson, JoAnn, E1 aMaixner, William1 aMeng, Yan, A1 aMonroe, Kristine, R1 aMorhason-Bello, Imran1 aMurphy, Adam, B1 aMychaleckyj, Josyf, C1 aNadukuru, Raj1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aWu, Suh-Yuh1 aLeske, Cristina1 aNeslund-Dudas, Christine1 aNeuhouser, Marian1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgunniyi, Adesola1 aOgundiran, Temidayo, O1 aOjengbede, Oladosu1 aOlopade, Olufunmilayo, I1 aPalmer, Julie, R1 aRuiz-Narvaez, Edward, A1 aPalmer, Nicholette, D1 aPress, Michael, F1 aRampersaud, Evandine1 aRasmussen-Torvik, Laura, J1 aRodriguez-Gil, Jorge, L1 aSalako, Babatunde1 aSchadt, Eric, E1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSiscovick, David1 aSmith, Shad, B1 aWassertheil-Smoller, Sylvia1 aSpeliotes, Elizabeth, K1 aSpitz, Margaret, R1 aSucheston, Lara1 aTaylor, Herman1 aTayo, Bamidele, O1 aTucker, Margaret, A1 aVan Den Berg, David, J1 aEdwards, Digna, R Velez1 aWang, Zhaoming1 aWiencke, John, K1 aWinkler, Thomas, W1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYang, James, J1 aLevin, Albert, M1 aYoung, Taylor, R1 aZakai, Neil, A1 aCushman, Mary1 aZanetti, Krista, A1 aZhao, Jing Hua1 aZhao, Wei1 aZheng, Yonglan1 aZhou, Jie1 aZiegler, Regina, G1 aZmuda, Joseph, M1 aFernandes, Jyotika, K1 aGilkeson, Gary, S1 aKamen, Diane, L1 aHunt, Kelly, J1 aSpruill, Ida, J1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aArnett, Donna, K1 aAtwood, Larry1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBorecki, Ingrid, B1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBurke, Gregory1 aChanock, Stephen, J1 aCooper, Richard, S1 aDing, Jingzhong1 aDuggan, David1 aEvans, Michele, K1 aFox, Caroline1 aGarvey, Timothy1 aBradfield, Jonathan, P1 aHakonarson, Hakon1 aGrant, Struan, F A1 aHsing, Ann1 aChu, Lisa1 aHu, Jennifer, J1 aHuo, Dezheng1 aIngles, Sue, A1 aJohn, Esther, M1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKardia, Sharon, L R1 aKittles, Rick, A1 aGoodman, Phyllis, J1 aKlein, Eric, A1 aKolonel, Laurence, N1 aLe Marchand, Loïc1 aLiu, Simin1 aMcKnight, Barbara1 aMillikan, Robert, C1 aMosley, Thomas, H1 aPadhukasahasram, Badri1 aWilliams, Keoki1 aPatel, Sanjay, R1 aPeters, Ulrike1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRotimi, Charles, N1 aRybicki, Benjamin, A1 aSale, Michèle, M1 aSchreiner, Pamela, J1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aStanford, Janet, L1 aStrom, Sara, S1 aThun, Michael, J1 aVitolins, Mara1 aZheng, Wei1 aMoore, Jason, H1 aWilliams, Scott, M1 aKetkar, Shamika1 aZhu, Xiaofeng1 aZonderman, Alan, B1 aKooperberg, Charles1 aPapanicolaou, George, J1 aHenderson, Brian, E1 aReiner, Alex, P1 aHirschhorn, Joel, N1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aNABEC Consortium1 aUKBEC Consortium1 aBioBank Japan Project1 aAGEN Consortium uhttps://chs-nhlbi.org/node/607806851nas a2202401 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2013 eng d a1546-171800aMeta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.0 aMetaanalysis of 74046 individuals identifies 11 new susceptibili c2013 Dec a1452-80 v453 aEleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
10aAge of Onset10aAged10aAged, 80 and over10aAlzheimer Disease10aCase-Control Studies10aCohort Studies10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aLambert, J, C1 aIbrahim-Verbaas, C, A1 aHarold, D1 aNaj, A, C1 aSims, R1 aBellenguez, C1 aDeStafano, A, L1 aBis, J C1 aBeecham, G, W1 aGrenier-Boley, B1 aRusso, G1 aThorton-Wells, T, A1 aJones, N1 aSmith, A V1 aChouraki, V1 aThomas, C1 aIkram, M, A1 aZelenika, D1 aVardarajan, B, N1 aKamatani, Y1 aLin, C, F1 aGerrish, A1 aSchmidt, H1 aKunkle, B1 aDunstan, M, L1 aRuiz, A1 aBihoreau, M, T1 aChoi, S, H1 aReitz, C1 aPasquier, F1 aCruchaga, C1 aCraig, D1 aAmin, N1 aBerr, C1 aLopez, O, L1 aDe Jager, P, L1 aDeramecourt, V1 aJohnston, J, A1 aEvans, D1 aLovestone, S1 aLetenneur, L1 aMorón, F, J1 aRubinsztein, D, C1 aEiriksdottir, G1 aSleegers, K1 aGoate, A, M1 aFiévet, N1 aHuentelman, M, W1 aGill, M1 aBrown, K1 aKamboh, M, I1 aKeller, L1 aBarberger-Gateau, P1 aMcGuiness, B1 aLarson, E, B1 aGreen, R1 aMyers, A, J1 aDufouil, C1 aTodd, S1 aWallon, D1 aLove, S1 aRogaeva, E1 aGallacher, J1 aSt George-Hyslop, P1 aClarimon, J1 aLleo, A1 aBayer, A1 aTsuang, D, W1 aYu, L1 aTsolaki, M1 aBossù, P1 aSpalletta, G1 aProitsi, P1 aCollinge, J1 aSorbi, S1 aSanchez-Garcia, F1 aFox, N, C1 aHardy, J1 aNaranjo, M, C Deniz1 aBosco, P1 aClarke, R1 aBrayne, C1 aGalimberti, D1 aMancuso, M1 aMatthews, F1 aMoebus, S1 aMecocci, P1 aDel Zompo, M1 aMaier, W1 aHampel, H1 aPilotto, A1 aBullido, M1 aPanza, F1 aCaffarra, P1 aNacmias, B1 aGilbert, J, R1 aMayhaus, M1 aLannefelt, L1 aHakonarson, H1 aPichler, S1 aCarrasquillo, M, M1 aIngelsson, M1 aBeekly, D1 aAlvarez, V1 aZou, F1 aValladares, O1 aYounkin, S, G1 aCoto, E1 aHamilton-Nelson, K, L1 aGu, W1 aRazquin, C1 aPastor, P1 aMateo, I1 aOwen, M, J1 aFaber, K, M1 aJonsson, P, V1 aCombarros, O1 aO'Donovan, M, C1 aCantwell, L, B1 aSoininen, H1 aBlacker, D1 aMead, S1 aMosley, T, H1 aBennett, D, A1 aHarris, T B1 aFratiglioni, L1 aHolmes, C1 ade Bruijn, R, F1 aPassmore, P1 aMontine, T, J1 aBettens, K1 aRotter, J I1 aBrice, A1 aMorgan, K1 aForoud, T, M1 aKukull, W, A1 aHannequin, D1 aPowell, J, F1 aNalls, M, A1 aRitchie, K1 aLunetta, K, L1 aKauwe, J, S1 aBoerwinkle, E1 aRiemenschneider, M1 aBoada, M1 aHiltuenen, M1 aMartin, E, R1 aSchmidt, R1 aRujescu, D1 aWang, L, S1 aDartigues, J, F1 aMayeux, R1 aTzourio, C1 aHofman, A1 aNöthen, M, M1 aGraff, C1 aPsaty, B M1 aJones, L1 aHaines, J, L1 aHolmans, P, A1 aLathrop, M1 aPericak-Vance, M, A1 aLauner, L J1 aFarrer, L, A1 aDuijn, C M1 aVan Broeckhoven, C1 aMoskvina, V1 aSeshadri, S1 aWilliams, J1 aSchellenberg, G, D1 aAmouyel, P1 aEuropean Alzheimer's Disease Initiative (EADI)1 aGenetic and Environmental Risk in Alzheimer's Disease1 aAlzheimer's Disease Genetic Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology uhttps://chs-nhlbi.org/node/615605590nas a2201609 4500008004100000022001400041245011100055210006900166260000900235300001300244490000600257520112100263653001201384653001901396653001701415653001201432653004001444653003101484653003401515653001601549653001101565653001101576653000901587653003601596100002601632700001801658700001601676700001701692700002001709700002601729700001901755700002301774700002201797700002101819700002101840700001901861700001801880700002401898700001201922700002001934700001801954700002001972700002201992700001702014700002002031700002502051700001902076700002102095700001802116700002502134700002202159700002002181700002202201700002402223700002202247700001902269700002202288700001902310700002002329700002102349700002102370700002402391700002202415700002402437700002002461700001902481700002402500700002202524700002002546700002202566700001802588700001802606700001702624700002102641700001902662700002002681700002202701700002502723700002002748700002502768700002102793700002202814700002402836700002302860700002202883700002302905700001702928700001902945700002202964700002302986700002803009700001503037700002103052700001903073700002003092700002203112700002103134700001903155700002803174700002603202700001703228700002003245700001903265700002303284700001803307700002103325700001803346700002303364700002403387700002103411700002003432700001903452700002203471700002003493700001503513700002003528700002103548700001603569700002103585700001903606700001803625700001903643700002003662700001703682700002203699700002203721700003003743700002003773700002003793700002503813700001903838700002103857700002103878710002403899710002103923856003603944 2013 eng d a1553-740400aMeta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.0 aMetaanalysis of genomewide association studies identifies six ne c2013 ae10037960 v93 aCalcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
10aAnimals10aBone and Bones10aBone Density10aCalcium10aEuropean Continental Ancestry Group10aGene Expression Regulation10aGenome-Wide Association Study10aHomeostasis10aHumans10aKidney10aMice10aPolymorphism, Single Nucleotide1 aO'Seaghdha, Conall, M1 aWu, Hongsheng1 aYang, Qiong1 aKapur, Karen1 aGuessous, Idris1 aZuber, Annie, Mercier1 aKöttgen, Anna1 aStoudmann, Candice1 aTeumer, Alexander1 aKutalik, Zoltán1 aMangino, Massimo1 aDehghan, Abbas1 aZhang, Weihua1 aEiriksdottir, Gudny1 aLi, Guo1 aTanaka, Toshiko1 aPortas, Laura1 aLopez, Lorna, M1 aHayward, Caroline1 aLohman, Kurt1 aMatsuda, Koichi1 aPadmanabhan, Sandosh1 aFirsov, Dmitri1 aSorice, Rossella1 aUlivi, Sheila1 aBrockhaus, Catharina1 aKleber, Marcus, E1 aMahajan, Anubha1 aErnst, Florian, D1 aGudnason, Vilmundur1 aLauner, Lenore, J1 aMace, Aurelien1 aBoerwinckle, Eric1 aArking, Dan, E1 aTanikawa, Chizu1 aNakamura, Yusuke1 aBrown, Morris, J1 aGaspoz, Jean-Michel1 aTheler, Jean-Marc1 aSiscovick, David, S1 aPsaty, Bruce, M1 aBergmann, Sven1 aVollenweider, Peter1 aVitart, Veronique1 aWright, Alan, F1 aZemunik, Tatijana1 aBoban, Mladen1 aKolcic, Ivana1 aNavarro, Pau1 aBrown, Edward, M1 aEstrada, Karol1 aDing, Jingzhong1 aHarris, Tamara, B1 aBandinelli, Stefania1 aHernandez, Dena1 aSingleton, Andrew, B1 aGirotto, Giorgia1 aRuggiero, Daniela1 ad'Adamo, Adamo, Pio1 aRobino, Antonietta1 aMeitinger, Thomas1 aMeisinger, Christa1 aDavies, Gail1 aStarr, John, M1 aChambers, John, C1 aBoehm, Bernhard, O1 aWinkelmann, Bernhard, R1 aHuang, Jie1 aMurgia, Federico1 aWild, Sarah, H1 aCampbell, Harry1 aMorris, Andrew, P1 aFranco, Oscar, H1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aVölker, Uwe1 aHannemann, Anke1 aBiffar, Reiner1 aHoffmann, Wolfgang1 aShin, So-Youn1 aLescuyer, Pierre1 aHenry, Hughes1 aSchurmann, Claudia1 aMunroe, Patricia, B1 aGasparini, Paolo1 aPirastu, Nicola1 aCiullo, Marina1 aGieger, Christian1 aMärz, Winfried1 aLind, Lars1 aSpector, Tim, D1 aSmith, Albert, V1 aRudan, Igor1 aWilson, James, F1 aPolasek, Ozren1 aDeary, Ian, J1 aPirastu, Mario1 aFerrucci, Luigi1 aLiu, Yongmei1 aKestenbaum, Bryan1 aKooner, Jaspal, S1 aWitteman, Jacqueline, C M1 aNauck, Matthias1 aKao, Linda, W H1 aWallaschofski, Henri1 aBonny, Olivier1 aFox, Caroline, S1 aBochud, Murielle1 aSUNLIGHT Consortium1 aGEFOS Consortium uhttps://chs-nhlbi.org/node/629105839nas a2201429 4500008004100000022001400041245013600055210006900191260000900260300001300269490000600282520178500288653001102073653003402084653001102118653002002129653001902149653000902168653001402177653002602191653003602217653002402253653002402277653001802301653001602319653001402335100002002349700001802369700002002387700002402407700002102431700002102452700002002473700001802493700002402511700002302535700001602558700001602574700002002590700001902610700002602629700002002655700002002675700001802695700002502713700002002738700002302758700002202781700002402803700002302827700002502850700001702875700002802892700001402920700001602934700002502950700002102975700002002996700002603016700001803042700001903060700003603079700002303115700001903138700002603157700001503183700002303198700002203221700002103243700002503264700002203289700002703311700001903338700001803357700002003375700002003395700002303415700002003438700002603458700001703484700001903501700001903520700002503539700002003564700001903584700002003603700002303623700002003646700003003666700002203696700002203718700002303740700001903763700001903782700002603801700002103827700001803848700002103866700001803887700002303905700002003928700002103948700001903969700002703988700002604015700002404041700002304065700002304088700002804111700001804139700002004157700003004177700002304207700002204230700002004252700002104272700002104293700001804314700002204332700001904354856003604373 2013 eng d a1553-740400aA meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.0 ametaanalysis of thyroidrelated traits reveals novel loci and gen c2013 ae10032660 v93 aThyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
10aFemale10aGenome-Wide Association Study10aHumans10aHyperthyroidism10aHypothyroidism10aMale10aPhenotype10aPolymorphism, Genetic10aPolymorphism, Single Nucleotide10aSex Characteristics10aSignal Transduction10aThyroid Gland10aThyrotropin10aThyroxine1 aPorcu, Eleonora1 aMedici, Marco1 aPistis, Giorgio1 aVolpato, Claudia, B1 aWilson, Scott, G1 aCappola, Anne, R1 aBos, Steffan, D1 aDeelen, Joris1 aHeijer, Martin, den1 aFreathy, Rachel, M1 aLahti, Jari1 aLiu, Chunyu1 aLopez, Lorna, M1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aTanaka, Toshiko1 aTrompet, Stella1 aArnold, Alice1 aBandinelli, Stefania1 aBeekman, Marian1 aBöhringer, Stefan1 aBrown, Suzanne, J1 aBuckley, Brendan, M1 aCamaschella, Clara1 ade Craen, Anton, J M1 aDavies, Gail1 ade Visser, Marieke, C H1 aFord, Ian1 aForsen, Tom1 aFrayling, Timothy, M1 aFugazzola, Laura1 aGögele, Martin1 aHattersley, Andrew, T1 aHermus, Ad, R1 aHofman, Albert1 aHouwing-Duistermaat, Jeanine, J1 aJensen, Richard, A1 aKajantie, Eero1 aKloppenburg, Margreet1 aLim, Ee, M1 aMasciullo, Corrado1 aMariotti, Stefano1 aMinelli, Cosetta1 aMitchell, Braxton, D1 aNagaraja, Ramaiah1 aNetea-Maier, Romana, T1 aPalotie, Aarno1 aPersani, Luca1 aPiras, Maria, G1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRichards, Brent1 aRivadeneira, Fernando1 aSala, Cinzia1 aSabra, Mona, M1 aSattar, Naveed1 aShields, Beverley, M1 aSoranzo, Nicole1 aStarr, John, M1 aStott, David, J1 aSweep, Fred, C G J1 aUsala, Gianluca1 avan der Klauw, Melanie, M1 avan Heemst, Diana1 avan Mullem, Alies1 aVermeulen, Sita, H1 aVisser, Edward1 aWalsh, John, P1 aWestendorp, Rudi, G J1 aWiden, Elisabeth1 aZhai, Guangju1 aCucca, Francesco1 aDeary, Ian, J1 aEriksson, Johan, G1 aFerrucci, Luigi1 aFox, Caroline, S1 aJukema, Wouter1 aKiemeney, Lambertus, A1 aPramstaller, Peter, P1 aSchlessinger, David1 aShuldiner, Alan, R1 aSlagboom, Eline, P1 aUitterlinden, André, G1 aVaidya, Bijay1 aVisser, Theo, J1 aWolffenbuttel, Bruce, H R1 aMeulenbelt, Ingrid1 aRotter, Jerome, I1 aSpector, Tim, D1 aHicks, Andrew, A1 aToniolo, Daniela1 aSanna, Serena1 aPeeters, Robin, P1 aNaitza, Silvia uhttps://chs-nhlbi.org/node/587708187nas a2202209 4500008004100000022001400041245023300055210006900288260001600357300001200373490000800385520188600393653001502279653001002294653003902304653000902343653002202352653002802374653002802402653004002430653001102470653001502481653001702496653003802513653003402551653002302585653001102608653000902619653001602628653002602644653003602670653001702706653001102723653002702734653001602761100002502777700001502802700002002817700001902837700001902856700002302875700002202898700002002920700002102940700001702961700002402978700002003002700002303022700001803045700001903063700001703082700002303099700001803122700002003140700001603160700002003176700001903196700002803215700002103243700001703264700002503281700002203306700001903328700001703347700002003364700001603384700002003400700001803420700001903438700001903457700002003476700001603496700002003512700001503532700002203547700002103569700002103590700002503611700002303636700002103659700001903680700002003699700001703719700001703736700001703753700002103770700002203791700001903813700002703832700002003859700002403879700002503903700002103928700002003949700002603969700002803995700002104023700001904044700002204063700002304085700002304108700001304131700002504144700002304169700002204192700001904214700002004233700002204253700002004275700002004295700002204315700001804337700002104355700001804376700001904394700001904413700001504432700002704447700001704474700001904491700002204510700002304532700001804555700002404573700002004597700001904617700002404636700001604660700002004676700002204696700002004718700002404738700001804762700002104780700002104801700001904822700002804841700002204869700002004891700002204911700001704933700002104950700002304971700002404994700002305018700002205041700002105063700002205084700001705106700002705123700002205150700002405172700002205196700002405218700002905242700002005271700002305291700001805314700001805332700002005350700003005370700001905400700002205419700002205441700002105463700002105484700001905505700001805524700002005542700002005562700001805582700002205600700002505622700002305647700002005670700002005690700001805710700002305728700002005751700003005771710001905801710002205820710005405842710001905896710002605915856003605941 2013 eng d a1524-453900aMultiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.0 aMultiethnic metaanalysis of genomewide association studies in 10 c2013 Sep 17 a1310-240 v1283 aBACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.
METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.
CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aCardiovascular Diseases10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHispanic Americans10aHumans10aMale10aMiddle Aged10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke10aVenous Thromboembolism10aYoung Adult1 aSabater-Lleal, Maria1 aHuang, Jie1 aChasman, Daniel1 aNaitza, Silvia1 aDehghan, Abbas1 aJohnson, Andrew, D1 aTeumer, Alexander1 aReiner, Alex, P1 aFolkersen, Lasse1 aBasu, Saonli1 aRudnicka, Alicja, R1 aTrompet, Stella1 aMälarstig, Anders1 aBaumert, Jens1 aBis, Joshua, C1 aGuo, Xiuqing1 aHottenga, Jouke, J1 aShin, So-Youn1 aLopez, Lorna, M1 aLahti, Jari1 aTanaka, Toshiko1 aYanek, Lisa, R1 aOudot-Mellakh, Tiphaine1 aWilson, James, F1 aNavarro, Pau1 aHuffman, Jennifer, E1 aZemunik, Tatijana1 aRedline, Susan1 aMehra, Reena1 aPulanic, Drazen1 aRudan, Igor1 aWright, Alan, F1 aKolcic, Ivana1 aPolasek, Ozren1 aWild, Sarah, H1 aCampbell, Harry1 aCurb, David1 aWallace, Robert1 aLiu, Simin1 aEaton, Charles, B1 aBecker, Diane, M1 aBecker, Lewis, C1 aBandinelli, Stefania1 aRäikkönen, Katri1 aWiden, Elisabeth1 aPalotie, Aarno1 aFornage, Myriam1 aGreen, David1 aGross, Myron1 aDavies, Gail1 aHarris, Sarah, E1 aLiewald, David, C1 aStarr, John, M1 aWilliams, Frances, M K1 aGrant, Peter, J1 aSpector, Timothy, D1 aStrawbridge, Rona, J1 aSilveira, Angela1 aSennblad, Bengt1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aFranco, Oscar, H1 aHofman, Albert1 avan Dongen, Jenny1 aWillemsen, Gonneke1 aBoomsma, Dorret, I1 aYao, Jie1 aJenny, Nancy, Swords1 aHaritunians, Talin1 aMcKnight, Barbara1 aLumley, Thomas1 aTaylor, Kent, D1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aPeters, Annette1 aGieger, Christian1 aIllig, Thomas1 aGrotevendt, Anne1 aHomuth, Georg1 aVölzke, Henry1 aKocher, Thomas1 aGoel, Anuj1 aFranzosi, Maria Grazia1 aSeedorf, Udo1 aClarke, Robert1 aSteri, Maristella1 aTarasov, Kirill, V1 aSanna, Serena1 aSchlessinger, David1 aStott, David, J1 aSattar, Naveed1 aBuckley, Brendan, M1 aRumley, Ann1 aLowe, Gordon, D1 aMcArdle, Wendy, L1 aChen, Ming-Huei1 aTofler, Geoffrey, H1 aSong, Jaejoon1 aBoerwinkle, Eric1 aFolsom, Aaron, R1 aRose, Lynda, M1 aFranco-Cereceda, Anders1 aTeichert, Martina1 aIkram, Arfan, M1 aMosley, Thomas, H1 aBevan, Steve1 aDichgans, Martin1 aRothwell, Peter, M1 aSudlow, Cathie, L M1 aHopewell, Jemma, C1 aChambers, John, C1 aSaleheen, Danish1 aKooner, Jaspal, S1 aDanesh, John1 aNelson, Christopher, P1 aErdmann, Jeanette1 aReilly, Muredach, P1 aKathiresan, Sekar1 aSchunkert, Heribert1 aMorange, Pierre-Emmanuel1 aFerrucci, Luigi1 aEriksson, Johan, G1 aJacobs, David1 aDeary, Ian, J1 aSoranzo, Nicole1 aWitteman, Jacqueline, C M1 aGeus, Eco, J C1 aTracy, Russell, P1 aHayward, Caroline1 aKoenig, Wolfgang1 aCucca, Francesco1 aJukema, Wouter1 aEriksson, Per1 aSeshadri, Sudha1 aMarkus, Hugh, S1 aWatkins, Hugh1 aSamani, Nilesh, J1 aWallaschofski, Henri1 aSmith, Nicholas, L1 aTregouet, David1 aRidker, Paul, M1 aTang, Weihong1 aStrachan, David, P1 aHamsten, Anders1 aO'Donnell, Christopher, J1 aVTE Consortium1 aSTROKE Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2)1 aC4D Consortium1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/615502377nas a2200349 4500008004100000022001400041245013400055210006900189260001300258300001100271490000700282520138400289653000901673653002401682653003401706653001101740653002201751653001101773653001401784653000901798653001501807653002001822653001701842653001101859653001801870100002001888700002101908700001901929700002001948700002301968856003601991 2013 eng d a1532-541500aRacial differences in the incidence of and risk factors for atrial fibrillation in older adults: the cardiovascular health study.0 aRacial differences in the incidence of and risk factors for atri c2013 Feb a276-800 v613 aThis study examined whether different associations between risk factors and atrial fibrillation (AF) according to race could explain the lower incidence of AF in blacks. Baseline risk factor information was obtained from interviews, clinical examinations, and echocardiography in 4,774 white and 911 black Cardiovascular Health Study participants aged 65 and older without a history of AF at baseline in 1989/90 or 1992/93. Incident AF was determined according to hospital discharge diagnosis or annual study electrocardiogram. Cox regression was used to assess associations between risk factors and race and incident AF. During a mean 11.2 years of follow-up, 1,403 whites and 182 blacks had incident AF. Associations between all examined risk factors were similar in both races, except left ventricular posterior wall thickness, which was more strongly associated with AF in blacks (per 0.2 cm, blacks: hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.44-2.06; whites: HR = 1.30, 95% CI = 1.18-1.43). Overall, the relative risk of AF was 25% lower in blacks than whites after adjustment for age and sex (HR = 0.75, 95% CI = 0.64-0.87) and 45% lower after adjustment for all considered risk factors (HR = 0.55, 95% CI = 0.35-0.88). Different associations of the considered risk factors and incident AF by race do not explain the lower incidence of AF in blacks.
10aAged10aAtrial Fibrillation10aContinental Population Groups10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aPrevalence10aRisk Assessment10aRisk Factors10aStroke10aUnited States1 aJensen, Paul, N1 aThacker, Evan, L1 aDublin, Sascha1 aPsaty, Bruce, M1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/585205044nas a2200541 4500008004100000022001400041245015700055210006900212260001300281300001300294490000700307520354200314653001603856653002803872653001103900653003403911653001303945653001103958653001303969653001403982653003603996100001604032700001804048700001904066700002404085700001804109700001404127700001304141700002004154700001304174700001804187700002004205700001504225700001204240700001704252700001704269700001904286700002304305700001504328700001704343700001904360700001704379700001704396700002004413700001404433700001904447856003604466 2013 eng d a1460-235000aReplication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.0 aReplication of genetic loci for ages at menarche and menopause i c2013 Jun a1695-7060 v283 aSTUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?
SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.
WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.
STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.
MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.
MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.
LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.
WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.
10aAge Factors10aCross-Sectional Studies10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aMenarche10aMenopause10aPolymorphism, Single Nucleotide1 aCarty, C, L1 aSpencer, K, L1 aSetiawan, V, W1 aFernandez-Rhodes, L1 aMalinowski, J1 aBuyske, S1 aYoung, A1 aJorgensen, N, W1 aCheng, I1 aCarlson, C, S1 aBrown-Gentry, K1 aGoodloe, R1 aPark, A1 aParikh, N, I1 aHenderson, B1 aLe Marchand, L1 aWactawski-Wende, J1 aFornage, M1 aMatise, T, C1 aHindorff, L, A1 aArnold, A, M1 aHaiman, C, A1 aFranceschini, N1 aPeters, U1 aCrawford, D, C uhttps://chs-nhlbi.org/node/610603716nas a2200577 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520196800286653001502254653003102269653002802300653004202328653004202370653003102412653001102443653002202454653003802476653001302514653001102527653002502538653000902563653001802572653001602590653002602606653001402632653003602646653001702682653002402699653002702723100002302750700002002773700001902793700002102812700002002833700001902853700002502872700002902897700001902926700001802945700002202963700002102985700002003006700002103026700002503047700003003072856003603102 2013 eng d a1524-453900aResequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study.0 aResequencing and clinical associations of the 9p213 region a com c2013 Feb 19 a799-8100 v1273 aBACKGROUND: 9p21.3 is among the most strongly replicated regions for cardiovascular disease. There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical cardiovascular disease and its risk factors, as well as with copy number variation and gene expression, in the Framingham Heart Study (FHS).
METHODS AND RESULTS: We sequenced 281 individuals (94 with myocardial infarction, 94 with high coronary artery calcium levels, and 93 control subjects free of elevated coronary artery calcium or myocardial infarction), followed by genotyping and association in >7000 additional FHS individuals. We assessed genetic associations with clinical and subclinical cardiovascular disease, risk factor phenotypes, and gene expression levels of the protein-coding genes CDKN2A and CDKN2B and the noncoding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample, we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters and no evidence for association with traditional cardiovascular disease risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or copy number variation events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B.
CONCLUSIONS: Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations and provides further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.
10aCalcinosis10aChromosomes, Human, Pair 910aCoronary Artery Disease10aCyclin-Dependent Kinase Inhibitor p1510aCyclin-Dependent Kinase Inhibitor p1610aDNA Copy Number Variations10aFemale10aFollow-Up Studies10aGenetic Predisposition to Disease10aGenotype10aHumans10aLongitudinal Studies10aMale10aMassachusetts10aMiddle Aged10aMyocardial Infarction10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aRNA, Long Noncoding10aSequence Analysis, DNA1 aJohnson, Andrew, D1 aHwang, Shih-Jen1 aVoorman, Arend1 aMorrison, Alanna1 aPeloso, Gina, M1 aHsu, Yi-Hsiang1 aThanassoulis, George1 aNewton-Cheh, Christopher1 aRogers, Ian, S1 aHoffmann, Udo1 aFreedman, Jane, E1 aFox, Caroline, S1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aCupples, Adrienne, L1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/607404055nas a2200673 4500008004100000022001400041245023000055210006900285260001300354300001100367490000700378520196600385653002502351653001302376653003802389653001102427653004902438653001602487653001702503653002702520100002202547700002402569700002302593700001702616700002002633700002102653700001702674700002102691700002202712700002402734700002402758700001802782700001902800700001702819700002702836700001902863700002002882700001702902700001602919700002702935700002302962700002102985700003203006700002303038700002003061700002603081700003003107700001803137700002403155700002603179700001903205700002003224700001903244700002203263700001703285700002203302700002103324856003603345 2013 eng d a1573-728400aRisk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls.0 aRisk of venous thromboembolism associated with single and combin c2013 Aug a621-470 v283 aGenetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.
10aCase-Control Studies10aFactor V10aGenetic Predisposition to Disease10aHumans10aMethylenetetrahydrofolate Reductase (NADPH2)10aProthrombin10aRisk Factors10aVenous Thromboembolism1 aSimone, Benedetto1 aDe Stefano, Valerio1 aLeoncini, Emanuele1 aZacho, Jeppe1 aMartinelli, Ida1 aEmmerich, Joseph1 aRossi, Elena1 aFolsom, Aaron, R1 aAlmawi, Wassim, Y1 aScarabin, Pierre, Y1 aHeijer, Martin, den1 aCushman, Mary1 aPenco, Silvana1 aVaya, Amparo1 aAngchaisuksiri, Pantep1 aOkumus, Gulfer1 aGemmati, Donato1 aCima, Simona1 aAkar, Nejat1 aOguzulgen, Kivilcim, I1 aDucros, Véronique1 aLichy, Christoph1 aFernandez-Miranda, Consuelo1 aSzczeklik, Andrzej1 aNieto, José, A1 aTorres, Jose, Domingo1 aLe Cam-Duchez, Véronique1 aIvanov, Petar1 aCantu-Brito, Carlos1 aShmeleva, Veronika, M1 aStegnar, Mojka1 aOgunyemi, Dotun1 aEid, Suhair, S1 aNicolotti, Nicola1 aDe Feo, Emma1 aRicciardi, Walter1 aBoccia, Stefania uhttps://chs-nhlbi.org/node/600711004nas a2203505 4500008004100000022001400041245014700055210006900202260001300271300001300284490000600297520115200303653001801455653001601473653002001489653001601509653003001525653001101555653001701566653001801583653003401601653001101635653000901646653003601655653002401691653002401715653002001739100002301759700002301782700002101805700002101826700002101847700001901868700002801887700001601915700001801931700001601949700003101965700002101996700003002017700001802047700001502065700002102080700002302101700001902124700002002143700001902163700002202182700002002204700001802224700003202242700002502274700003002299700002302329700001902352700001902371700002202390700002202412700001902434700001802453700001902471700002202490700002302512700002302535700002202558700002402580700002102604700002202625700002202647700002602669700002302695700002202718700002302740700002402763700002202787700002202809700001202831700002502843700001802868700002802886700002402914700001802938700002502956700001902981700001603000700001903016700001903035700002503054700002503079700002603104700001903130700002003149700001703169700002403186700002003210700002303230700001603253700002003269700002203289700002803311700002103339700002403360700002003384700002303404700001803427700002203445700002103467700001903488700002603507700002203533700002803555700002003583700002803603700002703631700002003658700002303678700002003701700002103721700002403742700002003766700001503786700002803801700002603829700001903855700002803874700001903902700002503921700002403946700002703970700002003997700001404017700002004031700002204051700001904073700001804092700001804110700002104128700002004149700002204169700001604191700002204207700002204229700002604251700002604277700001704303700002004320700002304340700001904363700002304382700002004405700002304425700001904448700001804467700002304485700002504508700001904533700001904552700002004571700003004591700003504621700002104656700001704677700002104694700001904715700002504734700002404759700001804783700001504801700002404816700002204840700002504862700001504887700002304902700002004925700001904945700002204964700002004986700001805006700002205024700002005046700002105066700002105087700001705108700002105125700002005146700001605166700002105182700001905203700002505222700002405247700002305271700001905294700002205313700001805335700002005353700002005373700001905393700002105412700002405433700001805457700002005475700002105495700002005516700002505536700002105561700002105582700002405603700001805627700001605645700002105661700003705682700002205719700001805741700002005759700002105779700002005800700002605820700002305846700001905869700002005888700002305908700002405931700002005955700001905975700002005994700002406014700002506038700001906063700002106082700002106103700001806124700002106142700003006163700002006193700002306213700002206236700002006258700002806278700002206306700001906328700002406347700002206371700002006393700001906413700002306432700001506455700001706470700001506487700001806502700001906520700002706539700002306566700002206589700002106611700002206632700002206654700002306676700002506699700002106724700001906745700001806764700001906782700002106801700001906822700001806841700002906859700001906888700002106907700002306928700002006951700002106971700002206992700001907014700002307033700001807056700002007074700001907094700002107113700002607134700002407160700002307184700002107207700002307228700002507251700002207276700002407298700001107322700002007333700002507353700001907378700001807397710002307415710002407438856003607462 2013 eng d a1553-740400aSex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.0 aSexstratified genomewide association studies including 270000 in c2013 Jun ae10035000 v93 aGiven the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
10aAnthropometry10aBody Height10aBody Mass Index10aBody Weight10aBody Weights and Measures10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist Circumference10aWaist-Hip Ratio1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aKutalik, Zoltán1 aBerndt, Sonja, I1 aJackson, Anne, U1 aMonda, Keri, L1 aKilpeläinen, Tuomas, O1 aEsko, Tõnu1 aMägi, Reedik1 aLi, Shengxu1 aWorkalemahu, Tsegaselassie1 aFeitosa, Mary, F1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aFall, Tove1 aFerreira, Teresa1 aGustafsson, Stefan1 aLocke, Adam, E1 aMathieson, Iain1 aScherag, Andre1 aVedantam, Sailaja1 aWood, Andrew, R1 aLiang, Liming1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aDermitzakis, Emmanouil, T1 aDimas, Antigone, S1 aKarpe, Fredrik1 aMin, Josine, L1 aNicholson, George1 aClegg, Deborah, J1 aPerson, Thomas1 aKrohn, Jon, P1 aBauer, Sabrina1 aBuechler, Christa1 aEisinger, Kristina1 aBonnefond, Amélie1 aFroguel, Philippe1 aHottenga, Jouke-Jan1 aProkopenko, Inga1 aWaite, Lindsay, L1 aHarris, Tamara, B1 aSmith, Albert, Vernon1 aShuldiner, Alan, R1 aMcArdle, Wendy, L1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aGrönberg, Henrik1 aChen, Yii-Der Ida1 aLi, Guo1 aBeckmann, Jacques, S1 aJohnson, Toby1 aThorsteinsdottir, Unnur1 aTeder-Laving, Maris1 aKhaw, Kay-Tee1 aWareham, Nicholas, J1 aZhao, Jing Hua1 aAmin, Najaf1 aOostra, Ben, A1 aKraja, Aldi, T1 aProvince, Michael, A1 aCupples, Adrienne, L1 aHeard-Costa, Nancy, L1 aKaprio, Jaakko1 aRipatti, Samuli1 aSurakka, Ida1 aCollins, Francis, S1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aJula, Antti1 aSalomaa, Veikko1 aErdmann, Jeanette1 aHengstenberg, Christian1 aLoley, Christina1 aSchunkert, Heribert1 aLamina, Claudia1 aWichmann, Erich, H1 aAlbrecht, Eva1 aGieger, Christian1 aHicks, Andrew, A1 aJohansson, Asa1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aSpeliotes, Elizabeth, K1 aPenninx, Brenda1 aHartikainen, Anna-Liisa1 aJarvelin, Marjo-Riitta1 aGyllensten, Ulf1 aBoomsma, Dorret, I1 aCampbell, Harry1 aWilson, James, F1 aChanock, Stephen, J1 aFarrall, Martin1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aRivadeneira, Fernando1 aEstrada, Karol1 aUitterlinden, André, G1 aHofman, Albert1 aZillikens, Carola, M1 aHeijer, Martin, den1 aKiemeney, Lambertus, A1 aMaschio, Andrea1 aHall, Per1 aTyrer, Jonathan1 aTeumer, Alexander1 aVölzke, Henry1 aKovacs, Peter1 aTönjes, Anke1 aMangino, Massimo1 aSpector, Tim, D1 aHayward, Caroline1 aRudan, Igor1 aHall, Alistair, S1 aSamani, Nilesh, J1 aAttwood, Antony, Paul1 aSambrook, Jennifer, G1 aHung, Joseph1 aPalmer, Lyle, J1 aLokki, Marja-Liisa1 aSinisalo, Juha1 aBoucher, Gabrielle1 aHuikuri, Heikki1 aLorentzon, Mattias1 aOhlsson, Claes1 aEklund, Niina1 aEriksson, Johan, G1 aBarlassina, Cristina1 aRivolta, Carlo1 aNolte, Ilja, M1 aSnieder, Harold1 avan der Klauw, Melanie, M1 avan Vliet-Ostaptchouk, Jana, V1 aGejman, Pablo, V1 aShi, Jianxin1 aJacobs, Kevin, B1 aWang, Zhaoming1 aBakker, Stephan, J L1 aLeach, Irene, Mateo1 aNavis, Gerjan1 aHarst, Pim1 aMartin, Nicholas, G1 aMedland, Sarah, E1 aMontgomery, Grant, W1 aYang, Jian1 aChasman, Daniel, I1 aRidker, Paul, M1 aRose, Lynda, M1 aLehtimäki, Terho1 aRaitakari, Olli1 aAbsher, Devin1 aIribarren, Carlos1 aBasart, Hanneke1 aHovingh, Kees, G1 aHyppönen, Elina1 aPower, Chris1 aAnderson, Denise1 aBeilby, John, P1 aHui, Jennie1 aJolley, Jennifer1 aSager, Hendrik1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aKristiansson, Kati1 aPerola, Markus1 aLindström, Jaana1 aSwift, Amy, J1 aUusitupa, Matti1 aAtalay, Mustafa1 aLakka, Timo, A1 aRauramaa, Rainer1 aBolton, Jennifer, L1 aFowkes, Gerry1 aFraser, Ross, M1 aPrice, Jackie, F1 aFischer, Krista1 aKov, Kaarel, Krjutå1 aMetspalu, Andres1 aMihailov, Evelin1 aLangenberg, Claudia1 aLuan, Jian'an1 aOng, Ken, K1 aChines, Peter, S1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aEdkins, Sarah1 aFranks, Paul, W1 aHallmans, Göran1 aShungin, Dmitry1 aMorris, Andrew, David1 aPalmer, Colin, N A1 aErbel, Raimund1 aMoebus, Susanne1 aNöthen, Markus, M1 aPechlivanis, Sonali1 aHveem, Kristian1 aNarisu, Narisu1 aHamsten, Anders1 aHumphries, Steve, E1 aStrawbridge, Rona, J1 aTremoli, Elena1 aGrallert, Harald1 aThorand, Barbara1 aIllig, Thomas1 aKoenig, Wolfgang1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aBoehm, Bernhard, O1 aKleber, Marcus, E1 aMärz, Winfried1 aWinkelmann, Bernhard, R1 aKuusisto, Johanna1 aLaakso, Markku1 aArveiler, Dominique1 aCesana, Giancarlo1 aKuulasmaa, Kari1 aVirtamo, Jarmo1 aYarnell, John, W G1 aKuh, Diana1 aWong, Andrew1 aLind, Lars1 ade Faire, Ulf1 aGigante, Bruna1 aMagnusson, Patrik, K E1 aPedersen, Nancy, L1 aDedoussis, George1 aDimitriou, Maria1 aKolovou, Genovefa1 aKanoni, Stavroula1 aStirrups, Kathleen1 aBonnycastle, Lori, L1 aNjølstad, Inger1 aWilsgaard, Tom1 aGanna, Andrea1 aRehnberg, Emil1 aHingorani, Aroon1 aKivimaki, Mika1 aKumari, Meena1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David1 aIngelsson, Erik1 aKaplan, Robert1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aStrachan, David, P1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAbecasis, Goncalo, R1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aQi, Lu1 aLoos, Ruth, J F1 aLindgren, Cecilia, M1 aNorth, Kari, E1 aHeid, Iris, M1 aDIAGRAM Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/602804067nas a2200793 4500008004100000022001400041245014300055210006900198260001600267300001200283490000600295520178900301653002202090653001602112653000902128653002202137653002402159653001902183653002202202653004002224653001102264653001802275653001102293653001702304653001202321653001402333653000902347653001602356653002602372653001602398653003202414653002002446653001202466653001802478100001902496700002202515700001902537700002502556700002402581700002102605700002202626700002202648700002102670700002602691700002402717700002202741700002802763700002702791700002202818700002402840700002202864700002202886700002402908700002202932700002202954700002202976700001902998700001703017700002403034700001903058700001803077700002203095700002403117700002503141700002403166700002303190700002403213856003603237 2013 eng d a2047-998000aSimple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium.0 aSimple risk model predicts incidence of atrial fibrillation in a c2013 Mar 18 ae0001020 v23 aBACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.
METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.
CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.
10aAfrican Americans10aAge Factors10aAged10aAged, 80 and over10aAtrial Fibrillation10aCohort Studies10aDiabetes Mellitus10aEuropean Continental Ancestry Group10aFemale10aHeart Failure10aHumans10aHypertension10aIceland10aIncidence10aMale10aMiddle Aged10aMyocardial Infarction10aNetherlands10aProportional Hazards Models10aRisk Assessment10aSmoking10aUnited States1 aAlonso, Alvaro1 aKrijthe, Bouwe, P1 aAspelund, Thor1 aStepas, Katherine, A1 aPencina, Michael, J1 aMoser, Carlee, B1 aSinner, Moritz, F1 aSotoodehnia, Nona1 aFontes, João, D1 aJanssens, Cecile, J W1 aKronmal, Richard, A1 aMagnani, Jared, W1 aWitteman, Jacqueline, C1 aChamberlain, Alanna, M1 aLubitz, Steven, A1 aSchnabel, Renate, B1 aAgarwal, Sunil, K1 aMcManus, David, D1 aEllinor, Patrick, T1 aLarson, Martin, G1 aBurke, Gregory, L1 aLauner, Lenore, J1 aHofman, Albert1 aLevy, Daniel1 aGottdiener, John, S1 aKääb, Stefan1 aCouper, David1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aStricker, Bruno, H C1 aGudnason, Vilmundur1 aHeckbert, Susan, R1 aBenjamin, Emelia, J uhttps://chs-nhlbi.org/node/587802198nas a2200289 4500008004100000022001400041245012100055210006900176260001300245300001100258490000700269520133900276653001901615653002401634653002201658653003401680653001101714653001801725653002001743653003601763100001601799700001001815700001701825700001301842700001701855856003601872 2013 eng d a1098-227200aStrategy to control type I error increases power to identify genetic variation using the full biological trajectory.0 aStrategy to control type I error increases power to identify gen c2013 Jul a419-300 v373 aGenome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.
10aCohort Studies10aComputer Simulation10aGenetic Variation10aGenome-Wide Association Study10aHumans10aLinear Models10aModels, Genetic10aPolymorphism, Single Nucleotide1 aBenke, K, S1 aWu, Y1 aFallin, D, M1 aMaher, B1 aPalmer, L, J uhttps://chs-nhlbi.org/node/621804247nas a2200757 4500008004100000022001400041245023300055210006900288260000900357300001300366490000600379520199400385653004102379653001002420653002202430653000902452653002202461653001202483653002002495653002302515653003402538653004002572653001102612653003802623653003402661653001102695653002702706653000902733653001702742653001602759653001202775653001302787100001902800700001902819700002402838700001802862700001902880700001502899700002502914700002402939700001902963700002502982700001503007700001603022700002103038700001903059700001703078700001603095700001703111700002603128700002003154700001903174700001803193700002503211700001603236700002003252700002103272700002103293700002003314700002303334700002303357700002203380700002703402700002403429856003603453 2013 eng d a1553-740400aA systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.0 asystematic mapping approach of 16q122FTO and BMI in more than 20 c2013 ae10031710 v93 aGenetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.
10aAdaptor Proteins, Signal Transducing10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aAlleles10aBody Mass Index10aChromosome Mapping10aContinental Population Groups10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMale10aMetagenomics10aMiddle Aged10aObesity10aProteins1 aPeters, Ulrike1 aNorth, Kari, E1 aSethupathy, Praveen1 aBuyske, Steve1 aHaessler, Jeff1 aJiao, Shuo1 aFesinmeyer, Megan, D1 aJackson, Rebecca, D1 aKuller, Lew, H1 aRajkovic, Aleksandar1 aLim, Unhee1 aCheng, Iona1 aSchumacher, Fred1 aWilkens, Lynne1 aLi, Rongling1 aMonda, Keri1 aEhret, Georg1 aNguyen, Khanh-Dung, H1 aCooper, Richard1 aLewis, Cora, E1 aLeppert, Mark1 aIrvin, Marguerite, R1 aGu, Charles1 aHouston, Denise1 aBůzková, Petra1 aRitchie, Marylyn1 aMatise, Tara, C1 aLe Marchand, Loïc1 aHindorff, Lucia, A1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/662805266nas a2201201 4500008004100000022001400041245015400055210006900209260001300278300001300291490000600304520181500310653002202125653002202147653002102169653002102190653004002211653003402251653001102285653002202296653002202318653002702340653002602367653001802393100001302411700002202424700002102446700002102467700001902488700001802507700002102525700002102546700002502567700001902592700001602611700002102627700003002648700002202678700002202700700002302722700001702745700002402762700002302786700001402809700002002823700002202843700001802865700002302883700001202906700002202918700002802940700002502968700001902993700002603012700002103038700002503059700002003084700001703104700001803121700002003139700001903159700001903178700002103197700002003218700002803238700002103266700002603287700002403313700001803337700002103355700001703376700001703393700002003410700002003430700002303450700002603473700002203499700001903521700001903540700001403559700002103573700002003594700002003614700002103634700001903655700002403674700002103698700002203719700002003741700002303761700002003784700002003804700002103824700002703845700002103872700002403893700002903917700002203946700002003968700001903988700002104007856003604028 2013 eng d a1553-740400aTrans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.0 aTransethnic finemapping of lipid loci identifies populationspeci c2013 Mar ae10033790 v93 aGenome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
10aAfrican Americans10aApolipoproteins A10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aGenome-Wide Association Study10aHumans10aLipoproteins, HDL10aLipoproteins, LDL10aProprotein Convertases10aSerine Endopeptidases10aTriglycerides1 aWu, Ying1 aWaite, Lindsay, L1 aJackson, Anne, U1 aSheu, Wayne, H-H1 aBuyske, Steven1 aAbsher, Devin1 aArnett, Donna, K1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aCarty, Cara, L1 aCheng, Iona1 aCochran, Barbara1 aCroteau-Chonka, Damien, C1 aDumitrescu, Logan1 aEaton, Charles, B1 aFranceschini, Nora1 aGuo, Xiuqing1 aHenderson, Brian, E1 aHindorff, Lucia, A1 aKim, Eric1 aKinnunen, Leena1 aKomulainen, Pirjo1 aLee, Wen-Jane1 aLe Marchand, Loïc1 aLin, Yi1 aLindström, Jaana1 aLingaas-Holmen, Oddgeir1 aMitchell, Sabrina, L1 aNarisu, Narisu1 aRobinson, Jennifer, G1 aSchumacher, Fred1 aStančáková, Alena1 aSundvall, Jouko1 aSung, Yun-Ju1 aSwift, Amy, J1 aWang, Wen-Chang1 aWilkens, Lynne1 aWilsgaard, Tom1 aYoung, Alicia, M1 aAdair, Linda, S1 aBallantyne, Christie, M1 aBůzková, Petra1 aChakravarti, Aravinda1 aCollins, Francis, S1 aDuggan, David1 aFeranil, Alan, B1 aHo, Low-Tone1 aHung, Yi-Jen1 aHunt, Steven, C1 aHveem, Kristian1 aJuang, Jyh-Ming, J1 aKesäniemi, Antero, Y1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo, A1 aLee, I-Te1 aLeppert, Mark, F1 aMatise, Tara, C1 aMoilanen, Leena1 aNjølstad, Inger1 aPeters, Ulrike1 aQuertermous, Thomas1 aRauramaa, Rainer1 aRotter, Jerome, I1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aWang, Tzung-Dau1 aBoehnke, Michael1 aHaiman, Christopher, A1 aChen, Yii-der, I1 aKooperberg, Charles1 aAssimes, Themistocles, L1 aCrawford, Dana, C1 aHsiung, Chao, A1 aNorth, Kari, E1 aMohlke, Karen, L uhttps://chs-nhlbi.org/node/662902102nas a2200469 4500008004100000022001400041245008200055210006900137260001300206300001200219490000700231520073300238653002100971653002600992653002301018653002201041653001801063653003401081653001301115653001701128653001101145653002401156100002401180700001901204700002301223700001801246700001201264700001801276700001701294700001301311700001801324700001901342700001601361700001901377700003001396700002001426700002501446700001901471700002101490710008501511856003601596 2013 eng d a1546-171800aWhole-genome sequence-based analysis of high-density lipoprotein cholesterol.0 aWholegenome sequencebased analysis of highdensity lipoprotein ch c2013 Aug a899-9010 v453 aWe describe initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol (HDL-C). We report whole-genome sequencing and analysis of 962 individuals from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. From this analysis, we estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions.
10aCholesterol, HDL10aComputational Biology10aDatabases, Genetic10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aGenomics10aHeterozygote10aHumans10aOpen Reading Frames1 aMorrison, Alanna, C1 aVoorman, Arend1 aJohnson, Andrew, D1 aLiu, Xiaoming1 aYu, Jin1 aLi, Alexander1 aMuzny, Donna1 aYu, Fuli1 aRice, Kenneth1 aZhu, Chengsong1 aBis, Joshua1 aHeiss, Gerardo1 aO'Donnell, Christopher, J1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aGibbs, Richard1 aBoerwinkle, Eric1 aCohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium uhttps://chs-nhlbi.org/node/628303479nas a2200553 4500008004100000022001400041245016100055210006900216260001300285300001000298490000600308520190300314653001802217653000902235653002202244653001002266653001902276653001102295653002202306653003402328653001302362653001902375653001102394653000902405653000902414653001602423653003602439653002702475100002502502700001302527700002002540700002102560700001902581700001902600700002202619700002002641700001902661700002302680700001902703700002002722700002302742700001802765700001702783700002302800700002302823700002402846700001902870856003602889 2014 eng d a1942-326800aADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aADAM19 and HTR4 variants and pulmonary function Cohorts for Hear c2014 Jun a350-80 v73 aBACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.
METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.
CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.
10aADAM Proteins10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aLung10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aLondon, Stephanie, J1 aGao, Wei1 aGharib, Sina, A1 aHancock, Dana, B1 aWilk, Jemma, B1 aHouse, John, S1 aGibbs, Richard, A1 aMuzny, Donna, M1 aLumley, Thomas1 aFranceschini, Nora1 aNorth, Kari, E1 aPsaty, Bruce, M1 aKovar, Christie, L1 aCoresh, Josef1 aZhou, Yanhua1 aHeckbert, Susan, R1 aBrody, Jennifer, A1 aMorrison, Alanna, C1 aDupuis, Josée uhttps://chs-nhlbi.org/node/658003251nas a2200493 4500008004100000022001400041245013700055210006900192260001300261300001100274490000800285520184100293653000902134653001302143653002802156653001902184653002802203653001902231653002102250653001502271653001102286653003102297653003702328653001102365653001602376653001402392653001102406653000902417653002102426653003202447653001102479653002202490100002002512700002002532700002102552700001902573700002402592700001802616700002202634700002402656700002002680700002102700856003602721 2014 eng d a1879-148400aAdvanced glycation/glycoxidation endproduct carboxymethyl-lysine and incidence of coronary heart disease and stroke in older adults.0 aAdvanced glycationglycoxidation endproduct carboxymethyllysine a c2014 Jul a116-210 v2353 aBACKGROUND: Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress--such as diabetes, chronic kidney disease and aging--where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined.
METHODS: To test the hypothesis that circulating levels of N(ɛ)-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older.
RESULTS: During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase=1.11, 95% confidence interval [CI]=1.03-1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke.
CONCLUSIONS: In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML's value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population.
10aAged10aAlbumins10aAntihypertensive Agents10aBlood Pressure10aCardiovascular Diseases10aCohort Studies10aCoronary Disease10aCreatinine10aFemale10aGlomerular Filtration Rate10aGlycation End Products, Advanced10aHumans10aImmunoassay10aIncidence10aLysine10aMale10aOxidative Stress10aProportional Hazards Models10aStroke10aTreatment Outcome1 aKizer, Jorge, R1 aBenkeser, David1 aArnold, Alice, M1 aIx, Joachim, H1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aTracy, Russell, P1 aSiscovick, David, S1 aPsaty, Bruce, M1 aZieman, Susan, J uhttps://chs-nhlbi.org/node/657608212nas a2202197 4500008004100000022001400041245013100055210006900186260001600255300001000271490000800281520207900289653001002368653000902378653002602387653002102413653001502434653002102449653001102470653002002481653001302501653001102514653000902525653003702534653001602571653002402587653003602611653001102647100002302658700002202681700001902703700002702722700001502749700001402764700002502778700001902803700002002822700001702842700002002859700001902879700002502898700001702923700002002940700002102960700002202981700002503003700001903028700002403047700002603071700002803097700001703125700001603142700003103158700001503189700002003204700002103224700001803245700002003263700001903283700002403302700002003326700002103346700001803367700002103385700002003406700001903426700002103445700001903466700001803485700002803503700002103531700002503552700001503577700002303592700001903615700002703634700002403661700002403685700002403709700001803733700002103751700001603772700002603788700002303814700001503837700002103852700002303873700002403896700001803920700002603938700002203964700001903986700001804005700001804023700002104041700001904062700001704081700002104098700001904119700002104138700002404159700002404183700003404207700002004241700002204261700002504283700001904308700002104327700001904348700001804367700002004385700002004405700001504425700001904440700002804459700002004487700001404507700002104521700002404542700002504566700001804591700002004609700002804629700002204657700002304679700001504702700002504717700002904742700003104771700002204802700002204824700002204846700002004868700002304888700001804911700002004929700001904949700001904968700002504987700002205012700002005034700002405054700002305078700001805101700002505119700002405144700002005168700001905188700001805207700001505225700002205240700002505262700002005287700002105307700002105328700001905349700002305368700002205391700002205413700002205435700002105457700002505478700001905503700002705522700001905549700002205568700002005590700002505610700002105635700002005656700002105676700002105697700002005718700002405738700002805762700001805790700001905808700002405827700001905851700002005870700002405890700002105914700001905935710002405954856003605978 2014 eng d a1756-183300aAssociation between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.0 aAssociation between alcohol and cardiovascular disease Mendelian c2014 Jul 10 ag41640 v3493 aOBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.
DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.
PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.
MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.
RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).
CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
10aAdult10aAged10aAlcohol Dehydrogenase10aAlcohol Drinking10aBiomarkers10aCoronary Disease10aFemale10aGenetic Markers10aGenotype10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aModels, Statistical10aPolymorphism, Single Nucleotide10aStroke1 aHolmes, Michael, V1 aDale, Caroline, E1 aZuccolo, Luisa1 aSilverwood, Richard, J1 aGuo, Yiran1 aYe, Zheng1 aPrieto-Merino, David1 aDehghan, Abbas1 aTrompet, Stella1 aWong, Andrew1 aCavadino, Alana1 aDrogan, Dagmar1 aPadmanabhan, Sandosh1 aLi, Shanshan1 aYesupriya, Ajay1 aLeusink, Maarten1 aSundström, Johan1 aHubacek, Jaroslav, A1 aPikhart, Hynek1 aSwerdlow, Daniel, I1 aPanayiotou, Andrie, G1 aBorinskaya, Svetlana, A1 aFinan, Chris1 aShah, Sonia1 aKuchenbaecker, Karoline, B1 aShah, Tina1 aEngmann, Jorgen1 aFolkersen, Lasse1 aEriksson, Per1 aRicceri, Fulvio1 aMelander, Olle1 aSacerdote, Carlotta1 aGamble, Dale, M1 aRayaprolu, Sruti1 aRoss, Owen, A1 aMcLachlan, Stela1 aVikhireva, Olga1 aSluijs, Ivonne1 aScott, Robert, A1 aAdamkova, Vera1 aFlicker, Leon1 avan Bockxmeer, Frank, M1 aPower, Christine1 aMarques-Vidal, Pedro1 aMeade, Tom1 aMarmot, Michael, G1 aFerro, Jose, M1 aPaulos-Pinheiro, Sofia1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aLeach, Irene, Mateo1 aVerweij, Niek1 aLinneberg, Allan1 aSkaaby, Tea1 aDoevendans, Pieter, A1 aCramer, Maarten, J1 aHarst, Pim1 aKlungel, Olaf, H1 aDowling, Nicole, F1 aDominiczak, Anna, F1 aKumari, Meena1 aNicolaides, Andrew, N1 aWeikert, Cornelia1 aBoeing, Heiner1 aEbrahim, Shah1 aGaunt, Tom, R1 aPrice, Jackie, F1 aLannfelt, Lars1 aPeasey, Anne1 aKubinova, Ruzena1 aPajak, Andrzej1 aMalyutina, Sofia1 aVoevoda, Mikhail, I1 aTamosiunas, Abdonas1 avan der Zee, Anke, H Maitland1 aNorman, Paul, E1 aHankey, Graeme, J1 aBergmann, Manuela, M1 aHofman, Albert1 aFranco, Oscar, H1 aCooper, Jackie1 aPalmen, Jutta1 aSpiering, Wilko1 ade Jong, Pim, A1 aKuh, Diana1 aHardy, Rebecca1 aUitterlinden, André, G1 aIkram, Arfan, M1 aFord, Ian1 aHyppönen, Elina1 aAlmeida, Osvaldo, P1 aWareham, Nicholas, J1 aKhaw, Kay-Tee1 aHamsten, Anders1 aHusemoen, Lise, Lotte N1 aTjønneland, Anne1 aTolstrup, Janne, S1 aRimm, Eric1 aBeulens, Joline, W J1 aVerschuren, W, M Monique1 aOnland-Moret, Charlotte, N1 aHofker, Marten, H1 aWannamethee, Goya1 aWhincup, Peter, H1 aMorris, Richard1 aVicente, Astrid, M1 aWatkins, Hugh1 aFarrall, Martin1 aJukema, Wouter1 aMeschia, James1 aCupples, Adrienne, L1 aSharp, Stephen, J1 aFornage, Myriam1 aKooperberg, Charles1 aLaCroix, Andrea, Z1 aDai, James, Y1 aLanktree, Matthew, B1 aSiscovick, David, S1 aJorgenson, Eric1 aSpring, Bonnie1 aCoresh, Josef1 aLi, Yun, R1 aBuxbaum, Sarah, G1 aSchreiner, Pamela, J1 aEllison, Curtis1 aTsai, Michael, Y1 aPatel, Sanjay, R1 aRedline, Susan1 aJohnson, Andrew, D1 aHoogeveen, Ron, C1 aHakonarson, Hakon1 aRotter, Jerome, I1 aBoerwinkle, Eric1 ade Bakker, Paul, I W1 aKivimaki, Mika1 aAsselbergs, Folkert, W1 aSattar, Naveed1 aLawlor, Debbie, A1 aWhittaker, John1 aSmith, George, Davey1 aMukamal, Kenneth1 aPsaty, Bruce, M1 aWilson, James, G1 aLange, Leslie, A1 aHamidovic, Ajna1 aHingorani, Aroon, D1 aNordestgaard, Børge, G1 aBobak, Martin1 aLeon, David, A1 aLangenberg, Claudia1 aPalmer, Tom, M1 aReiner, Alex, P1 aKeating, Brendan, J1 aDudbridge, Frank1 aCasas, Juan, P1 aInterAct Consortium uhttps://chs-nhlbi.org/node/656902948nas a2200493 4500008004100000022001400041245015600055210006900211260001300280300001200293490000700305520153800312653001001850653000901860653002501869653001901894653001101913653001101924653002001935653000901955653002301964653001601987653002302003653001702026653002702043100001802070700002602088700001402114700001902128700002402147700002002171700001702191700002302208700002102231700001502252700002302267700002402290700001802314700001702332700002002349700002602369700002302395856003602418 2014 eng d a1524-463600aAssociation between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis.0 aAssociation between the metabolic syndrome its individual compon c2014 Nov a2478-850 v343 aOBJECTIVE: The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation.
APPROACH AND RESULTS: We performed a patient-level meta-analysis of case-control and cohort studies that evaluated the role of MetS and risk of unprovoked VTE. For case-control studies, odds ratios and 95% confidence intervals were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; χ(2) tests for trend were used to investigate the effect of increasing number of components of MetS on the risk of VTE and to explore the influence of abdominal obesity on this relationship. For cohort studies, hazard ratios and 95% confidence interval were calculated using multivariable Cox regression analysis. Six case-control studies were included (908 cases with unprovoked VTE and 1794 controls): in multivariate analysis, MetS was independently associated with VTE (odds ratio, 1.91; 95% confidence interval, 1.57-2.33), and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index. Two prospective cohort studies were included (26,531 subjects and 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE.
CONCLUSIONS: Case-control but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.
10aAdult10aAged10aCase-Control Studies10aCohort Studies10aFemale10aHumans10aLogistic Models10aMale10aMetabolic Syndrome10aMiddle Aged10aObesity, Abdominal10aRisk Factors10aVenous Thromboembolism1 aAgeno, Walter1 aDi Minno, Matteo, N D1 aAy, Cihan1 aJang, Moon, Ju1 aHansen, John-Bjarne1 aSteffen, Lyn, M1 aVaya, Amparo1 aRattazzi, Marcello1 aPabinger, Ingrid1 aOh, Doyeun1 aDi Minno, Giovanni1 aBraekkan, Sigrid, K1 aCushman, Mary1 aBonet, Elena1 aPauletto, Paolo1 aSquizzato, Alessandro1 aDentali, Francesco uhttps://chs-nhlbi.org/node/654203391nas a2200493 4500008004100000022001400041245014300055210006900198260001300267300001200280490000700292520197600299653000902275653001602284653001902300653001602319653001102335653003102346653001102377653002902388653002002417653000902437653001602446653001602462653003202478653002402510653001702534653001102551653001802562100002702580700002102607700002502628700001802653700002602671700001902697700001902716700002002735700002002755700002402775700002102799700002302820700001802843856003602861 2014 eng d a1524-462800aAssociation of kidney disease measures with ischemic versus hemorrhagic strokes: pooled analyses of 4 prospective community-based cohorts.0 aAssociation of kidney disease measures with ischemic versus hemo c2014 Jul a1925-310 v453 aBACKGROUND AND PURPOSE: Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.
METHODS: We pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression.
RESULTS: Among 29,595 participants (mean age, 61 [SD 12.5] years; 46% men; 17% black), 1261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m2 were 1.30 (95% confidence interval, 1.01-1.68) and 0.92 (0.47-1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27-2.07) for ischemic and 2.57 (1.37-4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P=0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.
CONCLUSIONS: Whereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.
10aAged10aAlbuminuria10aBrain Ischemia10aComorbidity10aFemale10aGlomerular Filtration Rate10aHumans10aIntracranial Hemorrhages10aKidney Diseases10aMale10aMiddle Aged10aNetherlands10aProportional Hazards Models10aProspective Studies10aRisk Factors10aStroke10aUnited States1 aMahmoodi, Bakhtawar, K1 aYatsuya, Hiroshi1 aMatsushita, Kunihiro1 aSang, Yinying1 aGottesman, Rebecca, F1 aAstor, Brad, C1 aWoodward, Mark1 aLongstreth, W T1 aPsaty, Bruce, M1 aShlipak, Michael, G1 aFolsom, Aaron, R1 aGansevoort, Ron, T1 aCoresh, Josef uhttps://chs-nhlbi.org/node/642404045nas a2200733 4500008004100000022001400041245022200055210006900277260001300346300001200359490000600371520185400377653000902231653002202240653001002262653001802272653003202290653001902322653005302341653003002394653001202424653001102436653001902447653002202466653003402488653001302522653004002535653001902575653001102594653001202605653000902617653001602626653003602642653002702678100002302705700002302728700002102751700002402772700001402796700002002810700001602830700001802846700002402864700001902888700002002907700001802927700002202945700002002967700001802987700002203005700001703027700002103044700002103065700002203086700002303108700001803131700002003149700002103169700002203190700002403212700001903236700002003255856003603275 2014 eng d a1942-326800aAssociation of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aAssociation of levels of fasting glucose and insulin with rare v c2014 Jun a374-3820 v73 aBACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.
METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.
CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
10aAged10aAged, 80 and over10aAging10aBlood Glucose10aChromosomes, Human, Pair 1110aCohort Studies10aDeath Domain Receptor Signaling Adaptor Proteins10aDiabetes Mellitus, Type 210aFasting10aFemale10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aGuanine Nucleotide Exchange Factors10aHeart Diseases10aHumans10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aCornes, Belinda, K1 aBrody, Jennifer, A1 aNikpoor, Naghmeh1 aMorrison, Alanna, C1 aChu, Huan1 aAhn, Byung, Soo1 aWang, Shuai1 aDauriz, Marco1 aBarzilay, Joshua, I1 aDupuis, Josée1 aFlorez, Jose, C1 aCoresh, Josef1 aGibbs, Richard, A1 aKao, Linda, W H1 aLiu, Ching-Ti1 aMcKnight, Barbara1 aMuzny, Donna1 aPankow, James, S1 aReid, Jeffrey, G1 aWhite, Charles, C1 aJohnson, Andrew, D1 aWong, Tien, Y1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aSiscovick, David, S1 aSladek, Robert1 aMeigs, James, B uhttps://chs-nhlbi.org/node/655505943nas a2201657 4500008004100000022001400041245014100055210006900196260001600265300001100281490000700292520126000299653005101559653001001610653003901620653000901659653001201668653001201680653002101692653002101713653001901734653002101753653004001774653001101814653001901825653003201844653001701876653002201893653001101915653001801926653000901944653000901953653002301962653003601985653001602021653001402037653002702051653001602078653001802094100002002112700001802132700001902150700001902169700002402188700002402212700002302236700002502259700002002284700002002304700001802324700002602342700002102368700001702389700002502406700002102431700001702452700001702469700001802486700002102504700002002525700001802545700001902563700002302582700001602605700001902621700002502640700002402665700002202689700002202711700002602733700002402759700002502783700002602808700002102834700001902855700002802874700002202902700002002924700002602944700002502970700002502995700001903020700002103039700002303060700001803083700001803101700002003119700002403139700001903163700002503182700002003207700001803227700002903245700002003274700001503294700002103309700002203330700002303352700001903375700002203394700001603416700002103432700002403453700002003477700001803497700002103515700001903536700001503555700002103570700002203591700001903613700002503632700002103657700001903678700001603697700002403713700002203737700002103759700001703780700001903797700002503816700002203841700001903863700001803882700002303900700001703923700002403940700002103964700002303985700002404008700002104032700002004053700002204073700003004095700001804125700002104143700002204164700002504186710003804211856003604249 2014 eng d a1537-660500aAssociation of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.0 aAssociation of lowfrequency and rare codingsequence variants wit c2014 Feb 06 a223-320 v943 aLow-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAdult10aAfrican Continental Ancestry Group10aAged10aAlleles10aAnimals10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Association Studies10aGenetic Code10aGenetic Variation10aHumans10aLinear Models10aMale10aMice10aMice, Inbred C57BL10aMicrotubule-Associated Proteins10aMiddle Aged10aPhenotype10aSequence Analysis, DNA10aSubtilisins10aTriglycerides1 aPeloso, Gina, M1 aAuer, Paul, L1 aBis, Joshua, C1 aVoorman, Arend1 aMorrison, Alanna, C1 aStitziel, Nathan, O1 aBrody, Jennifer, A1 aKhetarpal, Sumeet, A1 aCrosby, Jacy, R1 aFornage, Myriam1 aIsaacs, Aaron1 aJakobsdottir, Johanna1 aFeitosa, Mary, F1 aDavies, Gail1 aHuffman, Jennifer, E1 aManichaikul, Ani1 aDavis, Brian1 aLohman, Kurt1 aJoon, Aron, Y1 aSmith, Albert, V1 aGrove, Megan, L1 aZanoni, Paolo1 aRedon, Valeska1 aDemissie, Serkalem1 aLawson, Kim1 aPeters, Ulrike1 aCarlson, Christopher1 aJackson, Rebecca, D1 aRyckman, Kelli, K1 aMackey, Rachel, H1 aRobinson, Jennifer, G1 aSiscovick, David, S1 aSchreiner, Pamela, J1 aMychaleckyj, Josyf, C1 aPankow, James, S1 aHofman, Albert1 aUitterlinden, André, G1 aHarris, Tamara, B1 aTaylor, Kent, D1 aStafford, Jeanette, M1 aReynolds, Lindsay, M1 aMarioni, Riccardo, E1 aDehghan, Abbas1 aFranco, Oscar, H1 aPatel, Aniruddh, P1 aLu, Yingchang1 aHindy, George1 aGottesman, Omri1 aBottinger, Erwin, P1 aMelander, Olle1 aOrho-Melander, Marju1 aLoos, Ruth, J F1 aDuga, Stefano1 aMerlini, Piera, Angelica1 aFarrall, Martin1 aGoel, Anuj1 aAsselta, Rosanna1 aGirelli, Domenico1 aMartinelli, Nicola1 aShah, Svati, H1 aKraus, William, E1 aLi, Mingyao1 aRader, Daniel, J1 aReilly, Muredach, P1 aMcPherson, Ruth1 aWatkins, Hugh1 aArdissino, Diego1 aZhang, Qunyuan1 aWang, Judy1 aTsai, Michael, Y1 aTaylor, Herman, A1 aCorrea, Adolfo1 aGriswold, Michael, E1 aLange, Leslie, A1 aStarr, John, M1 aRudan, Igor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aOrdovas, Jose, M1 aLevy, Daniel1 aChen, Y-D, Ida1 aReiner, Alexander, P1 aHayward, Caroline1 aPolasek, Ozren1 aDeary, Ian, J1 aBorecki, Ingrid, B1 aLiu, Yongmei1 aGudnason, Vilmundur1 aWilson, James, G1 aDuijn, Cornelia, M1 aKooperberg, Charles1 aRich, Stephen, S1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aO'Donnell, Christopher, J1 aRice, Kenneth1 aBoerwinkle, Eric1 aKathiresan, Sekar1 aCupples, Adrienne, L1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659002904nas a2200373 4500008004100000022001400041245017000055210006900225260000900294300001200303490000600315520179500321653002102116653002002137653001902157653003402176653001102210653001102221653001402232653000902246653001602255653003002271653000902301653002102310653002402331100001902355700002002374700001902394700001702413700002002430700002102450700002302471856003602494 2014 eng d a1932-620300aAssociation of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study.0 aAssociation of sick sinus syndrome with incident cardiovascular c2014 ae1096620 v93 aBACKGROUND: Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.
METHODS: We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.
RESULTS: During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14-1.70), coronary heart disease (HR 1.72, 95%CI 1.11-2.66), heart failure (HR 2.87, 95%CI 2.17-3.80), stroke (HR 1.56, 95%CI 0.99-2.46), AF (HR 5.75, 95%CI 4.43-7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9-67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51-2.66), AF (HR 4.25, 95%CI 3.28-5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8-32.1).
CONCLUSION: Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.
10aAge Distribution10aAtherosclerosis10aCohort Studies10aContinental Population Groups10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aResidence Characteristics10aRisk10aSex Distribution10aSick Sinus Syndrome1 aAlonso, Alvaro1 aJensen, Paul, N1 aLopez, Faye, L1 aChen, Lin, Y1 aPsaty, Bruce, M1 aFolsom, Aaron, R1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/654303656nas a2200589 4500008004100000022001400041245015400055210006900209260000900278300001100287490000600298520189800304653003802202653004002240653001102280653003202291653002602323653001102349653001202360653001302372653000902385653002602394653003602420653002402456653002702480100001902507700002102526700001802547700002302565700002202588700002902610700002302639700002002662700001702682700002302699700002602722700001702748700002302765700002002788700001902808700001902827700001902846700002002865700002002885700002202905700002202927700002002949700002102969700002002990700002003010856003603030 2014 eng d a1932-620300aAssociations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium.0 aAssociations of NINJ2 sequence variants with incident ischemic s c2014 ae997980 v93 aBACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.
METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).
CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.
10aCell Adhesion Molecules, Neuronal10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aGenetic Heterogeneity10aHumans10aIntrons10aIschemia10aMale10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies10aSequence Analysis, DNA1 aBis, Joshua, C1 aDeStefano, Anita1 aLiu, Xiaoming1 aBrody, Jennifer, A1 aChoi, Seung, Hoan1 aVerhaaren, Benjamin, F J1 aDebette, Stephanie1 aIkram, Arfan, M1 aShahar, Eyal1 aButler, Kenneth, R1 aGottesman, Rebecca, F1 aMuzny, Donna1 aKovar, Christie, L1 aPsaty, Bruce, M1 aHofman, Albert1 aLumley, Thomas1 aGupta, Mayetri1 aWolf, Philip, A1 aDuijn, Cornelia1 aGibbs, Richard, A1 aMosley, Thomas, H1 aLongstreth, W T1 aBoerwinkle, Eric1 aSeshadri, Sudha1 aFornage, Myriam uhttps://chs-nhlbi.org/node/654804368nas a2200805 4500008004100000022001400041245016100055210006900216260001300285300001200298490000700310520202900317653000902346653002402355653001502379653002302394653001102417653001102428653001102439653001402450653000902464653003102473653002202504653003002526653002002556653001702576653001802593100002202611700002502633700002102658700002202679700001902701700002202720700002102742700002602763700002402789700002202813700002802835700002702863700002202890700002402912700002702936700002002963700002202983700002203005700002103027700001703048700002203065700002203087700002203109700001903131700001703150700002403167700001903191700001803210700002203228700001903250700002803269700002203297700002003319700002403339700002403363700002503387700002403412700002303436700002403459700002403483700001903507856003603526 2014 eng d a1532-209200aB-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies.0 aBtype natriuretic peptide and Creactive protein in the predictio c2014 Oct a1426-330 v163 aAIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
10aAged10aAtrial Fibrillation10aBiomarkers10aC-Reactive Protein10aEurope10aFemale10aHumans10aIncidence10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aRisk Assessment10aRisk Factors10aUnited States1 aSinner, Moritz, F1 aStepas, Katherine, A1 aMoser, Carlee, B1 aKrijthe, Bouwe, P1 aAspelund, Thor1 aSotoodehnia, Nona1 aFontes, João, D1 aJanssens, Cecile, J W1 aKronmal, Richard, A1 aMagnani, Jared, W1 aWitteman, Jacqueline, C1 aChamberlain, Alanna, M1 aLubitz, Steven, A1 aSchnabel, Renate, B1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aAgarwal, Sunil, K1 aMcManus, David, D1 aFranco, Oscar, H1 aYin, Xiaoyan1 aLarson, Martin, G1 aBurke, Gregory, L1 aLauner, Lenore, J1 aHofman, Albert1 aLevy, Daniel1 aGottdiener, John, S1 aKääb, Stefan1 aCouper, David1 aHarris, Tamara, B1 aAstor, Brad, C1 aBallantyne, Christie, M1 aHoogeveen, Ron, C1 aArai, Andrew, E1 aSoliman, Elsayed, Z1 aEllinor, Patrick, T1 aStricker, Bruno, H C1 aGudnason, Vilmundur1 aHeckbert, Susan, R1 aPencina, Michael, J1 aBenjamin, Emelia, J1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/660103125nas a2200553 4500008004100000022001400041245011100055210006900166260000900235300001200244490000600256520150100262653002101763653001101784653003401795653001101829653000901840653001601849653003601865100003001901700002901931700002001960700002201980700002102002700002202023700002202045700002402067700001202091700002302103700001902126700002202145700001802167700001902185700001902204700002602223700002802249700002102277700002802298700002402326700002002350700002502370700002702395700002002422700001802442700002802460700002402488700002302512856003602535 2014 eng d a1932-620300aThe challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.0 achallenges of genomewide interaction studies lessons to learn fr c2014 ae1092900 v93 aGenome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.
10aCholesterol, HDL10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 avan Leeuwen, Elisabeth, M1 aSmouter, Françoise, A S1 aKam-Thong, Tony1 aKarbalai, Nazanin1 aSmith, Albert, V1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSitlani, Colleen, M1 aLi, Guo1 aBrody, Jennifer, A1 aBis, Joshua, C1 aWhite, Charles, C1 aJaiswal, Alok1 aOostra, Ben, A1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aBoerwinkle, Eric1 aBallantyne, Christie, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aJarvelin, Marjo-Riitta1 aRipatti, Samuli1 aIsaacs, Aaron1 aMüller-Myhsok, Bertram1 aKarssen, Lennart, C1 aDuijn, Cornelia, M uhttps://chs-nhlbi.org/node/660703461nas a2200445 4500008004100000022001400041245012500055210006900180260001500249300001200264490000800276520219900284653000902483653002102492653001502513653001902528653002102547653002502568653002502593653002902618653001102647653002202658653001102680653001802691653000902709653002402718653002402742653001702766653001102783653001802794653001802812100001802830700002402848700001902872700001902891700002002910700002402930700002502954856003602979 2014 eng d a1524-453900aCirculating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the Cardiovascular Health Study.0 aCirculating omega6 polyunsaturated fatty acids and total and cau c2014 Oct 7 a1245-530 v1303 aBACKGROUND: Although omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort.
METHODS AND RESULTS: Among 2792 participants(aged ≥65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992-2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95% confidence interval, 0.32-0.82; P trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70-1.34; P trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality (P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.
CONCLUSIONS: High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.
10aAged10aArachidonic Acid10aBiomarkers10aCohort Studies10aCoronary Disease10aFatty Acids, Omega-310aFatty Acids, Omega-610aFatty Acids, Unsaturated10aFemale10aFollow-Up Studies10aHumans10aLinoleic Acid10aMale10aProspective Studies10aRegression Analysis10aRisk Factors10aStroke10aSurvival Rate10aUnited States1 aH Y Wu, Jason1 aLemaitre, Rozenn, N1 aKing, Irena, B1 aSong, Xiaoling1 aPsaty, Bruce, M1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/661303905nas a2200745 4500008004100000022001400041245017300055210006900228260001300297300001200310490000700322520172200329653001002051653000902061653002802070653001902098653002802117653002702145653003502172653001902207653001102226653001102237653001702248653000902265653002702274653001602301653002002317653001702337100002102354700002802375700002202403700002202425700002602447700002202473700001902495700002502514700002602539700001602565700001902581700002202600700001402622700002002636700002002656700002202676700002002698700001702718700002402735700002602759700001802785700002002803700002302823700002102846700002502867700002502892700002802917700001902945700002002964700002202984700002103006700002503027700002103052700002303073700002703096856003603123 2014 eng d a1524-456300aCommon carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration.0 aCommon carotid intimamedia thickness measurements do not improve c2014 Jun a1173-810 v633 aCarotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.
10aAdult10aAged10aAntihypertensive Agents10aBlood Pressure10aCardiovascular Diseases10aCarotid Artery, Common10aCarotid Intima-Media Thickness10aCohort Studies10aFemale10aHumans10aHypertension10aMale10aMeta-Analysis as Topic10aMiddle Aged10aRisk Assessment10aRisk Factors1 aBots, Michiel, L1 aGroenewegen, Karlijn, A1 aAnderson, Todd, J1 aBritton, Annie, R1 aDekker, Jacqueline, M1 aEngström, Gunnar1 aEvans, Greg, W1 ade Graaf, Jacqueline1 aGrobbee, Diederick, E1 aHedblad, Bo1 aHofman, Albert1 aHolewijn, Suzanne1 aIkeda, Ai1 aKavousi, Maryam1 aKitagawa, Kazuo1 aKitamura, Akihiko1 aIkram, Arfan, M1 aLonn, Eva, M1 aLorenz, Matthias, W1 aMathiesen, Ellisiv, B1 aNijpels, Giel1 aOkazaki, Shuhei1 aO'Leary, Daniel, H1 aPolak, Joseph, F1 aPrice, Jacqueline, F1 aRobertson, Christine1 aRembold, Christopher, M1 aRosvall, Maria1 aRundek, Tatjana1 aSalonen, Jukka, T1 aSitzer, Matthias1 aStehouwer, Coen, D A1 aFranco, Oscar, H1 aPeters, Sanne, A E1 aRuijter, Hester, M den uhttps://chs-nhlbi.org/node/654904012nas a2200793 4500008004100000022001400041245009500055210006900150260001300219300001000232490000700242520174500249653005001994653000902044653001502053653001202068653002502080653002702105653001602132653001102148653003802159653002202197653001302219653001102232653000902243653003602252653001702288100002402305700002602329700002502355700002202380700002202402700002202424700002402446700001902470700001902489700001802508700001502526700001202541700002002553700001702573700002502590700002002615700002902635700002402664700002502688700002802713700001902741700001902760700002302779700002202802700002202824700001802846700002202864700002202886700001902908700001902927700003002946700002602976700002303002700002303025700002203048700002203070700002103092700002603113700001903139700002403158856003603182 2014 eng d a1556-387100aCommon variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest.0 aCommon variation in fatty acid metabolic genes and risk of incid c2014 Mar a471-70 v113 aBACKGROUND: There is limited information on genetic factors associated with sudden cardiac arrest (SCA).
OBJECTIVE: To assess the association of common variation in genes in fatty acid pathways with SCA risk.
METHODS: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases.
RESULTS: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lower SCA risk (95% confidence interval -16% to -1%) in the replication phase.
CONCLUSIONS: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.
10a1-Acylglycerophosphocholine O-Acyltransferase10aAged10aAlgorithms10aAlleles10aCase-Control Studies10aDeath, Sudden, Cardiac10aFatty Acids10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aHumans10aMale10aPolymorphism, Single Nucleotide10aRisk Factors1 aLemaitre, Rozenn, N1 aJohnson, Catherine, O1 aHesselson, Stephanie1 aSotoodehnia, Nona1 aSotoodhenia, Nona1 aMcKnight, Barbara1 aSitlani, Colleen, M1 aRea, Thomas, D1 aKing, Irena, B1 aKwok, Pui-Yan1 aMak, Angel1 aLi, Guo1 aBrody, Jennifer1 aLarson, Eric1 aMozaffarian, Dariush1 aPsaty, Bruce, M1 aHuertas-Vazquez, Adriana1 aTardif, Jean-Claude1 aAlbert, Christine, M1 aLyytikäinen, Leo-Pekka1 aArking, Dan, E1 aKääb, Stefan1 aHuikuri, Heikki, V1 aKrijthe, Bouwe, P1 aEijgelsheim, Mark1 aWang, Ying, A1 aReinier, Kyndaron1 aLehtimäki, Terho1 aPulit, Sara, L1 aBrugada, Ramon1 aMüller-Nurasyid, Martina1 aNewton-Cheh, Chris, H1 aKarhunen, Pekka, J1 aStricker, Bruno, H1 aGoyette, Philippe1 aRotter, Jerome, I1 aChugh, Sumeet, S1 aChakravarti, Aravinda1 aJouven, Xavier1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/632502366nas a2200409 4500008004100000022001400041245008900055210006900144260001300213300001500226490000700241520124000248653000901488653001901497653001301516653001101529653001101540653000901551653001901560653003001579653002401609653003201633653002001665100002301685700002101708700001401729700002201743700001801765700002001783700001801803700002201821700002001843700002001863700001801883700001901901856003601920 2014 eng d a1552-527900aDevelopment and validation of a brief dementia screening indicator for primary care.0 aDevelopment and validation of a brief dementia screening indicat c2014 Nov a656-665.e10 v103 aBACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives.
METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening.
RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m(2) (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78).
CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.
10aAged10aCohort Studies10aDementia10aFemale10aHumans10aMale10aMass Screening10aPredictive Value of Tests10aPrimary Health Care10aProportional Hazards Models10aRisk Assessment1 aBarnes, Deborah, E1 aBeiser, Alexa, S1 aLee, Anne1 aLanga, Kenneth, M1 aKoyama, Alain1 aPreis, Sarah, R1 aNeuhaus, John1 aMcCammon, Ryan, J1 aYaffe, Kristine1 aSeshadri, Sudha1 aHaan, Mary, N1 aWeir, David, R uhttps://chs-nhlbi.org/node/630203989nas a2200829 4500008004100000022001400041245011400055210006900169260001300238300001100251490000700262520179800269653001002067653000902077653002202086653002502108653002802133653001102161653004002172653001102212653001102223653000902234653001602243653002402259653003002283653001402313653003102327653002002358653001702378653001602395653001702411653001802428653001602446100001902462700001702481700001502498700001702513700001702530700001702547700001602564700001702580700001702597700002502614700001502639700001402654700001602668700002102684700001902705700001502724700001702739700001702756700001602773700002202789700002002811700002302831700002102854700001302875700001502888700001402903700001702917700001702934700001502951700001902966700001402985700001802999700001703017700001703034700001603051700001703067710003903084856003603123 2014 eng d a2047-488100aDevelopment and validation of an ankle brachial index risk model for the prediction of cardiovascular events.0 aDevelopment and validation of an ankle brachial index risk model c2014 Mar a310-200 v213 aBACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS.
DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events.
METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events.
RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women.
CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.
10aAdult10aAged10aAged, 80 and over10aAnkle Brachial Index10aCardiovascular Diseases10aEurope10aEuropean Continental Ancestry Group10aFemale10aHumans10aMale10aMiddle Aged10aModels, Statistical10aPredictive Value of Tests10aPrognosis10aReproducibility of Results10aRisk Assessment10aRisk Factors10aSex Factors10aTime Factors10aUnited States10aYoung Adult1 aFowkes, F, G R1 aMurray, G, D1 aButcher, I1 aFolsom, A, R1 aHirsch, A, T1 aCouper, D, J1 adeBacker, G1 aKornitzer, M1 aNewman, A, B1 aSutton-Tyrrell, K, C1 aCushman, M1 aLee, A, J1 aPrice, J, F1 aD'Agostino, R, B1 aMurabito, J, M1 aNorman, Pe1 aMasaki, K, H1 aBouter, L, M1 aHeine, R, J1 aStehouwer, C, D A1 aMcDermott, M, M1 aStoffers, H, E J H1 aKnottnerus, J, A1 aOgren, M1 aHedblad, B1 aKoenig, W1 aMeisinger, C1 aCauley, J, A1 aFranco, Oh1 aHunink, M, G M1 aHofman, A1 aWitteman, J C1 aCriqui, M, H1 aLanger, R, D1 aHiatt, W, R1 aHamman, R, F1 aAnkle Brachial Index Collaboration uhttps://chs-nhlbi.org/node/680303835nas a2200949 4500008004100000022001400041245012900055210006900184260001300253300000900266490000700275520126900282653002401551653002801575653005201603653002401655653004001679653003301719653003401752653001101786653001801797653002101815653001801836653002101854653003601875653003401911100001601945700001801961700001601979700001601995700001302011700001802024700001802042700001902060700002102079700001902100700001902119700001602138700001202154700001702166700001602183700001602199700001802215700001502233700001402248700001502262700001402277700001702291700001302308700001502321700001802336700002002354700001702374700001102391700001002402700002102412700001902433700001902452700001602471700001702487700001502504700001202519700002202531700001602553700001502569700001402584700002002598700001902618700001502637700001902652700001602671700001802687700001602705700001502721700002202736700001702758700002302775700001802798700001802816700001502834856003602849 2014 eng d a1473-115000aDrug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.0 aDruggene interactions and the search for missing heritability a c2014 Feb a6-130 v143 aVariability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
10aComputer Simulation10aCross-Sectional Studies10aDrug-Related Side Effects and Adverse Reactions10aElectrocardiography10aEuropean Continental Ancestry Group10aGene-Environment Interaction10aGenome-Wide Association Study10aHumans10aLinear Models10aLong QT Syndrome10aMarkov Chains10aPharmacogenetics10aPolymorphism, Single Nucleotide10aQuantitative Trait, Heritable1 aAvery, C, L1 aSitlani, C, M1 aArking, D E1 aArnett, D K1 aBis, J C1 aBoerwinkle, E1 aBuckley, B, M1 aChen, Y-D, Ida1 ade Craen, A, J M1 aEijgelsheim, M1 aEnquobahrie, D1 aEvans, D, S1 aFord, I1 aGarcia, M, E1 aGudnason, V1 aHarris, T B1 aHeckbert, S R1 aHochner, H1 aHofman, A1 aHsueh, W-C1 aIsaacs, A1 aJukema, J, W1 aKnekt, P1 aKors, J, A1 aKrijthe, B, P1 aKristiansson, K1 aLaaksonen, M1 aLiu, Y1 aLi, X1 aMacfarlane, P, W1 aNewton-Cheh, C1 aNieminen, M, S1 aOostra, B A1 aPeloso, G, M1 aPorthan, K1 aRice, K1 aRivadeneira, F, F1 aRotter, J I1 aSalomaa, V1 aSattar, N1 aSiscovick, D, S1 aSlagboom, P, E1 aSmith, A V1 aSotoodehnia, N1 aStott, D, J1 aStricker, B H1 aStürmer, T1 aTrompet, S1 aUitterlinden, A G1 avan Duijn, C1 aWestendorp, R, G J1 aWitteman, J C1 aWhitsel, E, A1 aPsaty, B M uhttps://chs-nhlbi.org/node/597803225nas a2200541 4500008004100000022001400041245009000055210006900145260001300214300001100227490000700238520164600245653001901891653001901910653001101929653003201940653001701972653003801989653002202027653001102049653001702060653001102077653003602088653000902124653001102133100002202144700001802166700002702184700002302211700002102234700002002255700002002275700001902295700001902314700002002333700002002353700002102373700002502394700002302419700002202442700002602464700002802490700002502518700002102543700001902564710006402583856003602647 2014 eng d a1524-462800aEffect of genetic variants associated with plasma homocysteine levels on stroke risk.0 aEffect of genetic variants associated with plasma homocysteine l c2014 Jul a1920-40 v453 aBACKGROUND AND PURPOSE: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.
METHODS: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.
RESULTS: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.
CONCLUSIONS: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.
10aBrain Ischemia10aCohort Studies10aEurope10aGenetic Association Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome10aHomocysteine10aHumans10aPolymorphism, Single Nucleotide10aRisk10aStroke1 aCotlarciuc, Ioana1 aMalik, Rainer1 aHolliday, Elizabeth, G1 aAhmadi, Kourosh, R1 aParé, Guillaume1 aPsaty, Bruce, M1 aFornage, Myriam1 aHasan, Nazeeha1 aRinne, Paul, E1 aIkram, Arfan, M1 aMarkus, Hugh, S1 aRosand, Jonathan1 aMitchell, Braxton, D1 aKittner, Steven, J1 aMeschia, James, F1 avan Meurs, Joyce, B J1 aUitterlinden, André, G1 aWorrall, Bradford, B1 aDichgans, Martin1 aSharma, Pankaj1 aMETASTROKE and the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/655603970nas a2200877 4500008004100000022001400041245011500055210006900170260001600239300001000255490000700265520145800272653001901730653003401749653001101783653002501794653001401819653003601833653002801869100002201897700002301919700002201942700001701964700002201981700001902003700001702022700002102039700001802060700001502078700001702093700001902110700002002129700002702149700002302176700001802199700002402217700001702241700002002258700002702278700002902305700002202334700001602356700002202372700001502394700002202409700001302431700002002444700002402464700002302488700002202511700001902533700001202552700002102564700002202585700001402607700002102621700002402642700001302666700002802679700002602707700001902733700002302752700002102775700001402796700003002810700002402840700002402864700001902888700002002907700002002927700001702947700002002964700002602984710004603010856003603056 2014 eng d a1537-660500aEffects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations.0 aEffects of longterm averaging of quantitative blood pressure tra c2014 Jul 03 a49-650 v953 aBlood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.
10aBlood Pressure10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aGanesh, Santhi, K1 aChasman, Daniel, I1 aLarson, Martin, G1 aGuo, Xiuqing1 aVerwoert, Germain1 aBis, Joshua, C1 aGu, Xiangjun1 aSmith, Albert, V1 aYang, Min-Lee1 aZhang, Yan1 aEhret, Georg1 aRose, Lynda, M1 aHwang, Shih-Jen1 aPapanicolau, George, J1 aSijbrands, Eric, J1 aRice, Kenneth1 aEiriksdottir, Gudny1 aPihur, Vasyl1 aRidker, Paul, M1 aVasan, Ramachandran, S1 aNewton-Cheh, Christopher1 aRaffel, Leslie, J1 aAmin, Najaf1 aRotter, Jerome, I1 aLiu, Kiang1 aLauner, Lenore, J1 aXu, Ming1 aCaulfield, Mark1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aVaidya, Dhananjay1 aDehghan, Abbas1 aLi, Guo1 aBouchard, Claude1 aHarris, Tamara, B1 aZhang, He1 aBoerwinkle, Eric1 aSiscovick, David, S1 aGao, Wei1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aHofman, Albert1 aWiller, Cristen, J1 aFranco, Oscar, H1 aHuo, Yong1 aWitteman, Jacqueline, C M1 aMunroe, Patricia, B1 aGudnason, Vilmundur1 aPalmas, Walter1 aDuijn, Cornelia1 aFornage, Myriam1 aLevy, Daniel1 aPsaty, Bruce, M1 aChakravarti, Aravinda1 aGlobal Blood Pressure Genetics Consortium uhttps://chs-nhlbi.org/node/656303296nas a2200565 4500008004100000022001400041245008800055210006900143260001300212300001000225490000700235520169900242653000901941653003401950653002401984653001102008653003802019653001502057653001102072653002102083653000902104653001602113653001402129653003602143653002802179653003402207653001702241100002302258700002102281700002002302700002302322700002302345700001202368700001902380700001702399700002302416700002302439700002402462700002002486700001902506700002002525700002002545700002402565700002102589700001902610700001902629700002402648700002202672856003602694 2014 eng d a1531-548700aEvidence of heterogeneity by race/ethnicity in genetic determinants of QT interval.0 aEvidence of heterogeneity by raceethnicity in genetic determinan c2014 Nov a790-80 v253 aBACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.
METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.
RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.
CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.
10aAged10aContinental Population Groups10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aLong QT Syndrome10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRisk Factors1 aSeyerle, Amanda, A1 aYoung, Alicia, M1 aJeff, Janina, M1 aMelton, Phillip, E1 aJorgensen, Neal, W1 aLin, Yi1 aCarty, Cara, L1 aDeelman, Ewa1 aHeckbert, Susan, R1 aHindorff, Lucia, A1 aJackson, Rebecca, D1 aMartin, Lisa, W1 aOkin, Peter, M1 aPerez, Marco, V1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aWhitsel, Eric, A1 aNorth, Kari, E1 aLaston, Sandra1 aKooperberg, Charles1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/659803997nas a2200457 4500008004100000022001400041245009600055210006900151260000900220300001100229490000700240520273700247653001002984653002202994653001603016653000903032653003003041653004003071653001103111653001103122653001703133653003103150653000903181653001603190653001503206653001703221653001703238100002103255700002103276700002303297700001903320700001803339700002103357700002403378700001803402700002103420700002103441700001903462700002203481856003603503 2014 eng d a1421-978600aExtreme deep white matter hyperintensity volumes are associated with African American race.0 aExtreme deep white matter hyperintensity volumes are associated c2014 a244-500 v373 aBACKGROUND: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors.
METHODS: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl.
RESULTS: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26).
CONCLUSIONS: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population.
10aAdult10aAfrican Americans10aAge Factors10aAged10aCerebrovascular Disorders10aEuropean Continental Ancestry Group10aFemale10aHumans10aHypertension10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPrevalence10aRisk Factors10aWhite Matter1 aNyquist, Paul, A1 aBilgel, Murat, S1 aGottesman, Rebecca1 aYanek, Lisa, R1 aMoy, Taryn, F1 aBecker, Lewis, C1 aCuzzocreo, Jennifer1 aPrince, Jerry1 aYousem, David, M1 aBecker, Diane, M1 aKral, Brian, G1 aVaidya, Dhananjay uhttps://chs-nhlbi.org/node/658603407nas a2200553 4500008004100000022001400041245015800055210006900213260001600282300001200298490000800310520176800318653000902086653002202095653002402117653001602141653001802157653001102175653003102186653002202217653003102239653001802270653001102288653003402299653000902333653001602342653001502358653003202373653003302405653001702438653001802455653003402473653002702507653001402534100002002548700002202568700001602590700002302606700002302629700002502652700001902677700002102696700001502717700001902732700002402751700002202775700002002797856003602817 2014 eng d a1524-453900aFibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS).0 aFibroblast growth factor23 and incident atrial fibrillation the c2014 Jul 22 a298-3070 v1303 aBACKGROUND: Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction.
METHODS AND RESULTS: We tested the associations of circulating FGF-23 concentration with incident AF among 6398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over a median of 7.7 and 8.0 years of follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each 2-fold-higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (hazard ratio, 1.41; 95% confidence interval, 1.13-1.76; P=0.003) and a 30% higher risk of incident AF in CHS (hazard ratio, 1.30; 95% confidence interval, 1.05-1.61; P=0.016) after adjustment for potential confounding characteristics, including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (hazard ratio, 1.15 per 0.5 mg/dL; 95% confidence interval, 1.02-1.31; P=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjustment for FGF-23.
CONCLUSION: Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aComorbidity10aEthnic Groups10aFemale10aFibroblast Growth Factor 310aFollow-Up Studies10aGlomerular Filtration Rate10aHeart Failure10aHumans10aHypertrophy, Left Ventricular10aMale10aMiddle Aged10aPhosphates10aProportional Hazards Models10aRenal Insufficiency, Chronic10aRisk Factors10aUnited States10aVentricular Dysfunction, Left10aVentricular Remodeling10aVitamin D1 aMathew, Jehu, S1 aSachs, Michael, C1 aKatz, Ronit1 aPatton, Kristen, K1 aHeckbert, Susan, R1 aHoofnagle, Andrew, N1 aAlonso, Alvaro1 aChonchol, Michel1 aDeo, Rajat1 aIx, Joachim, H1 aSiscovick, David, S1 aKestenbaum, Bryan1 ade Boer, Ian, H uhttps://chs-nhlbi.org/node/639906392nas a2201669 4500008004100000022001400041245009700055210006900152260001600221300001200237490000700249520182200256653001002078653002202088653000902110653001202119653003702131653002002168653002602188653001702214653002102231653001802252653004002270653001102310653001902321653001102340653000902351653001602360653001202376653003602388653001302424100001402437700002802451700002002479700002002499700002002519700001902539700002102558700001902579700002002598700001802618700002302636700001802659700001802677700001602695700002402711700001202735700003202747700002302779700001502802700001902817700002002836700001902856700002502875700001702900700002302917700002202940700002302962700002202985700001503007700002503022700002703047700002003074700002203094700002403116700001203140700002103152700002103173700002103194700002503215700001903240700002003259700001903279700002603298700002103324700001703345700002403362700001703386700002303403700002103426700001603447700001803463700002503481700002003506700002003526700002103546700001903567700002303586700001903609700002403628700002303652700002203675700001803697700001803715700002303733700001703756700001203773700001703785700002003802700001703822700001903839700002503858700001603883700001903899700002003918700002003938700002303958700002203981700002804003700002504031700002104056700001604077700001804093700002404111700001504135700002904150700002404179700002504203700003004228700001504258700002004273700001704293700001804310700002204328700002004350700002304370700002104393700002104414700002004435700002504455700002004480700002504500700001404525700002304539700002004562700002904582700001704611700002004628700002704648700001104675856003604686 2014 eng d a1460-208300aFTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.0 aFTO genetic variants dietary intake and body mass index insights c2014 Dec 20 a6961-720 v233 aFTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
10aAdult10aAfrican Americans10aAged10aAlleles10aAsian Continental Ancestry Group10aBody Mass Index10aDietary Carbohydrates10aDietary Fats10aDietary Proteins10aEnergy Intake10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aHumans10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins1 aQi, Qibin1 aKilpeläinen, Tuomas, O1 aDowner, Mary, K1 aTanaka, Toshiko1 aSmith, Caren, E1 aSluijs, Ivonne1 aSonestedt, Emily1 aChu, Audrey, Y1 aRenstrom, Frida1 aLin, Xiaochen1 aÄngquist, Lars, H1 aHuang, Jinyan1 aLiu, Zhonghua1 aLi, Yanping1 aAli, Muhammad, Asif1 aXu, Min1 aAhluwalia, Tarunveer, Singh1 aBoer, Jolanda, M A1 aChen, Peng1 aDaimon, Makoto1 aEriksson, Johan1 aPerola, Markus1 aFriedlander, Yechiel1 aGao, Yu-Tang1 aHeppe, Denise, H M1 aHolloway, John, W1 aHouston, Denise, K1 aKanoni, Stavroula1 aKim, Yu-Mi1 aLaaksonen, Maarit, A1 aJääskeläinen, Tiina1 aLee, Nanette, R1 aLehtimäki, Terho1 aLemaitre, Rozenn, N1 aLu, Wei1 aLuben, Robert, N1 aManichaikul, Ani1 aMännistö, Satu1 aMarques-Vidal, Pedro1 aMonda, Keri, L1 aNgwa, Julius, S1 aPerusse, Louis1 avan Rooij, Frank, J A1 aXiang, Yong-Bing1 aWen, Wanqing1 aWojczynski, Mary, K1 aZhu, Jingwen1 aBorecki, Ingrid, B1 aBouchard, Claude1 aCai, Qiuyin1 aCooper, Cyrus1 aDedoussis, George, V1 aDeloukas, Panos1 aFerrucci, Luigi1 aForouhi, Nita, G1 aHansen, Torben1 aChristiansen, Lene1 aHofman, Albert1 aJohansson, Ingegerd1 aJørgensen, Torben1 aKarasawa, Shigeru1 aKhaw, Kay-Tee1 aKim, Mi-Kyung1 aKristiansson, Kati1 aLi, Huaixing1 aLin, Xu1 aLiu, Yongmei1 aLohman, Kurt, K1 aLong, Jirong1 aMikkilä, Vera1 aMozaffarian, Dariush1 aNorth, Kari1 aPedersen, Oluf1 aRaitakari, Olli1 aRissanen, Harri1 aTuomilehto, Jaakko1 aSchouw, Yvonne, T1 aUitterlinden, André, G1 aZillikens, Carola, M1 aFranco, Oscar, H1 aTai, Shyong1 aShu, Xiao, Ou1 aSiscovick, David, S1 aToft, Ulla1 aVerschuren, W, M Monique1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWitteman, Jacqueline, C M1 aZheng, Wei1 aRidker, Paul, M1 aKang, Jae, H1 aLiang, Liming1 aJensen, Majken, K1 aCurhan, Gary, C1 aPasquale, Louis, R1 aHunter, David, J1 aMohlke, Karen, L1 aUusitupa, Matti1 aCupples, Adrienne, L1 aRankinen, Tuomo1 aOrho-Melander, Marju1 aWang, Tao1 aChasman, Daniel, I1 aFranks, Paul, W1 aSørensen, Thorkild, I A1 aHu, Frank, B1 aLoos, Ruth, J F1 aNettleton, Jennifer, A1 aQi, Lu uhttps://chs-nhlbi.org/node/693804052nas a2200913 4500008004100000022001400041245006900055210006600124260001300190300001000203490000700213520168500220653001001905653000901915653002201924653001001946653001101956653001101967653000901978653001601987653001602003653001302019100002102032700001602053700001702069700001902086700001902105700002102124700002402145700001702169700002202186700002702208700001902235700002002254700002602274700001402300700001802314700002302332700001802355700001502373700001502388700002002403700002502423700001702448700002902465700001802494700002002512700001802532700001902550700001902569700002102588700002002609700001802629700001802647700002102665700001902686700001902705700002402724700002302748700001202771700001902783700002002802700001602822700002102838700001702859700001702876700001602893700001502909700001402924700001502938700002802953700002002981700001603001700001503017700002603032700002103058710002303079856003603102 2014 eng d a1873-681500aGender and telomere length: systematic review and meta-analysis.0 aGender and telomere length systematic review and metaanalysis c2014 Mar a15-270 v513 aBACKGROUND: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.
METHODS: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.
RESULTS: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error.
CONCLUSIONS: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.
10aAdult10aAged10aAged, 80 and over10aAging10aFemale10aHumans10aMale10aMiddle Aged10aSex Factors10aTelomere1 aGardner, Michael1 aBann, David1 aWiley, Laura1 aCooper, Rachel1 aHardy, Rebecca1 aNitsch, Dorothea1 aMartin-Ruiz, Carmen1 aShiels, Paul1 aSayer, Avan Aihie1 aBarbieri, Michelangela1 aBekaert, Sofie1 aBischoff, Claus1 aBrooks-Wilson, Angela1 aChen, Wei1 aCooper, Cyrus1 aChristensen, Kaare1 aDe Meyer, Tim1 aDeary, Ian1 aDer, Geoff1 aRoux, Ana, Diez1 aFitzpatrick, Annette1 aHajat, Anjum1 aHalaschek-Wiener, Julius1 aHarris, Sarah1 aHunt, Steven, C1 aJagger, Carol1 aJeon, Hyo-Sung1 aKaplan, Robert1 aKimura, Masayuki1 aLansdorp, Peter1 aLi, Changyong1 aMaeda, Toyoki1 aMangino, Massimo1 aNawrot, Tim, S1 aNilsson, Peter1 aNordfjall, Katarina1 aPaolisso, Giuseppe1 aRen, Fu1 aRiabowol, Karl1 aRobertson, Tony1 aRoos, Goran1 aStaessen, Jan, A1 aSpector, Tim1 aTang, Nelson1 aUnryn, Brad1 aHarst, Pim1 aWoo, Jean1 aXing, Chao1 aYadegarfar, Mohammad, E1 aPark, Jae, Yong1 aYoung, Neal1 aKuh, Diana1 avon Zglinicki, Thomas1 aBen-Shlomo, Yoav1 aHalcyon study team uhttps://chs-nhlbi.org/node/624602046nas a2200229 4500008004100000022001400041245009800055210006900153260000900222300001000231490000600241520135400247100002401601700002301625700002301648700002201671700002201693700001801715700002001733700002701753856003601780 2014 eng d a1948-175600aGene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes.0 aGene expression in thiazide diuretic or statin users in relation c2014 a22-300 v53 aThiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value<0.05. Among thiazide users, diabetes cases had significantly different expression of CCL14 (down-regulated 6%, Q-value=0.0257), compared with controls. Among statin users, diabetes cases had marginal but insignificantly different expression of ZNF532 (up-regulated 15%, Q-value=0.0584), CXORF21 (up-regulated 11%, Q-value=0.0584), and ZNHIT3 (up-regulated 19%, Q-value=0.0959), compared with controls. These genes comprise potential targets for future expression or mechanistic research on medication-related diabetes development.1 aSuchy-Dicey, Astrid1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aMcKnight, Barbara1 aRotter, Jerome, I1 aChen, Yd, Ida1 aPsaty, Bruce, M1 aEnquobahrie, Daniel, A uhttps://chs-nhlbi.org/node/660305870nas a2201489 4500008004100000022001400041245013500055210006900190260001600259300001000275490000700285520175700292653001502049653001002064653001602074653000902090653001902099653001902118653001102137653001602148653001602164100002202180700001402202700001902216700002302235700002002258700001702278700001702295700002002312700002002332700002102352700002602373700003102399700001702430700001502447700002002462700001802482700002302500700001502523700001802538700002202556700002602578700001802604700002802622700001902650700001702669700001702686700002702703700001802730700001902748700001602767700002102783700002102804700001902825700002402844700002002868700002102888700002202909700002202931700002002953700001902973700001902992700002303011700002003034700001803054700002103072700002203093700002203115700001203137700001703149700001503166700002403181700001803205700002303223700002703246700002303273700002003296700002203316700002303338700001803361700002603379700001903405700001803424700002103442700002403463700002103487700002803508700002203536700003003558700002703588700003203615700001703647700001903664700001803683700002003701700001403721700002103735700002003756700002603776700001603802700002303818700002203841700002003863700001703883700002003900700002003920700001903940700002003959700001903979700001803998700001504016700002504031700002004056700002004076700002004096700002404116700001704140700001904157700002004176700002204196700002304218700003004241700002604271700002004297710002704317856003604344 2014 eng d a1537-660500aGene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.0 aGeneage interactions in blood pressure regulation a largescale i c2014 Jul 03 a24-380 v953 aAlthough age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.
10aAdolescent10aAdult10aAge Factors10aAged10aBlood Pressure10aCohort Studies10aHumans10aMiddle Aged10aYoung Adult1 aSimino, Jeannette1 aShi, Gang1 aBis, Joshua, C1 aChasman, Daniel, I1 aEhret, Georg, B1 aGu, Xiangjun1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aSijbrands, Eric1 aSmith, Albert, V1 aVerwoert, Germaine, C1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aChen, Peng1 aCheng, Ching-Yu1 aCorre, Tanguy1 ade Boer, Rudolf, A1 aGoel, Anuj1 aJohnson, Toby1 aKhor, Chiea-Chuen1 aLluís-Ganella, Carla1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aSim, Xueling1 aSõber, Siim1 avan der Most, Peter, J1 aVerweij, Niek1 aZhao, Jing Hua1 aAmin, Najaf1 aBoerwinkle, Eric1 aBouchard, Claude1 aDehghan, Abbas1 aEiriksdottir, Gudny1 aElosua, Roberto1 aFranco, Oscar, H1 aGieger, Christian1 aHarris, Tamara, B1 aHercberg, Serge1 aHofman, Albert1 aJames, Alan, L1 aJohnson, Andrew, D1 aKähönen, Mika1 aKhaw, Kay-Tee1 aKutalik, Zoltán1 aLarson, Martin, G1 aLauner, Lenore, J1 aLi, Guo1 aLiu, Jianjun1 aLiu, Kiang1 aMorrison, Alanna, C1 aNavis, Gerjan1 aOng, Rick Twee-Hee1 aPapanicolau, George, J1 aPenninx, Brenda, W1 aPsaty, Bruce, M1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRice, Kenneth1 aRivadeneira, Fernando1 aRose, Lynda, M1 aSanna, Serena1 aScott, Robert, A1 aSiscovick, David, S1 aStolk, Ronald, P1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Klauw, Melanie, M1 aVasan, Ramachandran, S1 aVithana, Eranga, Nishanthie1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Hugh1 aYoung, Terri, L1 aAung, Tin1 aBochud, Murielle1 aFarrall, Martin1 aHartman, Catharina, A1 aLaan, Maris1 aLakatta, Edward, G1 aLehtimäki, Terho1 aLoos, Ruth, J F1 aLucas, Gavin1 aMeneton, Pierre1 aPalmer, Lyle, J1 aRettig, Rainer1 aSnieder, Harold1 aTai, Shyong, E1 aTeo, Yik-Ying1 aHarst, Pim1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aWong, Tien, Yin1 aFornage, Myriam1 aGudnason, Vilmundur1 aLevy, Daniel1 aPalmas, Walter1 aRidker, Paul, M1 aRotter, Jerome, I1 aDuijn, Cornelia, M1 aWitteman, Jacqueline, C M1 aChakravarti, Aravinda1 aRao, Dabeeru, C1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/659905300nas a2201225 4500008004100000022001400041245016600055210006900221260001600290300001300306490000700319520181200326653001402138653001002152653000902162653002202171653002002193653004002213653001102253653003402264653001102298653000902309653001602318653002402334653002002358653001602378100002202394700001502416700002502431700002302456700002102479700002602500700002502526700002102551700001802572700002302590700002402613700002302637700001902660700001602679700001402695700002902709700001802738700002202756700001402778700002002792700002302812700001802835700002402853700002302877700001902900700003102919700002702950700002602977700001803003700001603021700002003037700002203057700001803079700001603097700001903113700002103132700002103153700002903174700002003203700002103223700002403244700002203268700001503290700002203305700002303327700001803350700002203368700002003390700002103410700002403431700002203455700001903477700002503496700002103521700002103542700002503563700001903588700002103607700002203628700002403650700002203674700001903696700002303715700002103738700002003759700001703779700002203796700002103818700002303839700002103862700001903883700002003902700002103922700002003943710003003963710002103993710002404014856003604038 2014 eng d a1460-208300aGene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.0 aGenecentric metaanalyses for central adiposity traits in up to 5 c2014 May 01 a2498-5100 v233 aWaist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
10aAdiposity10aAdult10aAged10aAged, 80 and over10aBody Mass Index10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aWaist Circumference10aWaist-Hip Ratio10aYoung Adult1 aYoneyama, Sachiko1 aGuo, Yiran1 aLanktree, Matthew, B1 aBarnes, Michael, R1 aElbers, Clara, C1 aKarczewski, Konrad, J1 aPadmanabhan, Sandosh1 aBauer, Florianne1 aBaumert, Jens1 aBeitelshees, Amber1 aBerenson, Gerald, S1 aBoer, Jolanda, M A1 aBurke, Gregory1 aCade, Brian1 aChen, Wei1 aCooper-Dehoff, Rhonda, M1 aGaunt, Tom, R1 aGieger, Christian1 aGong, Yan1 aGorski, Mathias1 aHeard-Costa, Nancy1 aJohnson, Toby1 aLamonte, Michael, J1 aMcDonough, Caitrin1 aMonda, Keri, L1 aOnland-Moret, Charlotte, N1 aNelson, Christopher, P1 aO'Connell, Jeffrey, R1 aOrdovas, Jose1 aPeter, Inga1 aPeters, Annette1 aShaffer, Jonathan1 aShen, Haiqinq1 aSmith, Erin1 aSpeilotes, Liz1 aThomas, Fridtjof1 aThorand, Barbara1 aVerschuren, W, M Monique1 aAnand, Sonia, S1 aDominiczak, Anna1 aDavidson, Karina, W1 aHegele, Robert, A1 aHeid, Iris1 aHofker, Marten, H1 aHuggins, Gordon, S1 aIllig, Thomas1 aJohnson, Julie, A1 aKirkland, Susan1 aKönig, Wolfgang1 aLangaee, Taimour, Y1 aMcCaffery, Jeanne1 aMelander, Olle1 aMitchell, Braxton, D1 aMunroe, Patricia1 aMurray, Sarah, S1 aPapanicolaou, George1 aRedline, Susan1 aReilly, Muredach1 aSamani, Nilesh, J1 aSchork, Nicholas, J1 aSchouw, Yvonne, T1 aShimbo, Daichi1 aShuldiner, Alan, R1 aTobin, Martin, D1 aWijmenga, Cisca1 aYusuf, Salim1 aHakonarson, Hakon1 aLange, Leslie, A1 aDemerath, Ellen, W1 aFox, Caroline, S1 aNorth, Kari, E1 aReiner, Alex, P1 aKeating, Brendan1 aTaylor, Kira, C1 aLook AHEAD Research Group1 aGIANT Consortium1 aCARe IBC Consortium uhttps://chs-nhlbi.org/node/636803165nas a2200505 4500008004100000022001400041245011400055210006900169260001300238300001000251490000800261520171800269653001001987653000901997653002802006653001802034653001302052653001102065653004302076653001502119653003202134653001302166653001102179653000902190653001602199653004402215653003602259653001602295100001802311700001802329700002102347700002302368700001902391700003002410700001702440700002502457700002302482700002202505700002302527700001802550700001602568700002102584700001802605856003602623 2014 eng d a1879-247200aA genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups.0 agenetic association study of Ddimer levels with 50K SNPs from a c2014 Aug a462-70 v1343 aINTRODUCTION: D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.
MATERIALS AND METHODS: We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.
RESULTS: Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p<2.0×10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p=0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p=0.006). No additional SNPs were significantly associated with D-dimer.
CONCLUSIONS: Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.
10aAdult10aAged10aCardiovascular Diseases10aEthnic Groups10aFactor V10aFemale10aFibrin Fibrinogen Degradation Products10aFibrinogen10aGenetic Association Studies10aGenotype10aHumans10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aPolymorphism, Single Nucleotide10aYoung Adult1 aWeng, Lu-Chen1 aTang, Weihong1 aRich, Stephen, S1 aSmith, Nicholas, L1 aRedline, Susan1 aO'Donnell, Christopher, J1 aBasu, Saonli1 aReiner, Alexander, P1 aDelaney, Joseph, A1 aTracy, Russell, P1 aPalmer, Cameron, D1 aYoung, Taylor1 aYang, Qiong1 aFolsom, Aaron, R1 aCushman, Mary uhttps://chs-nhlbi.org/node/661110059nas a2203157 4500008004100000022001400041245012200055210006900177260001300246300001100259490000700270520116100277653001001438653000901448653002501457653002201482653002701504653002401531653001101555653003801566653003401604653001301638653002101651653001101672653002101683653000901704653001601713653001501729653003601744100001901780700001901799700001601818700001501834700002401849700002401873700002201897700002501919700002001944700001801964700002301982700001902005700002802024700002502052700002202077700001902099700002302118700001802141700003002159700002502189700001902214700002602233700001902259700001802278700002502296700002102321700001902342700001902361700002802380700002102408700001802429700002202447700002202469700001702491700001802508700002002526700002102546700002302567700002302590700001802613700002302631700002002654700002502674700002302699700002302722700002602745700001802771700002202789700002502811700002302836700002502859700002102884700002202905700002202927700002302949700001902972700001902991700001703010700002003027700002003047700002103067700002503088700001803113700002303131700002203154700002403176700002003200700001803220700002203238700003903260700001703299700002103316700002203337700002303359700002003382700002203402700001803424700001903442700002003461700001903481700001803500700002003518700001603538700002803554700002103582700001803603700002303621700002003644700002103664700002203685700003003707700001703737700001703754700002203771700002103793700002403814700002103838700002403859700002203883700001603905700002203921700002203943700002103965700001903986700001904005700001904024700001804043700002404061700001904085700002304104700002204127700002004149700001904169700002204188700002204210700002004232700002004252700001804272700002204290700002604312700002304338700001704361700003104378700002704409700001804436700002404454700001804478700002304496700002004519700002704539700002404566700003004590700001704620700002004637700002004657700001904677700002104696700002404717700002404741700002504765700002304790700002604813700002604839700002704865700002604892700001604918700002204934700002004956700001904976700002504995700001805020700002705038700002405065700001805089700002905107700002805136700002005164700002205184700002105206700001905227700001705246700002805263700003005291700002205321700002005343700001905363700002505382700002305407700002105430700001705451700002405468700001705492700002605509700001705535700002005552700002405572700001905596700001505615700002205630700002805652700001905680700002005699700001805719700002305737700002205760700001905782700001905801700001705820700002605837700002405863700002305887700002405910700002005934700002205954700002405976700002506000700002306025700002006048700002006068700002106088700002106109700001606130700001806146700002606164700002606190700002506216700002406241700001806265700001706283700002306300700002406323700002406347700002006371700002006391700002206411700001806433700002406451700002306475700002106498700002106519700002306540700002106563700001706584700002306601700001906624700002606643700002506669700001806694700002506712700002906737710002006766710002206786710001406808710002206822710002106844856003606865 2014 eng d a1546-171800aGenetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.0 aGenetic association study of QT interval highlights role for cal c2014 Aug a826-360 v463 aThe QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
10aAdult10aAged10aArrhythmias, Cardiac10aCalcium Signaling10aDeath, Sudden, Cardiac10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHeart Ventricles10aHumans10aLong QT Syndrome10aMale10aMiddle Aged10aMyocardium10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aPulit, Sara, L1 aCrotti, Lia1 aHarst, Pim1 aMunroe, Patricia, B1 aKoopmann, Tamara, T1 aSotoodehnia, Nona1 aRossin, Elizabeth, J1 aMorley, Michael1 aWang, Xinchen1 aJohnson, Andrew, D1 aLundby, Alicia1 aGudbjartsson, Daniel, F1 aNoseworthy, Peter, A1 aEijgelsheim, Mark1 aBradford, Yuki1 aTarasov, Kirill, V1 aDörr, Marcus1 aMüller-Nurasyid, Martina1 aLahtinen, Annukka, M1 aNolte, Ilja, M1 aSmith, Albert, Vernon1 aBis, Joshua, C1 aIsaacs, Aaron1 aNewhouse, Stephen, J1 aEvans, Daniel, S1 aPost, Wendy, S1 aWaggott, Daryl1 aLyytikäinen, Leo-Pekka1 aHicks, Andrew, A1 aEisele, Lewin1 aEllinghaus, David1 aHayward, Caroline1 aNavarro, Pau1 aUlivi, Sheila1 aTanaka, Toshiko1 aTester, David, J1 aChatel, Stéphanie1 aGustafsson, Stefan1 aKumari, Meena1 aMorris, Richard, W1 aNaluai, Åsa, T1 aPadmanabhan, Sandosh1 aKluttig, Alexander1 aStrohmer, Bernhard1 aPanayiotou, Andrie, G1 aTorres, Maria1 aKnoflach, Michael1 aHubacek, Jaroslav, A1 aSlowikowski, Kamil1 aRaychaudhuri, Soumya1 aKumar, Runjun, D1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShuldiner, Alan, R1 aAlonso, Alvaro1 aBader, Joel, S1 aEhret, Georg1 aHuang, Hailiang1 aKao, Linda, W H1 aStrait, James, B1 aMacfarlane, Peter, W1 aBrown, Morris1 aCaulfield, Mark, J1 aSamani, Nilesh, J1 aKronenberg, Florian1 aWilleit, Johann1 aSmith, Gustav1 aGreiser, Karin, H1 aSchwabedissen, Henriette, Meyer Zu1 aWerdan, Karl1 aCarella, Massimo1 aZelante, Leopoldo1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aKolcic, Ivana1 aPolasek, Ozren1 aWright, Alan, F1 aGriffin, Maura1 aDaly, Mark, J1 aArnar, David, O1 aHolm, Hilma1 aThorsteinsdottir, Unnur1 aDenny, Joshua, C1 aRoden, Dan, M1 aZuvich, Rebecca, L1 aEmilsson, Valur1 aPlump, Andrew, S1 aLarson, Martin, G1 aO'Donnell, Christopher, J1 aYin, Xiaoyan1 aBobbo, Marco1 aD'Adamo, Adamo, P1 aIorio, Annamaria1 aSinagra, Gianfranco1 aCarracedo, Angel1 aCummings, Steven, R1 aNalls, Michael, A1 aJula, Antti1 aKontula, Kimmo, K1 aMarjamaa, Annukka1 aOikarinen, Lasse1 aPerola, Markus1 aPorthan, Kimmo1 aErbel, Raimund1 aHoffmann, Per1 aJöckel, Karl-Heinz1 aKälsch, Hagen1 aNöthen, Markus, M1 aHoed, Marcel, den1 aLoos, Ruth, J F1 aThelle, Dag, S1 aGieger, Christian1 aMeitinger, Thomas1 aPerz, Siegfried1 aPeters, Annette1 aPrucha, Hanna1 aSinner, Moritz, F1 aWaldenberger, Melanie1 ade Boer, Rudolf, A1 aFranke, Lude1 avan der Vleuten, Pieter, A1 aBeckmann, Britt, Maria1 aMartens, Eimo1 aBardai, Abdennasser1 aHofman, Nynke1 aWilde, Arthur, A M1 aBehr, Elijah, R1 aDalageorgou, Chrysoula1 aGiudicessi, John, R1 aMedeiros-Domingo, Argelia1 aBarc, Julien1 aKyndt, Florence1 aProbst, Vincent1 aGhidoni, Alice1 aInsolia, Roberto1 aHamilton, Robert, M1 aScherer, Stephen, W1 aBrandimarto, Jeffrey1 aMargulies, Kenneth1 aMoravec, Christine, E1 aM, Fabiola, del Greco1 aFuchsberger, Christian1 aO'Connell, Jeffrey, R1 aLee, Wai, K1 aWatt, Graham, C M1 aCampbell, Harry1 aWild, Sarah, H1 aMokhtari, Nour, E El1 aFrey, Norbert1 aAsselbergs, Folkert, W1 aLeach, Irene, Mateo1 aNavis, Gerjan1 avan den Berg, Maarten, P1 avan Veldhuisen, Dirk, J1 aKellis, Manolis1 aKrijthe, Bouwe, P1 aFranco, Oscar, H1 aHofman, Albert1 aKors, Jan, A1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aKedenko, Lyudmyla1 aLamina, Claudia1 aOostra, Ben, A1 aAbecasis, Goncalo, R1 aLakatta, Edward, G1 aMulas, Antonella1 aOrrù, Marco1 aSchlessinger, David1 aUda, Manuela1 aMarkus, Marcello, R P1 aVölker, Uwe1 aSnieder, Harold1 aSpector, Timothy, D1 aArnlöv, Johan1 aLind, Lars1 aSundström, Johan1 aSyvänen, Ann-Christine1 aKivimaki, Mika1 aKähönen, Mika1 aMononen, Nina1 aRaitakari, Olli, T1 aViikari, Jorma, S1 aAdamkova, Vera1 aKiechl, Stefan1 aBrion, Maria1 aNicolaides, Andrew, N1 aPaulweber, Bernhard1 aHaerting, Johannes1 aDominiczak, Anna, F1 aNyberg, Fredrik1 aWhincup, Peter, H1 aHingorani, Aroon, D1 aSchott, Jean-Jacques1 aBezzina, Connie, R1 aIngelsson, Erik1 aFerrucci, Luigi1 aGasparini, Paolo1 aWilson, James, F1 aRudan, Igor1 aFranke, Andre1 aMühleisen, Thomas, W1 aPramstaller, Peter, P1 aLehtimäki, Terho, J1 aPaterson, Andrew, D1 aParsa, Afshin1 aLiu, Yongmei1 aDuijn, Cornelia, M1 aSiscovick, David, S1 aGudnason, Vilmundur1 aJamshidi, Yalda1 aSalomaa, Veikko1 aFelix, Stephan, B1 aSanna, Serena1 aRitchie, Marylyn, D1 aStricker, Bruno, H1 aStefansson, Kari1 aBoyer, Laurie, A1 aCappola, Thomas, P1 aOlsen, Jesper, V1 aLage, Kasper1 aSchwartz, Peter, J1 aKääb, Stefan1 aChakravarti, Aravinda1 aAckerman, Michael, J1 aPfeufer, Arne1 ade Bakker, Paul, I W1 aNewton-Cheh, Christopher1 aCARe Consortium1 aCOGENT Consortium1 aDCCT/EDIC1 aeMERGE Consortium1 aHRGEN Consortium uhttps://chs-nhlbi.org/node/654403582nas a2200829 4500008004100000022001400041245006100055210006000116260000900176300000800185490000700193520130000200653003401500653001701534653001101551653001401562653003601576653003201612100002501644700002301669700002601692700002401718700001601742700002301758700002001781700001701801700001201818700002401830700002201854700001801876700002101894700002301915700001801938700001801956700002001974700002401994700002402018700002202042700001502064700001902079700002102098700002002119700001702139700002102156700002302177700001402200700002002214700002302234700002202257700001802279700001902297700002402316700002002340700001602360700002702376700002402403700001802427700002102445700001902466700001902485700002402504700002502528700001902553700002502572700001802597700002202615700002202637700001902659700001902678700001902697856003602716 2014 eng d a1471-215600aGenetic diversity is a predictor of mortality in humans.0 aGenetic diversity is a predictor of mortality in humans c2014 a1590 v153 aBACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.
CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
10aGenome-Wide Association Study10aHeterozygote10aHumans10aMortality10aPolymorphism, Single Nucleotide10aProportional Hazards Models1 aBihlmeyer, Nathan, A1 aBrody, Jennifer, A1 aSmith, Albert, Vernon1 aLunetta, Kathryn, L1 aNalls, Mike1 aSmith, Jennifer, A1 aTanaka, Toshiko1 aDavies, Gail1 aYu, Lei1 aMirza, Saira, Saeed1 aTeumer, Alexander1 aCoresh, Josef1 aPankow, James, S1 aFranceschini, Nora1 aScaria, Anish1 aOshima, Junko1 aPsaty, Bruce, M1 aGudnason, Vilmundur1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLi, Hanyue1 aKarasik, David1 aKiel, Douglas, P1 aGarcia, Melissa1 aLiu, Yongmei1 aFaul, Jessica, D1 aKardia, Sharon, Lr1 aZhao, Wei1 aFerrucci, Luigi1 aAllerhand, Michael1 aLiewald, David, C1 aRedmond, Paul1 aStarr, John, M1 aDe Jager, Philip, L1 aEvans, Denis, A1 aDirek, Nese1 aIkram, Mohammed, Arfan1 aUitterlinden, Andre1 aHomuth, Georg1 aLorbeer, Roberto1 aGrabe, Hans, J1 aLauner, Lenore1 aMurabito, Joanne, M1 aSingleton, Andrew, B1 aWeir, David, R1 aBandinelli, Stefania1 aDeary, Ian, J1 aBennett, David, A1 aTiemeier, Henning1 aKocher, Thomas1 aLumley, Thomas1 aArking, Dan, E uhttps://chs-nhlbi.org/node/669002698nas a2200385 4500008004100000022001400041245010500055210006900160260001600229300001100245490000800256520153600264653002201800653000901822653002401831653001601855653001801871653004001889653001101929653003801940653001101978653002501989653000902014653003602023653003202059653001702091100002602108700002202134700002402156700002002180700002302200700002902223700002402252856003602276 2014 eng d a1476-625600aGenetic variants related to height and risk of atrial fibrillation: the cardiovascular health study.0 aGenetic variants related to height and risk of atrial fibrillati c2014 Jul 15 a215-220 v1803 aIncreased height is a known independent risk factor for atrial fibrillation (AF). However, whether genetic determinants of height influence risk is uncertain. In this candidate gene study, we examined the association of 209 height-associated single-nucleotide polymorphisms (SNPs) with incident AF in 3,309 persons of European descent from the Cardiovascular Health Study, a prospective cohort study of older adults (aged ≥ 65 years) enrolled in 1989-1990. After a median follow-up period of 13.2 years, 879 participants developed incident AF. The height-associated SNPs together explained approximately 10% of the variation in height (P = 6.0 × 10(-8)). Using an unweighted genetic height score, we found a nonsignificant association with risk of AF (per allele, hazard ratio = 1.01, 95% confidence interval: 1.00, 1.02; P = 0.06). In weighted analyses, we found that genetically predicted height was strongly associated with AF risk (per 10 cm, hazard ratio = 1.30, 95% confidence interval: 1.03, 1.64; P = 0.03). Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP (rs1046934) that was independently associated with AF and may warrant future study. In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets.
10aAfrican Americans10aAged10aAtrial Fibrillation10aBody Height10aEndonucleases10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aHumans10aLongitudinal Studies10aMale10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aRisk Factors1 aRosenberg, Michael, A1 aKaplan, Robert, C1 aSiscovick, David, S1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aNewton-Cheh, Christopher1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/659508236nas a2202509 4500008004100000022001400041245008500055210006900140260000900209300001100218490000600229520112800235653002201363653002101385653002501406653003401431653002401465653001101489653003601500653003101536100002801567700002401595700001801619700002101637700001901658700001801677700001901695700001701714700002301731700002401754700002401778700002601802700003001828700001701858700001801875700001701893700001901910700002101929700002801950700002101978700003001999700002002029700002102049700002202070700002102092700002002113700002002133700002502153700002302178700002002201700002002221700001802241700002402259700002102283700002302304700001802327700003002345700002202375700002302397700002302420700001902443700002802462700002302490700002302513700001902536700002102555700001602576700002402592700002102616700001702637700001602654700001902670700002002689700002402709700002502733700002302758700001702781700002102798700001902819700002202838700002602860700002402886700002202910700002102932700002202953700002702975700001803002700002103020700001803041700001703059700003003076700002703106700002003133700002103153700002003174700001803194700001803212700001503230700002303245700002003268700002803288700002003316700001803336700001903354700002103373700001203394700001903406700001803425700002603443700001903469700001903488700001803507700003203525700001703557700001603574700003103590700001703621700001903638700001803657700002403675700001903699700002303718700002603741700002403767700002003791700002203811700002103833700002003854700001903874700002103893700002303914700002103937700002403958700002003982700002304002700001904025700002004044700001904064700002204083700002104105700002904126700002204155700001804177700002204195700001804217700002104235700002304256700001804279700002904297700001204326700002204338700001604360700001904376700002104395700002104416700002204437700002204459700002604481700002304507700002104530700002104551700001604572700002204588700002204610700002204632700002304654700001804677700002804695700002004723700002304743700002204766700002204788700001804810700001804828700002304846700002204869700002204891700002004913700002204933700001904955700002404974700002104998700002105019700003005040700001705070700002005087700002005107700002205127700001705149700003005166700002005196700002405216700001905240700002305259700002005282700002005302700002405322700001805346700003105364700002205395700003105417700002305448700002305471700002105494700002005515700002805535700002205563700002005585710004705605710003805652856003605690 2014 eng d a1932-620300aGene-wide analysis detects two new susceptibility genes for Alzheimer's disease.0 aGenewide analysis detects two new susceptibility genes for Alzhe c2014 ae946610 v93 aBACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.
SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
10aAlzheimer Disease10aCarrier Proteins10aCase-Control Studies10aGenome-Wide Association Study10aHeat-Shock Proteins10aHumans10aPolymorphism, Single Nucleotide10aReceptors, Antigen, B-Cell1 aEscott-Price, Valentina1 aBellenguez, Céline1 aSan Wang, Li-1 aChoi, Seung-Hoan1 aHarold, Denise1 aJones, Lesley1 aHolmans, Peter1 aGerrish, Amy1 aVedernikov, Alexey1 aRichards, Alexander1 aDeStefano, Anita, L1 aLambert, Jean-Charles1 aIbrahim-Verbaas, Carla, A1 aNaj, Adam, C1 aSims, Rebecca1 aJun, Gyungah1 aBis, Joshua, C1 aBeecham, Gary, W1 aGrenier-Boley, Benjamin1 aRusso, Giancarlo1 aThornton-Wells, Tricia, A1 aDenning, Nicola1 aSmith, Albert, V1 aChouraki, Vincent1 aThomas, Charlene1 aIkram, Arfan, M1 aZelenika, Diana1 aVardarajan, Badri, N1 aKamatani, Yoichiro1 aLin, Chiao-Feng1 aSchmidt, Helena1 aKunkle, Brian1 aDunstan, Melanie, L1 aVronskaya, Maria1 aJohnson, Andrew, D1 aRuiz, Agustin1 aBihoreau, Marie-Thérèse1 aReitz, Christiane1 aPasquier, Florence1 aHollingworth, Paul1 aHanon, Olivier1 aFitzpatrick, Annette, L1 aBuxbaum, Joseph, D1 aCampion, Dominique1 aCrane, Paul, K1 aBaldwin, Clinton1 aBecker, Tim1 aGudnason, Vilmundur1 aCruchaga, Carlos1 aCraig, David1 aAmin, Najaf1 aBerr, Claudine1 aLopez, Oscar, L1 aDe Jager, Philip, L1 aDeramecourt, Vincent1 aJohnston, Janet, A1 aEvans, Denis1 aLovestone, Simon1 aLetenneur, Luc1 aHernandez, Isabel1 aRubinsztein, David, C1 aEiriksdottir, Gudny1 aSleegers, Kristel1 aGoate, Alison, M1 aFiévet, Nathalie1 aHuentelman, Matthew, J1 aGill, Michael1 aBrown, Kristelle1 aKamboh, Ilyas1 aKeller, Lina1 aBarberger-Gateau, Pascale1 aMcGuinness, Bernadette1 aLarson, Eric, B1 aMyers, Amanda, J1 aDufouil, Carole1 aTodd, Stephen1 aWallon, David1 aLove, Seth1 aRogaeva, Ekaterina1 aGallacher, John1 aSt George-Hyslop, Peter1 aClarimon, Jordi1 aLleo, Alberto1 aBayer, Anthony1 aTsuang, Debby, W1 aYu, Lei1 aTsolaki, Magda1 aBossù, Paola1 aSpalletta, Gianfranco1 aProitsi, Petra1 aCollinge, John1 aSorbi, Sandro1 aGarcia, Florentino, Sanchez1 aFox, Nick, C1 aHardy, John1 aNaranjo, Maria, Candida De1 aBosco, Paolo1 aClarke, Robert1 aBrayne, Carol1 aGalimberti, Daniela1 aScarpini, Elio1 aBonuccelli, Ubaldo1 aMancuso, Michelangelo1 aSiciliano, Gabriele1 aMoebus, Susanne1 aMecocci, Patrizia1 aDel Zompo, Maria1 aMaier, Wolfgang1 aHampel, Harald1 aPilotto, Alberto1 aFrank-García, Ana1 aPanza, Francesco1 aSolfrizzi, Vincenzo1 aCaffarra, Paolo1 aNacmias, Benedetta1 aPerry, William1 aMayhaus, Manuel1 aLannfelt, Lars1 aHakonarson, Hakon1 aPichler, Sabrina1 aCarrasquillo, Minerva, M1 aIngelsson, Martin1 aBeekly, Duane1 aAlvarez, Victoria1 aZou, Fanggeng1 aValladares, Otto1 aYounkin, Steven, G1 aCoto, Eliecer1 aHamilton-Nelson, Kara, L1 aGu, Wei1 aRazquin, Cristina1 aPastor, Pau1 aMateo, Ignacio1 aOwen, Michael, J1 aFaber, Kelley, M1 aJonsson, Palmi, V1 aCombarros, Onofre1 aO'Donovan, Michael, C1 aCantwell, Laura, B1 aSoininen, Hilkka1 aBlacker, Deborah1 aMead, Simon1 aMosley, Thomas, H1 aBennett, David, A1 aHarris, Tamara, B1 aFratiglioni, Laura1 aHolmes, Clive1 ade Bruijn, Renee, F A G1 aPassmore, Peter1 aMontine, Thomas, J1 aBettens, Karolien1 aRotter, Jerome, I1 aBrice, Alexis1 aMorgan, Kevin1 aForoud, Tatiana, M1 aKukull, Walter, A1 aHannequin, Didier1 aPowell, John, F1 aNalls, Michael, A1 aRitchie, Karen1 aLunetta, Kathryn, L1 aKauwe, John, S K1 aBoerwinkle, Eric1 aRiemenschneider, Matthias1 aBoada, Merce1 aHiltunen, Mikko1 aMartin, Eden, R1 aSchmidt, Reinhold1 aRujescu, Dan1 aDartigues, Jean-François1 aMayeux, Richard1 aTzourio, Christophe1 aHofman, Albert1 aNöthen, Markus, M1 aGraff, Caroline1 aPsaty, Bruce, M1 aHaines, Jonathan, L1 aLathrop, Mark1 aPericak-Vance, Margaret, A1 aLauner, Lenore, J1 aVan Broeckhoven, Christine1 aFarrer, Lindsay, A1 aDuijn, Cornelia, M1 aRamirez, Alfredo1 aSeshadri, Sudha1 aSchellenberg, Gerard, D1 aAmouyel, Philippe1 aWilliams, Julie1 aUnited Kingdom Brain Expression Consortium1 aCardiovascular Health Study (CHS) uhttps://chs-nhlbi.org/node/661707147nas a2202257 4500008004100000022001400041245010000055210006900155260001300224300001100237490000700248520092000255653001901175653002301194653002201217653002901239653001701268653003801285653001801323653003401341653001101375653001801386653002701404653003601431653001401467653002801481653003101509653001501540653001901555100001801574700002601592700002001618700002001638700002301658700001601681700002301697700002601720700001501746700002101761700002001782700002301802700001901825700002501844700002201869700002601891700002501917700001901942700001801961700001901979700002001998700002202018700001802040700002002058700001702078700002402095700003102119700001902150700001902169700002002188700001502208700001802223700002202241700002002263700002002283700001202303700001902315700001602334700002102350700001902371700002202390700001902412700002402431700001602455700001702471700001902488700002002507700002402527700002002551700001802571700001802589700002102607700002702628700001702655700001702672700002702689700001902716700002202735700001702757700002002774700002102794700001802815700001902833700001902852700002002871700002602891700001902917700001902936700002402955700002402979700002203003700001303025700002203038700002003060700002103080700001903101700001903120700001803139700002003157700002003177700001703197700002503214700002803239700002003267700002303287700002203310700001503332700001803347700002303365700001603388700002603404700001703430700001603447700001703463700001903480700002303499700001903522700002003541700002403561700002003585700002103605700002103626700002103647700002203668700001903690700002003709700002103729700002203750700001903772700002003791700002003811700002203831700001803853700002803871700002403899700001703923700002803940700002403968700002103992700001904013700001904032700002204051700001804073700002204091700001904113700001804132700002304150700002504173700002004198700001904218700002404237700001904261700001604280700001904296700002204315700001804337700001904355700001704374700002704391700002104418700001504439700002304454700002204477700002404499700001704523700002504540700002104565700001704586700001904603700002204622700001704644700002404661700002504685700001704710700002204727700001904749700001704768700002204785700002104807700002504828856003604853 2014 eng d a1546-171800aGenome-wide association analysis identifies six new loci associated with forced vital capacity.0 aGenomewide association analysis identifies six new loci associat c2014 Jul a669-770 v463 aForced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
10aCohort Studies10aDatabases, Genetic10aFollow-Up Studies10aForced Expiratory Volume10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLung Diseases10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aPrognosis10aQuantitative Trait Loci10aRespiratory Function Tests10aSpirometry10aVital Capacity1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aWain, Louise, V1 aFranceschini, Nora1 aKoch, Beate1 aPottinger, Tess, D1 aSmith, Albert, Vernon1 aDuan, Qing1 aOldmeadow, Chris1 aLee, Mi, Kyeong1 aStrachan, David, P1 aJames, Alan, L1 aHuffman, Jennifer, E1 aVitart, Veronique1 aRamasamy, Adaikalavan1 aWareham, Nicholas, J1 aKaprio, Jaakko1 aWang, Xin-Qun1 aTrochet, Holly1 aKähönen, Mika1 aFlexeder, Claudia1 aAlbrecht, Eva1 aLopez, Lorna, M1 ade Jong, Kim1 aThyagarajan, Bharat1 aAlves, Alexessander, Couto1 aEnroth, Stefan1 aOmenaas, Ernst1 aJoshi, Peter, K1 aFall, Tove1 aViñuela, Ana1 aLauner, Lenore, J1 aLoehr, Laura, R1 aFornage, Myriam1 aLi, Guo1 aWilk, Jemma, B1 aTang, Wenbo1 aManichaikul, Ani1 aLahousse, Lies1 aHarris, Tamara, B1 aNorth, Kari, E1 aRudnicka, Alicja, R1 aHui, Jennie1 aGu, Xiangjun1 aLumley, Thomas1 aWright, Alan, F1 aHastie, Nicholas, D1 aCampbell, Susan1 aKumar, Rajesh1 aPin, Isabelle1 aScott, Robert, A1 aPietiläinen, Kirsi, H1 aSurakka, Ida1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aSchulz, Holger1 aHeinrich, Joachim1 aDavies, Gail1 aVonk, Judith, M1 aWojczynski, Mary1 aPouta, Anneli1 aJohansson, Asa1 aWild, Sarah, H1 aIngelsson, Erik1 aRivadeneira, Fernando1 aVölzke, Henry1 aHysi, Pirro, G1 aEiriksdottir, Gudny1 aMorrison, Alanna, C1 aRotter, Jerome, I1 aGao, Wei1 aPostma, Dirkje, S1 aWhite, Wendy, B1 aRich, Stephen, S1 aHofman, Albert1 aAspelund, Thor1 aCouper, David1 aSmith, Lewis, J1 aPsaty, Bruce, M1 aLohman, Kurt1 aBurchard, Esteban, G1 aUitterlinden, André, G1 aGarcia, Melissa1 aJoubert, Bonnie, R1 aMcArdle, Wendy, L1 aMusk, Bill1 aHansel, Nadia1 aHeckbert, Susan, R1 aZgaga, Lina1 avan Meurs, Joyce, B J1 aNavarro, Pau1 aRudan, Igor1 aOh, Yeon-Mok1 aRedline, Susan1 aJarvis, Deborah, L1 aZhao, Jing Hua1 aRantanen, Taina1 aO'Connor, George, T1 aRipatti, Samuli1 aScott, Rodney, J1 aKarrasch, Stefan1 aGrallert, Harald1 aGaddis, Nathan, C1 aStarr, John, M1 aWijmenga, Cisca1 aMinster, Ryan, L1 aLederer, David, J1 aPekkanen, Juha1 aGyllensten, Ulf1 aCampbell, Harry1 aMorris, Andrew, P1 aGläser, Sven1 aHammond, Christopher, J1 aBurkart, Kristin, M1 aBeilby, John1 aKritchevsky, Stephen, B1 aGudnason, Vilmundur1 aHancock, Dana, B1 aWilliams, Dale1 aPolasek, Ozren1 aZemunik, Tatijana1 aKolcic, Ivana1 aPetrini, Marcy, F1 aWjst, Matthias1 aKim, Woo, Jin1 aPorteous, David, J1 aScotland, Generation1 aSmith, Blair, H1 aViljanen, Anne1 aHeliövaara, Markku1 aAttia, John, R1 aSayers, Ian1 aHampel, Regina1 aGieger, Christian1 aDeary, Ian, J1 aBoezen, Marike1 aNewman, Anne1 aJarvelin, Marjo-Riitta1 aWilson, James, F1 aLind, Lars1 aStricker, Bruno, H1 aTeumer, Alexander1 aSpector, Timothy, D1 aMelén, Erik1 aPeters, Marjolein, J1 aLange, Leslie, A1 aBarr, Graham1 aBracke, Ken, R1 aVerhamme, Fien, M1 aSung, Joohon1 aHiemstra, Pieter, S1 aCassano, Patricia, A1 aSood, Akshay1 aHayward, Caroline1 aDupuis, Josée1 aHall, Ian, P1 aBrusselle, Guy, G1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/658206414nas a2201585 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2014 eng d a1524-463600aGenome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.0 aGenomewide association study for circulating tissue plasminogen c2014 May a1093-1010 v343 aOBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.
APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.
CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
10aAged10aCells, Cultured10aCoronary Artery Disease10aEndothelial Cells10aEurope10aFemale10aGene Expression Regulation10aGene Silencing10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aR-SNARE Proteins10aRisk Factors10aStroke10aSyntaxin 110aTissue Plasminogen Activator10aTransfection10aUnited States10aUp-Regulation1 aHuang, Jie1 aHuffman, Jennifer, E1 aYamakuchi, Munekazu1 aYamkauchi, Munekazu1 aTrompet, Stella1 aAsselbergs, Folkert, W1 aSabater-Lleal, Maria1 aTrégouët, David-Alexandre1 aChen, Wei-Min1 aSmith, Nicholas, L1 aKleber, Marcus, E1 aShin, So-Youn1 aBecker, Diane, M1 aTang, Weihong1 aDehghan, Abbas1 aJohnson, Andrew, D1 aTruong, Vinh1 aFolkersen, Lasse1 aYang, Qiong1 aOudot-Mellkah, Tiphaine1 aBuckley, Brendan, M1 aMoore, Jason, H1 aWilliams, Frances, M K1 aCampbell, Harry1 aSilbernagel, Günther1 aVitart, Veronique1 aRudan, Igor1 aTofler, Geoffrey, H1 aNavis, Gerjan, J1 aDeStefano, Anita1 aWright, Alan, F1 aChen, Ming-Huei1 ade Craen, Anton, J M1 aWorrall, Bradford, B1 aRudnicka, Alicja, R1 aRumley, Ann1 aBookman, Ebony, B1 aPsaty, Bruce, M1 aChen, Fang1 aKeene, Keith, L1 aFranco, Oscar, H1 aBöhm, Bernhard, O1 aUitterlinden, André, G1 aCarter, Angela, M1 aJukema, Wouter1 aSattar, Naveed1 aBis, Joshua, C1 aIkram, Mohammad, A1 aSale, Michèle, M1 aMcKnight, Barbara1 aFornage, Myriam1 aFord, Ian1 aTaylor, Kent1 aSlagboom, Eline1 aMcArdle, Wendy, L1 aHsu, Fang-Chi1 aFranco-Cereceda, Anders1 aGoodall, Alison, H1 aYanek, Lisa, R1 aFurie, Karen, L1 aCushman, Mary1 aHofman, Albert1 aWitteman, Jacqueline, C M1 aFolsom, Aaron, R1 aBasu, Saonli1 aMatijevic, Nena1 aGilst, Wiek, H1 aWilson, James, F1 aWestendorp, Rudi, G J1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTracy, Russell, P1 aPolasek, Ozren1 aWinkelmann, Bernhard, R1 aGrant, Peter, J1 aHillege, Hans, L1 aCambien, Francois1 aStott, David, J1 aLowe, Gordon, D1 aSpector, Timothy, D1 aMeigs, James, B1 aMärz, Winfried1 aEriksson, Per1 aBecker, Lewis, C1 aMorange, Pierre-Emmanuel1 aSoranzo, Nicole1 aWilliams, Scott, M1 aHayward, Caroline1 aHarst, Pim1 aHamsten, Anders1 aLowenstein, Charles, J1 aStrachan, David, P1 aO'Donnell, Christopher, J1 aCohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium Neurology Working Group1 aCARDIoGRAM consortium1 aCHARGE Consortium Hemostatic Factor Working Group uhttps://chs-nhlbi.org/node/636704635nas a2200913 4500008004100000022001400041245013400055210006900189260001300258300001100271490000600282520207800288653001002366653000902376653002002385653001302405653001802418653001902436653001102455653001702466653003402483653001302517653001702530653001102547653000902558653002102567653001602588653003602604653003202640653001702672653001102689653002602700653001802726100002202744700001902766700001802785700002002803700001602823700002202839700002302861700002202884700002302906700002002929700002702949700002702976700002003003700002003023700002103043700002403064700002003088700002003108700002103128700001703149700001803166700002403184700002203208700002003230700002203250700002103272700002203293700001803315700002303333700002203356700002103378700002403399700002003423700002203443700002303465700002003488700001803508700002403526700002403550700002203574700002003596700002003616700002703636700002203663856003603685 2014 eng d a1942-326800aGenome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.0 aGenomewide association study of Larginine and dimethylarginines c2014 Dec a864-720 v73 aBACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.
METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.
10aAdult10aAged10aAmidohydrolases10aArginine10aBinding Sites10aCohort Studies10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHEK293 Cells10aHumans10aMale10aMediator Complex10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Structure, Tertiary10aRisk Factors10aStroke10aSubstrate Specificity10aTransaminases1 aLüneburg, Nicole1 aLieb, Wolfgang1 aZeller, Tanja1 aChen, Ming-Huei1 aMaas, Renke1 aCarter, Angela, M1 aXanthakis, Vanessa1 aGlazer, Nicole, L1 aSchwedhelm, Edzard1 aSeshadri, Sudha1 aIkram, Mohammad, Arfan1 aLongstreth, William, T1 aFornage, Myriam1 aKönig, Inke, R1 aLoley, Christina1 aOjeda, Francisco, M1 aSchillert, Arne1 aWang, Thomas, J1 aSticht, Heinrich1 aKittel, Anja1 aKönig, Jörg1 aBenjamin, Emelia, J1 aSullivan, Lisa, M1 aBernges, Isabel1 aAnderssohn, Maike1 aZiegler, Andreas1 aGieger, Christian1 aIllig, Thomas1 aMeisinger, Christa1 aWichmann, H-Erich1 aWild, Philipp, S1 aSchunkert, Heribert1 aPsaty, Bruce, M1 aWiggins, Kerri, L1 aHeckbert, Susan, R1 aSmith, Nicholas1 aLackner, Karl1 aLunetta, Kathryn, L1 aBlankenberg, Stefan1 aErdmann, Jeanette1 aMünzel, Thomas1 aGrant, Peter, J1 aVasan, Ramachandran, S1 aBöger, Rainer, H uhttps://chs-nhlbi.org/node/681903759nas a2200649 4500008004100000022001400041245015900055210006900214260001300283300001200296490000600308520187100314653001002185653000902195653002202204653001002226653003202236653003202268653003102300653002702331653002502358653001102383653003402394653001302428653001902441653001102460653000902471653001602480653003602496653002402532653002702556100001702583700002202600700002402622700001802646700002002664700002102684700001902705700002102724700001302745700002702758700001802785700001702803700002502820700001902845700002202864700002002886700002102906700001802927700002202945700002002967700002002987700002503007700002103032700002003053856003603073 2014 eng d a1942-326800aGenome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.0 aGenomewide association study of plasma N6 polyunsaturated fatty c2014 Jun a321-3310 v73 aBACKGROUND: Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.
METHODS AND RESULTS: To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1×10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2×10(-15), 5.0×10(-11), 7.6×10(-65), and 2.4×10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1×10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3×10(-72), 2.6×10(-151), and 6.3×10(-140), respectively).
CONCLUSIONS: Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.
10aAdult10aAged10aAged, 80 and over10aAging10aChromosomes, Human, Pair 1010aChromosomes, Human, Pair 1610aChromosomes, Human, Pair 610aFatty Acid Desaturases10aFatty Acids, Omega-610aFemale10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies10aSequence Analysis, DNA1 aGuan, Weihua1 aSteffen, Brian, T1 aLemaitre, Rozenn, N1 aH Y Wu, Jason1 aTanaka, Toshiko1 aManichaikul, Ani1 aFoy, Millennia1 aRich, Stephen, S1 aWang, Lu1 aNettleton, Jennifer, A1 aTang, Weihong1 aGu, Xiangjun1 aBandinelli, Stafania1 aKing, Irena, B1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aSiscovick, David1 aDjoussé, Luc1 aChen, Yii-Der Ida1 aFerrucci, Luigi1 aFornage, Myriam1 aMozafarrian, Dariush1 aTsai, Michael, Y1 aSteffen, Lyn, M uhttps://chs-nhlbi.org/node/656705794nas a2201213 4500008004100000022001400041245007800055210006900133260001600202300001200218490000800230520237200238653000902610653002302619653002102642653002102663653002202684653001102706653002602717653001102743653000902754653001602763653003002779653002402809653002002833653001102853110004002864700003002904700001302934700001702947700002502964700001902989700002103008700003703029700001903066700001903085700001903104700002003123700002503143700001803168700002003186700002103206700002103227700002603248700002203274700001903296700002003315700002103335700002203356700002103378700002103399700002103420700002203441700002403463700002403487700002303511700001903534700002503553700002203578700001403600700001903614700003503633700002003668700002003688700002203708700002503730700002503755700001903780700003203799700001603831700003103847700002203878700001903900700002103919700002203940700002803962700001803990700002104008700002004029700002204049700002004071700003004091700002004121700002404141700001704165700002304182700001804205700002504223700002004248700002104268700002204289700001904311700002304330700002104353700002204374700002004396700002204416700001904438700002504457700002204482700002304504700001704527856003604544 2014 eng d a1538-359800aGlycated hemoglobin measurement and prediction of cardiovascular disease.0 aGlycated hemoglobin measurement and prediction of cardiovascular c2014 Mar 26 a1225-330 v3113 aIMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.
OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk.
DESIGN, SETTING, AND PARTICIPANTS: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment.
MAIN OUTCOMES AND MEASURES: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk.
RESULTS: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels.
CONCLUSIONS AND RELEVANCE: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.
10aAged10aC-Reactive Protein10aCholesterol, HDL10aCoronary Disease10aDiabetes Mellitus10aFemale10aGlycated Hemoglobin A10aHumans10aMale10aMiddle Aged10aPredictive Value of Tests10aProspective Studies10aRisk Assessment10aStroke1 aEmerging Risk Factors Collaboration1 aDi Angelantonio, Emanuele1 aGao, Pei1 aKhan, Hassan1 aButterworth, Adam, S1 aWormser, David1 aKaptoge, Stephen1 aSeshasai, Sreenivasa, Rao Kondap1 aThompson, Alex1 aSarwar, Nadeem1 aWilleit, Peter1 aRidker, Paul, M1 aBarr, Elizabeth, L M1 aKhaw, Kay-Tee1 aPsaty, Bruce, M1 aBrenner, Hermann1 aBalkau, Beverley1 aDekker, Jacqueline, M1 aLawlor, Debbie, A1 aDaimon, Makoto1 aWilleit, Johann1 aNjølstad, Inger1 aNissinen, Aulikki1 aBrunner, Eric, J1 aKuller, Lewis, H1 aPrice, Jackie, F1 aSundström, Johan1 aKnuiman, Matthew, W1 aFeskens, Edith, J M1 aVerschuren, W, M M1 aWald, Nicholas1 aBakker, Stephan, J L1 aWhincup, Peter, H1 aFord, Ian1 aGoldbourt, Uri1 aGómez-de-la-Cámara, Agustín1 aGallacher, John1 aSimons, Leon, A1 aRosengren, Annika1 aSutherland, Susan, E1 aBjörkelund, Cecilia1 aBlazer, Dan, G1 aWassertheil-Smoller, Sylvia1 aOnat, Altan1 aIbañez, Alejandro, Marín1 aCasiglia, Edoardo1 aJukema, Wouter1 aSimpson, Lara, M1 aGiampaoli, Simona1 aNordestgaard, Børge, G1 aSelmer, Randi1 aWennberg, Patrik1 aKauhanen, Jussi1 aSalonen, Jukka, T1 aDankner, Rachel1 aBarrett-Connor, Elizabeth1 aKavousi, Maryam1 aGudnason, Vilmundur1 aEvans, Denis1 aWallace, Robert, B1 aCushman, Mary1 aD'Agostino, Ralph, B1 aUmans, Jason, G1 aKiyohara, Yutaka1 aNakagawa, Hidaeki1 aSato, Shinichi1 aGillum, Richard, F1 aFolsom, Aaron, R1 aSchouw, Yvonne, T1 aMoons, Karel, G1 aGriffin, Simon, J1 aSattar, Naveed1 aWareham, Nicholas, J1 aSelvin, Elizabeth1 aThompson, Simon, G1 aDanesh, John uhttps://chs-nhlbi.org/node/655903142nas a2200445 4500008004100000022001400041245009800055210006900153260001300222300001100235490000700246520191900253653000902172653001002181653002802191653001102219653003802230653001302268653002002281653001102301653001402312653000902326653001402335653002602349653001702375653001802392653001802410100002202428700002102450700002102471700002102492700002402513700002302537700002002560700002302580700001902603700001802622700002002640856003602660 2014 eng d a1758-535X00aHeritability of and mortality prediction with a longevity phenotype: the healthy aging index.0 aHeritability of and mortality prediction with a longevity phenot c2014 Apr a479-850 v693 aBACKGROUND: Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.
METHODS: The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model.
RESULTS: Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.
CONCLUSION: The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.
10aAged10aAging10aCardiovascular Diseases10aFemale10aGenetic Predisposition to Disease10aGenotype10aHealth Behavior10aHumans10aLongevity10aMale10aPhenotype10aRetrospective Studies10aRisk Factors10aSurvival Rate10aUnited States1 aSanders, Jason, L1 aMinster, Ryan, L1 aBarmada, Michael1 aMatteini, Amy, M1 aBoudreau, Robert, M1 aChristensen, Kaare1 aMayeux, Richard1 aBorecki, Ingrid, B1 aZhang, Qunyuan1 aPerls, Thomas1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/628006926nas a2201669 4500008004100000022001400041245011700055210006900172260001300241300001300254490000700267520222800274653001902502653001702521653003402538653001902572653002202591653001102613653002202624653001702646653002802663653001602691100001802707700002002725700002002745700002202765700002202787700002302809700001802832700001902850700002302869700002302892700001602915700002502931700002802956700002302984700002503007700002003032700001803052700001703070700001803087700002303105700002403128700001703152700001703169700002003186700001903206700002203225700001803247700001903265700002003284700001903304700001903323700002603342700002203368700002403390700001203414700001803426700001803444700002203462700002003484700002403504700002003528700002503548700001503573700001803588700002503606700002603631700001803657700002503675700002303700700002503723700001503748700001703763700002203780700001603802700002503818700002603843700002403869700002003893700002103913700001903934700002203953700001603975700001603991700002104007700001604028700002104044700002504065700001904090700001904109700002504128700002304153700002204176700002304198700001804221700002104239700002804260700001604288700002304304700001904327700001804346700001804364700002304382700002304405700002204428700001904450700001804469700002004487700002004507700001904527700001904546700002404565700002504589700002004614700002404634700002704658700002704685700002404712700003904736700002504775700002304800700002104823700002304844700002404867700002704891700002604918700002804944700001904972700002304991700002405014700002005038700002405058700002105082700001905103700001805122700002105140700001805161700001905179700002205198856003605220 2014 eng d a1553-740400aIdentification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.0 aIdentification of novel genetic Loci associated with thyroid per c2014 Feb ae10041230 v103 aAutoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
10aAutoantibodies10aGenetic Loci10aGenome-Wide Association Study10aGraves Disease10aHashimoto Disease10aHumans10aIodide Peroxidase10aRisk Factors10aThyroiditis, Autoimmune10aThyrotropin1 aMedici, Marco1 aPorcu, Eleonora1 aPistis, Giorgio1 aTeumer, Alexander1 aBrown, Suzanne, J1 aJensen, Richard, A1 aRawal, Rajesh1 aRoef, Greet, L1 aPlantinga, Theo, S1 aVermeulen, Sita, H1 aLahti, Jari1 aSimmonds, Matthew, J1 aHusemoen, Lise, Lotte N1 aFreathy, Rachel, M1 aShields, Beverley, M1 aPietzner, Diana1 aNagy, Rebecca1 aBroer, Linda1 aChaker, Layal1 aKorevaar, Tim, I M1 aPlia, Maria, Grazia1 aSala, Cinzia1 aVölker, Uwe1 aRichards, Brent1 aSweep, Fred, C1 aGieger, Christian1 aCorre, Tanguy1 aKajantie, Eero1 aThuesen, Betina1 aTaes, Youri, E1 aVisser, Edward1 aHattersley, Andrew, T1 aKratzsch, Jürgen1 aHamilton, Alexander1 aLi, Wei1 aHomuth, Georg1 aLobina, Monia1 aMariotti, Stefano1 aSoranzo, Nicole1 aCocca, Massimiliano1 aNauck, Matthias1 aSpielhagen, Christin1 aRoss, Alec1 aArnold, Alice1 avan de Bunt, Martijn1 aLiyanarachchi, Sandya1 aHeier, Margit1 aGrabe, Hans, Jörgen1 aMasciullo, Corrado1 aGalesloot, Tessel, E1 aLim, Ee, M1 aReischl, Eva1 aLeedman, Peter, J1 aLai, Sandra1 aDelitala, Alessandro1 aBremner, Alexandra, P1 aPhilips, David, I W1 aBeilby, John, P1 aMulas, Antonella1 aVocale, Matteo1 aAbecasis, Goncalo1 aForsen, Tom1 aJames, Alan1 aWiden, Elisabeth1 aHui, Jennie1 aProkisch, Holger1 aRietzschel, Ernst, E1 aPalotie, Aarno1 aFeddema, Peter1 aFletcher, Stephen, J1 aSchramm, Katharina1 aRotter, Jerome, I1 aKluttig, Alexander1 aRadke, Dörte1 aTraglia, Michela1 aSurdulescu, Gabriela, L1 aHe, Huiling1 aFranklyn, Jayne, A1 aTiller, Daniel1 aVaidya, Bijay1 aDe Meyer, Tim1 aJørgensen, Torben1 aEriksson, Johan, G1 aO'Leary, Peter, C1 aWichmann, Eric1 aHermus, Ad, R1 aPsaty, Bruce, M1 aIttermann, Till1 aHofman, Albert1 aBosi, Emanuele1 aSchlessinger, David1 aWallaschofski, Henri1 aPirastu, Nicola1 aAulchenko, Yurii, S1 ade la Chapelle, Albert1 aNetea-Maier, Romana, T1 aGough, Stephen, C L1 aSchwabedissen, Henriette, Meyer Zu1 aFrayling, Timothy, M1 aKaufman, Jean-Marc1 aLinneberg, Allan1 aRäikkönen, Katri1 aSmit, Johannes, W A1 aKiemeney, Lambertus, A1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWalsh, John, P1 aMeisinger, Christa1 aHeijer, Martin, den1 aVisser, Theo, J1 aSpector, Timothy, D1 aWilson, Scott, G1 aVölzke, Henry1 aCappola, Anne1 aToniolo, Daniela1 aSanna, Serena1 aNaitza, Silvia1 aPeeters, Robin, P uhttps://chs-nhlbi.org/node/629404762nas a2201117 4500008004100000022001400041245011700055210006900172260001500241300001200256490000800268520162700276653000901903653001201912653002401924653002301948653001601971653001101987653001101998653003002009653001702039653003802056653001302094653002502107653001102132653001002143653000902153653001602162653002002178653002102198653002802219653002302247653002602270653002602296653003002322653001402352653002302366100002202389700002202411700002402433700001902457700001802476700002002494700001902514700001902533700001902552700002202571700002202593700002202615700002202637700001902659700002302678700002302701700003002724700002002754700002002774700002102794700001902815700002302834700002002857700002302877700001902900700002302919700002502942700001802967700002302985700002503008700002203033700001903055700001803074700002103092700002403113700001903137700002803156700002403184700002003208700001803228700002103246700002103267700002603288700002403314700002003338700001903358700002303377700001403400700001703414700001803431700002203449700002503471700002203496700001903518700002403537710002603561710002103587856003603608 2014 eng d a1524-453900aIntegrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.0 aIntegrating genetic transcriptional and functional analyses to i c2014 Oct 7 a1225-350 v1303 aBACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.
METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).
CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.
10aAged10aAnimals10aAtrial Fibrillation10aChromosome Mapping10aConnexin 4310aEurope10aFemale10aGene Knockdown Techniques10aGenetic Loci10aGenetic Predisposition to Disease10aGenotype10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aMuscle Proteins10aNuclear Proteins10aQuantitative Trait Loci10aRepressor Proteins10aT-Box Domain Proteins10aTranscription Factors10aUbiquitin-Protein Ligases10aZebrafish10aZebrafish Proteins1 aSinner, Moritz, F1 aTucker, Nathan, R1 aLunetta, Kathryn, L1 aOzaki, Kouichi1 aSmith, Gustav1 aTrompet, Stella1 aBis, Joshua, C1 aLin, Honghuang1 aChung, Mina, K1 aNielsen, Jonas, B1 aLubitz, Steven, A1 aKrijthe, Bouwe, P1 aMagnani, Jared, W1 aYe, Jiangchuan1 aGollob, Michael, H1 aTsunoda, Tatsuhiko1 aMüller-Nurasyid, Martina1 aLichtner, Peter1 aPeters, Annette1 aDolmatova, Elena1 aKubo, Michiaki1 aSmith, Jonathan, D1 aPsaty, Bruce, M1 aSmith, Nicholas, L1 aJukema, Wouter1 aChasman, Daniel, I1 aAlbert, Christine, M1 aEbana, Yusuke1 aFurukawa, Tetsushi1 aMacfarlane, Peter, W1 aHarris, Tamara, B1 aDarbar, Dawood1 aDörr, Marcus1 aHolst, Anders, G1 aSvendsen, Jesper, H1 aHofman, Albert1 aUitterlinden, André, G1 aGudnason, Vilmundur1 aIsobe, Mitsuaki1 aMalik, Rainer1 aDichgans, Martin1 aRosand, Jonathan1 aVan Wagoner, David, R1 aBenjamin, Emelia, J1 aMilan, David, J1 aMelander, Olle1 aHeckbert, Susan, R1 aFord, Ian1 aLiu, Yongmei1 aBarnard, John1 aOlesen, Morten, S1 aStricker, Bruno, H C1 aTanaka, Toshihiro1 aKääb, Stefan1 aEllinor, Patrick, T1 aMETASTROKE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/660004043nas a2200769 4500008004100000022001400041245014200055210006900197260001300266300001100279490000800290520183700298653001002135653002202145653000902167653001502176653002302191653002802214653001802242653001102260653001702271653003802288653002502326653003402351653001102385653002702396653001602423653003602439653001702475100001802492700002002510700001202530700001902542700001802561700002302579700002402602700001702626700001802643700002302661700001702684700001802701700002302719700002402742700002102766700001702787700002002804700001902824700001502843700002702858700002302885700002102908700002102929700002802950700002202978700002803000700002003028700002203048700002103070700001903091700002103110700002203131700001903153700002003172700002403192700002103216856003603237 2014 eng d a1432-120300aLarge multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans.0 aLarge multiethnic Candidate Gene Study for Creactive protein lev c2014 Aug a985-950 v1333 aC-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.
10aAdult10aAfrican Americans10aAged10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aCD36 Antigens10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetics, Population10aGenome-Wide Association Study10aHumans10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aEllis, Jaclyn1 aLange, Ethan, M1 aLi, Jin1 aDupuis, Josée1 aBaumert, Jens1 aWalston, Jeremy, D1 aKeating, Brendan, J1 aDurda, Peter1 aFox, Ervin, R1 aPalmer, Cameron, D1 aMeng, Yan, A1 aYoung, Taylor1 aFarlow, Deborah, N1 aSchnabel, Renate, B1 aMarzi, Carola, S1 aLarkin, Emma1 aMartin, Lisa, W1 aBis, Joshua, C1 aAuer, Paul1 aRamachandran, Vasan, S1 aGabriel, Stacey, B1 aWillis, Monte, S1 aPankow, James, S1 aPapanicolaou, George, J1 aRotter, Jerome, I1 aBallantyne, Christie, M1 aGross, Myron, D1 aLettre, Guillaume1 aWilson, James, G1 aPeters, Ulrike1 aKoenig, Wolfgang1 aTracy, Russell, P1 aRedline, Susan1 aReiner, Alex, P1 aBenjamin, Emelia, J1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/655805294nas a2201225 4500008004100000022001400041245011300055210006900168260000900237300001200246490000600258520192600264653001002190653003202200653001102232653003102243653001702274653003402291653001102325653002502336653000902361653001602370100001602386700002102402700001802423700002602441700002302467700001702490700002002507700002102527700002002548700002402568700002302592700002202615700002102637700002202658700002402680700002302704700001802727700002402745700002302769700001702792700002202809700002102831700001902852700001702871700001802888700001902906700001502925700001902940700002302959700001302982700001802995700001703013700002103030700002203051700001903073700001903092700002003111700001603131700002103147700001603168700002803184700001803212700001903230700001203249700001503261700002203276700001703298700001703315700001903332700002203351700001903373700002203392700002403414700001503438700001903453700002003472700002903492700002003521700002603541700002203567700001903589700002003608700001703628700001903645700002303664700002203687700002803709700001903737700001903756700002003775700002103795700001903816700001903835700002303854700002303877700002503900700002003925700002103945700002403966700001703990700002504007856003604032 2014 eng d a1932-620300aLarge-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.0 aLargescale genomewide association studies and metaanalyses of lo c2014 ae1007760 v93 aBACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
10aAdult10aChromosomes, Human, Pair 1110aFemale10aGene Expression Regulation10aGenetic Loci10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aMale10aRespiration1 aTang, Wenbo1 aKowgier, Matthew1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aJoubert, Bonnie, R1 aHodge, Emily1 aGharib, Sina, A1 aSmith, Albert, V1 aRuczinski, Ingo1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aHarris, Tamara, B1 aHansel, Nadia, N1 aLauner, Lenore, J1 aBarnes, Kathleen, C1 aHansen, Joyanna, G1 aAlbrecht, Eva1 aAldrich, Melinda, C1 aAllerhand, Michael1 aBarr, Graham1 aBrusselle, Guy, G1 aCouper, David, J1 aCurjuric, Ivan1 aDavies, Gail1 aDeary, Ian, J1 aDupuis, Josée1 aFall, Tove1 aFoy, Millennia1 aFranceschini, Nora1 aGao, Wei1 aGläser, Sven1 aGu, Xiangjun1 aHancock, Dana, B1 aHeinrich, Joachim1 aHofman, Albert1 aImboden, Medea1 aIngelsson, Erik1 aJames, Alan1 aKarrasch, Stefan1 aKoch, Beate1 aKritchevsky, Stephen, B1 aKumar, Ashish1 aLahousse, Lies1 aLi, Guo1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLohman, Kurt1 aLumley, Thomas1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMusk, Bill1 aNorth, Kari, E1 aPalmer, Lyle, J1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchulz, Holger1 aSmith, Lewis, J1 aSood, Akshay1 aStarr, John, M1 aStrachan, David, P1 aTeumer, Alexander1 aUitterlinden, André, G1 aVölzke, Henry1 aVoorman, Arend1 aWain, Louise, V1 aWells, Martin, T1 aWilk, Jemma, B1 aWilliams, Dale1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aLondon, Stephanie, J1 aFornage, Myriam1 aTobin, Martin, D1 aO'Connor, George, T1 aHall, Ian, P1 aCassano, Patricia, A uhttps://chs-nhlbi.org/node/660404090nas a2200949 4500008004100000022001400041245011600055210006900171260001300240300001100253490000700264520106600271653002501337653001701362653003801379653003401417653001301451653001101464653002201475653003601497653001701533100001901550700002101569700002301590700001801613700002301631700001801654700002401672700001801696700001501714700001701729700002101746700002301767700002201790700002401812700001901836700002301855700001601878700001901894700001901913700001601932700002001948700002501968700003101993700001902024700002002043700002402063700001802087700001802105700001702123700002502140700002602165700002202191700002302213700002102236700001902257700001902276700001802295700002202313700001902335700001902354700001802373700002202391700001902413700001802432700002302450700002002473700002502493710006602518710010002584710001202684710001102696710004502707710004702752710004202799710007502841710005502916710005502971710004103026710003703067856003603104 2014 eng d a1546-171800aLarge-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.0 aLargescale metaanalysis of genomewide association data identifie c2014 Sep a989-930 v463 aWe conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
10aCase-Control Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aParkinson Disease10aPolymorphism, Single Nucleotide10aRisk Factors1 aNalls, Mike, A1 aPankratz, Nathan1 aLill, Christina, M1 aDo, Chuong, B1 aHernandez, Dena, G1 aSaad, Mohamad1 aDeStefano, Anita, L1 aKara, Eleanna1 aBras, Jose1 aSharma, Manu1 aSchulte, Claudia1 aKeller, Margaux, F1 aArepalli, Sampath1 aLetson, Christopher1 aEdsall, Connor1 aStefansson, Hreinn1 aLiu, Xinmin1 aPliner, Hannah1 aLee, Joseph, H1 aCheng, Rong1 aIkram, Arfan, M1 aIoannidis, John, P A1 aHadjigeorgiou, Georgios, M1 aBis, Joshua, C1 aMartinez, Maria1 aPerlmutter, Joel, S1 aGoate, Alison1 aMarder, Karen1 aFiske, Brian1 aSutherland, Margaret1 aXiromerisiou, Georgia1 aMyers, Richard, H1 aClark, Lorraine, N1 aStefansson, Kari1 aHardy, John, A1 aHeutink, Peter1 aChen, Honglei1 aWood, Nicholas, W1 aHoulden, Henry1 aPayami, Haydeh1 aBrice, Alexis1 aScott, William, K1 aGasser, Thomas1 aBertram, Lars1 aEriksson, Nicholas1 aForoud, Tatiana1 aSingleton, Andrew, B1 aInternational Parkinson's Disease Genomics Consortium (IPDGC)1 aParkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI)1 a23andMe1 aGenePD1 aNeuroGenetics Research Consortium (NGRC)1 aHussman Institute of Human Genomics (HIHG)1 aAshkenazi Jewish Dataset Investigator1 aCohorts for Health and Aging Research in Genetic Epidemiology (CHARGE)1 aNorth American Brain Expression Consortium (NABEC)1 aUnited Kingdom Brain Expression Consortium (UKBEC)1 aGreek Parkinson's Disease Consortium1 aAlzheimer Genetic Analysis Group uhttps://chs-nhlbi.org/node/678905734nas a2201333 4500008004100000022001400041245007800055210006900133260001500202300001000217490000800227520196900235653003902204653002502243653002102268653004002289653001002329653001302339653001702352653001102369653001002380653001302390653001702403653002702420653001802447110010402465700001702569700002002586700001802606700002302624700002402647700002102671700001802692700002202710700001402732700001802746700002002764700002302784700002202807700001202829700001302841700001402854700002002868700001602888700001502904700002002919700001802939700002802957700002102985700002203006700002303028700002303051700001203074700001903086700002503105700002103130700002003151700002303171700001803194700002303212700002903235700002303264700002303287700001903310700002003329700001903349700001903368700002203387700002403409700002403433700002303457700002203480700001703502700002203519700002003541700001903561700001903580700002003599700001903619700002603638700002003664700002403684700003003708700002003738700002803758700002203786700002103808700001903829700001803848700002503866700002103891700002003912700002003932700002303952700002203975700002203997700002204019700002004041700002404061700002104085700002404106700002104130700002204151700001604173700002104189700002004210700002604230700002004256700002504276700002004301700002104321700002204342856003604364 2014 eng d a1533-440600aLoss-of-function mutations in APOC3, triglycerides, and coronary disease.0 aLossoffunction mutations in APOC3 triglycerides and coronary dis c2014 Jul 3 a22-310 v3713 aBACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.
METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.
RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).
CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).
10aAfrican Continental Ancestry Group10aApolipoprotein C-III10aCoronary Disease10aEuropean Continental Ancestry Group10aExome10aGenotype10aHeterozygote10aHumans10aLiver10aMutation10aRisk Factors10aSequence Analysis, DNA10aTriglycerides1 aTG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute1 aCrosby, Jacy1 aPeloso, Gina, M1 aAuer, Paul, L1 aCrosslin, David, R1 aStitziel, Nathan, O1 aLange, Leslie, A1 aLu, Yingchang1 aTang, Zheng-Zheng1 aZhang, He1 aHindy, George1 aMasca, Nicholas1 aStirrups, Kathleen1 aKanoni, Stavroula1 aDo, Ron1 aJun, Goo1 aHu, Youna1 aKang, Hyun, Min1 aXue, Chenyi1 aGoel, Anuj1 aFarrall, Martin1 aDuga, Stefano1 aMerlini, Pier, Angelica1 aAsselta, Rosanna1 aGirelli, Domenico1 aOlivieri, Oliviero1 aMartinelli, Nicola1 aYin, Wu1 aReilly, Dermot1 aSpeliotes, Elizabeth1 aFox, Caroline, S1 aHveem, Kristian1 aHolmen, Oddgeir, L1 aNikpay, Majid1 aFarlow, Deborah, N1 aAssimes, Themistocles, L1 aFranceschini, Nora1 aRobinson, Jennifer1 aNorth, Kari, E1 aMartin, Lisa, W1 aDePristo, Mark1 aGupta, Namrata1 aEscher, Stefan, A1 aJansson, Jan-Håkan1 aVan Zuydam, Natalie1 aPalmer, Colin, N A1 aWareham, Nicholas1 aKoch, Werner1 aMeitinger, Thomas1 aPeters, Annette1 aLieb, Wolfgang1 aErbel, Raimund1 aKönig, Inke, R1 aKruppa, Jochen1 aDegenhardt, Franziska1 aGottesman, Omri1 aBottinger, Erwin, P1 aO'Donnell, Christopher, J1 aPsaty, Bruce, M1 aBallantyne, Christie, M1 aAbecasis, Goncalo1 aOrdovas, Jose, M1 aMelander, Olle1 aWatkins, Hugh1 aOrho-Melander, Marju1 aArdissino, Diego1 aLoos, Ruth, J F1 aMcPherson, Ruth1 aWiller, Cristen, J1 aErdmann, Jeanette1 aHall, Alistair, S1 aSamani, Nilesh, J1 aDeloukas, Panos1 aSchunkert, Heribert1 aWilson, James, G1 aKooperberg, Charles1 aRich, Stephen, S1 aTracy, Russell, P1 aLin, Dan-Yu1 aAltshuler, David1 aGabriel, Stacey1 aNickerson, Deborah, A1 aJarvik, Gail, P1 aCupples, Adrienne, L1 aReiner, Alex, P1 aBoerwinkle, Eric1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/660503736nas a2200577 4500008004100000022001400041245014100055210006900196260001300265490000600278520210100284653001002385653000902395653002802404653001802432653001002450653001102460653001302471653001102484653001802495653002002513653000902533653002502542653001602567653004002583653004002623653001202663653001502675653003602690653001402726653001702740653002702757100002402784700001102808700001802819700001902837700002502856700002102881700002002902700002102922700001902943700001702962700002002979700002202999700001903021700002003040700002303060700001803083700002103101856003603122 2014 eng d a2047-998000aA low-frequency variant in MAPK14 provides mechanistic evidence of a link with myeloperoxidase: a prognostic cardiovascular risk marker.0 alowfrequency variant in MAPK14 provides mechanistic evidence of c2014 Aug0 v33 aBACKGROUND: Genetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen-activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in MAPK11/14 genes by exome sequencing and follow-up genotyping or imputation in participants well-phenotyped for cardiovascular and metabolic traits.
METHODS AND RESULTS: Investigation of genetic variation in MAPK11 and MAPK14 genes using additive genetic models in linear or logistic regression with cardiovascular, metabolic, and biomarker phenotypes highlighted an association of RS2859144 in MAPK14 with myeloperoxidase in a dyslipidemic population (Genetic Epidemiology of Metabolic Syndrome Study), P=2.3×10(-6)). This variant (or proxy) was consistently associated with myeloperoxidase in the Framingham Heart Study and Cardiovascular Health Study studies (replication meta-P=0.003), leading to a meta-P value of 9.96×10(-7) in the 3 dyslipidemic groups. The variant or its proxy was then profiled in additional population-based cohorts (up to a total of 58 930 subjects) including Cohorte Lausannoise, Ely, Fenland, European Prospective Investigation of Cancer, London Life Sciences Prospective Population Study, and the Genetics of Obesity Associations study obesity case-control for up to 40 cardiovascular and metabolic traits. Overall analysis identified the same single nucleotide polymorphisms to be nominally associated consistently with glomerular filtration rate (P=0.002) and risk of obesity (body mass index ≥30 kg/m(2), P=0.004).
CONCLUSIONS: As myeloperoxidase is a prognostic marker of coronary events, the MAPK14 variant may provide a mechanistic link between p38 map kinase and these events, providing information consistent with current indication of Losmapimod for acute coronary syndrome. If replicated, the association with glomerular filtration rate, along with previous biological findings, also provides support for kidney diseases as alternative indications.
10aAdult10aAged10aCardiovascular Diseases10aDyslipidemias10aExome10aFemale10aGenotype10aHumans10aLinear Models10aLogistic Models10aMale10aMetabolic Syndrome X10aMiddle Aged10aMitogen-Activated Protein Kinase 1110aMitogen-Activated Protein Kinase 1410aObesity10aPeroxidase10aPolymorphism, Single Nucleotide10aPrognosis10aRisk Factors10aSequence Analysis, DNA1 aWaterworth, Dawn, M1 aLi, Li1 aScott, Robert1 aWarren, Liling1 aGillson, Christopher1 aAponte, Jennifer1 aSarov-Blat, Lea1 aSprecher, Dennis1 aDupuis, Josée1 aReiner, Alex1 aPsaty, Bruce, M1 aTracy, Russell, P1 aLin, Honghuang1 aMcPherson, Ruth1 aChissoe, Stephanie1 aWareham, Nick1 aEhm, Margaret, G uhttps://chs-nhlbi.org/node/661004120nas a2200841 4500008004100000022001400041245010400055210006900159260001600228300001100244490000700255520154500262653001901807653002401826653003201850653003801882653003401920653001301954653001101967653003601978653000902014653001102023100002302034700002402057700002202081700002102103700001802124700001902142700001902161700001902180700002302199700001902222700002102241700002502262700002202287700001502309700001902324700002002343700001702363700002502380700002002405700001402425700001802439700001902457700002302476700002202499700002702521700002002548700001702568700002702585700002802612700002002640700002502660700002002685700001902705700002302724700001902747700002802766700001902794700002002813700002102833700001902854700002502873700002002898700002102918700002502939700002002964700002102984700002003005700001703025710020003042856003603242 2014 eng d a1526-632X00aMeta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12.0 aMetaanalysis in more than 17900 cases of ischemic stroke reveals c2014 Aug 19 a678-850 v833 aOBJECTIVES: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.
METHODS: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.
RESULTS: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).
CONCLUSION: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
10aBrain Ischemia10aCerebral Hemorrhage10aChromosomes, Human, Pair 1210aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aPolymorphism, Single Nucleotide10aRisk10aStroke1 aKilarski, Laura, L1 aAchterberg, Sefanja1 aDevan, William, J1 aTraylor, Matthew1 aMalik, Rainer1 aLindgren, Arne1 aPare, Guillame1 aSharma, Pankaj1 aSlowik, Agniesczka1 aThijs, Vincent1 aWalters, Matthew1 aWorrall, Bradford, B1 aSale, Michèle, M1 aAlgra, Ale1 aKappelle, Jaap1 aWijmenga, Cisca1 aNorrving, Bo1 aSandling, Johanna, K1 aRönnblom, Lars1 aGoris, An1 aFranke, Andre1 aSudlow, Cathie1 aRothwell, Peter, M1 aLevi, Christopher1 aHolliday, Elizabeth, G1 aFornage, Myriam1 aPsaty, Bruce1 aGretarsdottir, Solveig1 aThorsteinsdottir, Unnar1 aSeshadri, Sudha1 aMitchell, Braxton, D1 aKittner, Steven1 aClarke, Robert1 aHopewell, Jemma, C1 aBis, Joshua, C1 aBoncoraglio, Giorgio, B1 aMeschia, James1 aIkram, Arfan, M1 aHansen, Bjorn, M1 aMontaner, Joan1 aThorleifsson, Gudmar1 aStefanson, Kari1 aRosand, Jonathan1 ade Bakker, Paul, I W1 aFarrall, Martin1 aDichgans, Martin1 aMarkus, Hugh, S1 aBevan, Steve1 aGARNET Collaborative Research Group, Wellcome Trust Case Control Consortium 2, Australian Stroke Genetic Collaborative, the METASTROKE Consortium, and the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/657405814nas a2201345 4500008004100000022001400041245014200055210006900197260001300266300001300279490000700292520193700299653002202236653003002258653003402288653002002322653001802342653001102360653002802371653002902399653003602428653004202464100001902506700002002525700001902545700001402564700001802578700001702596700001802613700002602631700001902657700002202676700002002698700003102718700002302749700002102772700001602793700001302809700002102822700001802843700001702861700002402878700002302902700001802925700002402943700002602967700001902993700002303012700002003035700002303055700002603078700001503104700002203119700002203141700001903163700002203182700001903204700001603223700001803239700002103257700002103278700002303299700001803322700001803340700002303358700002203381700002503403700002303428700001903451700001903470700002503489700002403514700002203538700001803560700001703578700001903595700001403614700002403628700001603652700002503668700002403693700002003717700001603737700001503753700002103768700002103789700002503810700002203835700002003857700002103877700002003898700001703918700002003935700002303955700002403978700002404002700002004026700002004046700002204066700002204088700002104110700002004131700002104151700002204172700002204194700001504216700002304231700002204254710002004276710002204296710002304318710002204341710006904363856003604432 2014 eng d a1553-740400aMeta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.0 aMetaanalysis of genomewide association studies in African Americ c2014 Aug ae10045170 v103 aType 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)
10aAfrican Americans10aDiabetes Mellitus, Type 210aGenome-Wide Association Study10aHLA-B27 Antigen10aHMGA2 Protein10aHumans10aKCNQ1 Potassium Channel10aMutant Chimeric Proteins10aPolymorphism, Single Nucleotide10aTranscription Factor 7-Like 2 Protein1 aC Y Ng, Maggie1 aShriner, Daniel1 aChen, Brian, H1 aLi, Jiang1 aChen, Wei-Min1 aGuo, Xiuqing1 aLiu, Jiankang1 aBielinski, Suzette, J1 aYanek, Lisa, R1 aNalls, Michael, A1 aComeau, Mary, E1 aRasmussen-Torvik, Laura, J1 aJensen, Richard, A1 aEvans, Daniel, S1 aSun, Yan, V1 aAn, Ping1 aPatel, Sanjay, R1 aLu, Yingchang1 aLong, Jirong1 aArmstrong, Loren, L1 aWagenknecht, Lynne1 aYang, Lingyao1 aSnively, Beverly, M1 aPalmer, Nicholette, D1 aMudgal, Poorva1 aLangefeld, Carl, D1 aKeene, Keith, L1 aFreedman, Barry, I1 aMychaleckyj, Josyf, C1 aNayak, Uma1 aRaffel, Leslie, J1 aGoodarzi, Mark, O1 aChen, Y-D, Ida1 aTaylor, Herman, A1 aCorrea, Adolfo1 aSims, Mario1 aCouper, David1 aPankow, James, S1 aBoerwinkle, Eric1 aAdeyemo, Adebowale1 aDoumatey, Ayo1 aChen, Guanjie1 aMathias, Rasika, A1 aVaidya, Dhananjay1 aSingleton, Andrew, B1 aZonderman, Alan, B1 aIgo, Robert, P1 aSedor, John, R1 aKabagambe, Edmond, K1 aSiscovick, David, S1 aMcKnight, Barbara1 aRice, Kenneth1 aLiu, Yongmei1 aHsueh, Wen-Chi1 aZhao, Wei1 aBielak, Lawrence, F1 aKraja, Aldi1 aProvince, Michael, A1 aBottinger, Erwin, P1 aGottesman, Omri1 aCai, Qiuyin1 aZheng, Wei1 aBlot, William, J1 aLowe, William, L1 aPacheco, Jennifer, A1 aCrawford, Dana, C1 aGrundberg, Elin1 aRich, Stephen, S1 aHayes, Geoffrey1 aShu, Xiao-Ou1 aLoos, Ruth, J F1 aBorecki, Ingrid, B1 aPeyser, Patricia, A1 aCummings, Steven, R1 aPsaty, Bruce, M1 aFornage, Myriam1 aIyengar, Sudha, K1 aEvans, Michele, K1 aBecker, Diane, M1 aKao, Linda, W H1 aWilson, James, G1 aRotter, Jerome, I1 aSale, Michèle, M1 aLiu, Simin1 aRotimi, Charles, N1 aBowden, Donald, W1 aFIND Consortium1 aeMERGE Consortium1 aDIAGRAM Consortium1 aMuTHER Consortium1 aMEta-analysis of type 2 DIabetes in African Americans Consortium uhttps://chs-nhlbi.org/node/658503769nas a2200937 4500008004100000022001400041245009400055210006900149260001600218300001200234490000700246520111800253653002201371653001601393653002301409653004001432653001101472653001701483653002201500653003401522653001101556653001401567653001801581100002501599700001801624700001801642700002501660700002101685700001801706700002301724700002301747700002201770700001201792700002001804700002301824700002201847700002201869700002001891700002801911700002201939700002201961700002001983700002302003700001802026700002802044700001802072700002202090700002202112700001902134700002002153700001702173700002302190700002302213700002202236700002102258700001802279700002202297700002202319700002202341700002002363700002202383700001402405700001502419700002202434700002202456700002402478700002402502700002402526700001702550700002202567700001702589700002102606700002402627700002302651700002502674700002302699700002402722700002402746700002502770856003602795 2014 eng d a1460-208300aMeta-analysis of loci associated with age at natural menopause in African-American women.0 aMetaanalysis of loci associated with age at natural menopause in c2014 Jun 15 a3327-420 v233 a
Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.
10aAfrican Americans10aAge Factors10aChromosomes, Human10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMenopause10aUnited States1 aChen, Christina, T L1 aLiu, Ching-Ti1 aChen, Gary, K1 aAndrews, Jeanette, S1 aArnold, Alice, M1 aDreyfus, Jill1 aFranceschini, Nora1 aGarcia, Melissa, E1 aKerr, Kathleen, F1 aLi, Guo1 aLohman, Kurt, K1 aMusani, Solomon, K1 aNalls, Michael, A1 aRaffel, Leslie, J1 aSmith, Jennifer1 aAmbrosone, Christine, B1 aBandera, Elisa, V1 aBernstein, Leslie1 aBritton, Angela1 aBrzyski, Robert, G1 aCappola, Anne1 aCarlson, Christopher, S1 aCouper, David1 aDeming, Sandra, L1 aGoodarzi, Mark, O1 aHeiss, Gerardo1 aJohn, Esther, M1 aLu, Xiaoning1 aLe Marchand, Loïc1 aMarciante, Kristin1 aMcKnight, Barbara1 aMillikan, Robert1 aNock, Nora, L1 aOlshan, Andrew, F1 aPress, Michael, F1 aVaiyda, Dhananjay1 aWoods, Nancy, F1 aTaylor, Herman, A1 aZhao, Wei1 aZheng, Wei1 aEvans, Michele, K1 aHarris, Tamara, B1 aHenderson, Brian, E1 aKardia, Sharon, L R1 aKooperberg, Charles1 aLiu, Yongmei1 aMosley, Thomas, H1 aPsaty, Bruce1 aWellons, Melissa1 aWindham, Beverly, G1 aZonderman, Alan, B1 aCupples, Adrienne, L1 aDemerath, Ellen, W1 aHaiman, Christopher1 aMurabito, Joanne, M1 aRajkovic, Aleksandar uhttps://chs-nhlbi.org/node/655204252nas a2200745 4500008004100000022001400041245016200055210006900217260001300286300001100299490000600310520207600316653001002392653003902402653000902441653003702450653002302487653001102510653002202521653003402543653002302577653001102600653002802611653001702639653000902656653001602665653003602681653001802717653001602735100002602751700002602777700001902803700002102822700002802843700001602871700001702887700002302904700001702927700001902944700001502963700002602978700002003004700002603024700001803050700001803068700002103086700002103107700002103128700002203149700002103171700002303192700002003215700002203235700002703257700002503284700002003309700001603329700002103345700002303366700002303389700002203412700001703434700001903451856003603470 2014 eng d a1942-326800aMultiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study.0 aMultiancestral analysis of inflammationrelated genetic variants c2014 Apr a178-880 v73 aBACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.
METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).
CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
10aAdult10aAfrican Continental Ancestry Group10aAged10aAsian Continental Ancestry Group10aC-Reactive Protein10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHispanic Americans10aHumans10aIndians, North American10aInflammation10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aUnited States10aYoung Adult1 aKocarnik, Jonathan, M1 aPendergrass, Sarah, A1 aCarty, Cara, L1 aPankow, James, S1 aSchumacher, Fredrick, R1 aCheng, Iona1 aDurda, Peter1 aAmbite, Jose, Luis1 aDeelman, Ewa1 aCook, Nancy, R1 aLiu, Simin1 aWactawski-Wende, Jean1 aHutter, Carolyn1 aBrown-Gentry, Kristin1 aWilson, Sarah1 aBest, Lyle, G1 aPankratz, Nathan1 aHong, Ching-Ping1 aCole, Shelley, A1 aVoruganti, Saroja1 aBůzková, Petra1 aJorgensen, Neal, W1 aJenny, Nancy, S1 aWilkens, Lynne, R1 aHaiman, Christopher, A1 aKolonel, Laurence, N1 aLaCroix, Andrea1 aNorth, Kari1 aJackson, Rebecca1 aLe Marchand, Loïc1 aHindorff, Lucia, A1 aCrawford, Dana, C1 aGross, Myron1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/636004102nas a2200769 4500008004100000022001400041245011400055210006900169260001300238300001200251490000700263520188300270653001002153653000902163653002202172653002402194653001902218653001902237653002502256653001902281653002802300653001102328653003802339653002202377653003402399653001102433653001702444653000902461653001602470653003102486653003602517653001502553653002402568653003102592653002002623653001702643653001602660653001102676100001802687700001702705700002202722700002702744700002202771700002002793700003002813700002902843700001902872700001802891700002502909700002002934700002002954700002002974700002202994700002303016700001903039700002503058700002103083700002203104700002203126700002303148700001903171700002003190700002003210700002103230710004503251856003603296 2014 eng d a1524-462800aMultilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.0 aMultilocus genetic risk score associates with ischemic stroke in c2014 Feb a394-4020 v453 aBACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.
METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.
RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.
CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.
10aAdult10aAged10aAged, 80 and over10aAtrial Fibrillation10aBlood Pressure10aBrain Ischemia10aCase-Control Studies10aCohort Studies10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMiddle Aged10aMultilocus Sequence Typing10aPolymorphism, Single Nucleotide10aPopulation10aProspective Studies10aReproducibility of Results10aRisk Assessment10aRisk Factors10aSex Factors10aStroke1 aMalik, Rainer1 aBevan, Steve1 aNalls, Michael, A1 aHolliday, Elizabeth, G1 aDevan, William, J1 aCheng, Yu-Ching1 aIbrahim-Verbaas, Carla, A1 aVerhaaren, Benjamin, F J1 aBis, Joshua, C1 aJoon, Aron, Y1 ade Stefano, Anita, L1 aFornage, Myriam1 aPsaty, Bruce, M1 aIkram, Arfan, M1 aLauner, Lenore, J1 aDuijn, Cornelia, M1 aSharma, Pankaj1 aMitchell, Braxton, D1 aRosand, Jonathan1 aMeschia, James, F1 aLevi, Christopher1 aRothwell, Peter, M1 aSudlow, Cathie1 aMarkus, Hugh, S1 aSeshadri, Sudha1 aDichgans, Martin1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/629705936nas a2201453 4500008004100000022001400041245016600055210006900221260000900290300001200299490000600311520182200317653002102139653002002160653001502180653003302195653001302228653001102241653001202252100001802264700001502282700002202297700002502319700002202344700001902366700002002385700002002405700002002425700002202445700001802467700002402485700002302509700002402532700002002556700001602576700002002592700002202612700002502634700002902659700001902688700001702707700001602724700002002740700002402760700002502784700001802809700001802827700001902845700001802864700002102882700002002903700001502923700001802938700003002956700002102986700001703007700002003024700001903044700001903063700003003082700002503112700001903137700001703156700002403173700001803197700001903215700001803234700002203252700001403274700001903288700002403307700002103331700002703352700001803379700002603397700001903423700002403442700002303466700002803489700002603517700002303543700002303566700002103589700002003610700002603630700002003656700002103676700002503697700002503722700001703747700002103764700001903785700002403804700002203828700002103850700002103871700001903892700001503911700002003926700001903946700002103965700002803986700002004014700001704034700002504051700002004076700002304096700001904119700001904138700002004157700002104177700001904198700001904217700002004236700001904256700001804275700002504293700003204318700003004350700002304380700002004403700002304423856003604446 2014 eng d a1932-620300aNo evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.0 aNo evidence for genomewide interactions on plasma fibrinogen by c2014 ae1111560 v93 aPlasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
10aAlcohol Drinking10aBody Mass Index10aFibrinogen10aGene-Environment Interaction10aGenomics10aHumans10aSmoking1 aBaumert, Jens1 aHuang, Jie1 aMcKnight, Barbara1 aSabater-Lleal, Maria1 aSteri, Maristella1 aChu, Audrey, Y1 aTrompet, Stella1 aLopez, Lorna, M1 aFornage, Myriam1 aTeumer, Alexander1 aTang, Weihong1 aRudnicka, Alicja, R1 aMälarstig, Anders1 aHottenga, Jouke-Jan1 aKavousi, Maryam1 aLahti, Jari1 aTanaka, Toshiko1 aHayward, Caroline1 aHuffman, Jennifer, E1 aMorange, Pierre-Emmanuel1 aRose, Lynda, M1 aBasu, Saonli1 aRumley, Ann1 aStott, David, J1 aBuckley, Brendan, M1 ade Craen, Anton, J M1 aSanna, Serena1 aMasala, Marco1 aBiffar, Reiner1 aHomuth, Georg1 aSilveira, Angela1 aSennblad, Bengt1 aGoel, Anuj1 aWatkins, Hugh1 aMüller-Nurasyid, Martina1 aRückerl, Regina1 aTaylor, Kent1 aChen, Ming-Huei1 aGeus, Eco, J C1 aHofman, Albert1 aWitteman, Jacqueline, C M1 ade Maat, Moniek, P M1 aPalotie, Aarno1 aDavies, Gail1 aSiscovick, David, S1 aKolcic, Ivana1 aWild, Sarah, H1 aSong, Jaejoon1 aMcArdle, Wendy, L1 aFord, Ian1 aSattar, Naveed1 aSchlessinger, David1 aGrotevendt, Anne1 aFranzosi, Maria Grazia1 aIllig, Thomas1 aWaldenberger, Melanie1 aLumley, Thomas1 aTofler, Geoffrey, H1 aWillemsen, Gonneke1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aRäikkönen, Katri1 aChasman, Daniel, I1 aFolsom, Aaron, R1 aLowe, Gordon, D1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aCucca, Francesco1 aWallaschofski, Henri1 aStrawbridge, Rona, J1 aSeedorf, Udo1 aKoenig, Wolfgang1 aBis, Joshua, C1 aMukamal, Kenneth, J1 avan Dongen, Jenny1 aWiden, Elisabeth1 aFranco, Oscar, H1 aStarr, John, M1 aLiu, Kiang1 aFerrucci, Luigi1 aPolasek, Ozren1 aWilson, James, F1 aOudot-Mellakh, Tiphaine1 aCampbell, Harry1 aNavarro, Pau1 aBandinelli, Stefania1 aEriksson, Johan1 aBoomsma, Dorret, I1 aDehghan, Abbas1 aClarke, Robert1 aHamsten, Anders1 aBoerwinkle, Eric1 aJukema, Wouter1 aNaitza, Silvia1 aRidker, Paul, M1 aVölzke, Henry1 aDeary, Ian, J1 aReiner, Alexander, P1 aTrégouët, David-Alexandre1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aPeters, Annette1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/666703240nas a2200517 4500008004100000022001400041245009600055210006900151260001300220300000900233490000700242520182300249653000902072653002202081653002902103653003602132653003102168653001102199653002202210653003402232653001302266653001502279653001102294653001702305653004602322653001902368653000902387653003602396100001902432700001002451700001602461700001402477700001602491700001502507700001202522700001602534700001602550700001702566700001902583700001502602700001802617700001602635700001702651700001802668856003602686 2014 eng d a1096-002300aNovel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.0 aNovel gene variants predict serum levels of the cytokines IL18 a c2014 Jan a10-60 v653 aActivation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9×10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3×10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7×10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.
10aAged10aAged, 80 and over10aCalcium-Binding Proteins10aCARD Signaling Adaptor Proteins10aChromosomes, Human, Pair 210aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHaplotypes10aHumans10aInflammation10aInterleukin 1 Receptor Antagonist Protein10aInterleukin-1810aMale10aPolymorphism, Single Nucleotide1 aMatteini, A, M1 aLi, J1 aLange, E, M1 aTanaka, T1 aLange, L, A1 aTracy, R P1 aWang, Y1 aBiggs, M, L1 aArking, D E1 aFallin, M, D1 aChakravarti, A1 aPsaty, B M1 aBandinelli, S1 aFerrucci, L1 aReiner, A, P1 aWalston, J, D uhttps://chs-nhlbi.org/node/613304953nas a2201105 4500008004100000022001400041245009300055210006900148260001500217300001200232490000700244520183400251653001002085653000902095653002202104653003702126653002402163653002302187653003102210653001102241653004002252653001102292653002002303653003802323653002502361653001102386653001002397653000902407653001602416653003602432653002602468100002202494700002402516700001902540700001902559700002002578700001202598700002202610700002302632700001802655700002202673700001802695700001902713700002102732700003002753700001902783700002202802700001902824700002302843700001702866700002402883700001402907700002102921700002202942700001902964700001902983700001903002700002203021700001903043700002203062700002503084700002203109700002203131700002203153700002003175700002003195700001903215700002203234700002603256700002303282700002203305700002003327700002003347700002403367700002303391700002803414700002603442700001703468700001903485700002403504700002203528700002403550700002203574700002003596700001603616700002503632700002303657700002203680700002303702700001903725700001903744700002403763700002403787856003603811 2014 eng d a1558-359700aNovel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.0 aNovel genetic markers associate with atrial fibrillation risk in c2014 Apr 1 a1200-100 v633 aOBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factors1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aLin, Honghuang1 aArking, Dan, E1 aTrompet, Stella1 aLi, Guo1 aKrijthe, Bouwe, P1 aChasman, Daniel, I1 aBarnard, John1 aKleber, Marcus, E1 aDörr, Marcus1 aOzaki, Kouichi1 aSmith, Albert, V1 aMüller-Nurasyid, Martina1 aWalter, Stefan1 aAgarwal, Sunil, K1 aBis, Joshua, C1 aBrody, Jennifer, A1 aChen, Lin, Y1 aEverett, Brendan, M1 aFord, Ian1 aFranco, Oscar, H1 aHarris, Tamara, B1 aHofman, Albert1 aKääb, Stefan1 aMahida, Saagar1 aKathiresan, Sekar1 aKubo, Michiaki1 aLauner, Lenore, J1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aMcKnight, Barbara1 aMcManus, David, D1 aPeters, Annette1 aPsaty, Bruce, M1 aRose, Lynda, M1 aRotter, Jerome, I1 aSilbernagel, Guenther1 aSmith, Jonathan, D1 aSotoodehnia, Nona1 aStott, David, J1 aTaylor, Kent, D1 aTomaschitz, Andreas1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aMurabito, Joanne, M1 aSinner, Moritz, F1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aMärz, Winfried1 aChung, Mina1 aAlbert, Christine, M1 aStricker, Bruno, H1 aTanaka, Toshihiro1 aHeckbert, Susan, R1 aJukema, Wouter1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/682004872nas a2201453 4500008004100000022001400041245010900055210006900164260001600233300000900249490000600258520072200264653002100986653003401007653001101041653005101052653002101103653003601124100001801160700002001178700002501198700002301223700001601246700002101262700002301283700001701306700002501323700002401348700002201372700002201394700001901416700001701435700002001452700001201472700002101484700002101505700002801526700002301554700002501577700002001602700002401622700001401646700002601660700002001686700001901706700002401725700001701749700001801766700001901784700002201803700001801825700002201843700001901865700002601884700002101910700002501931700002401956700001801980700002501998700002202023700002102045700001702066700002402083700001602107700001602123700001902139700002202158700001602180700001902196700001902215700001802234700002302252700001902275700002102294700001802315700002102333700002002354700003002374700002702404700001602431700002202447700001802469700001602487700001702503700002302520700001602543700002202559700002102581700002602602700002002628700002502648700002802673700002402701700002302725700002202748700001902770700002302789700002302812700002202835700002002857700002302877700002802900700001902928700002602947700002002973700002102993700002003014700002403034700001703058700002103075700002803096700002203124700002203146700002003168700002303188700002403211700002203235700001903257700002203276700001903298700002303317710004203340856003603382 2014 eng d a2041-172300aPharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.0 aPharmacogenetic metaanalysis of genomewide association studies o c2014 Oct 28 a50680 v53 aStatins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
10aCholesterol, LDL10aGenome-Wide Association Study10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aPharmacogenetics10aPolymorphism, Single Nucleotide1 aPostmus, Iris1 aTrompet, Stella1 aDeshmukh, Harshal, A1 aBarnes, Michael, R1 aLi, Xiaohui1 aWarren, Helen, R1 aChasman, Daniel, I1 aZhou, Kaixin1 aArsenault, Benoit, J1 aDonnelly, Louise, A1 aWiggins, Kerri, L1 aAvery, Christy, L1 aGriffin, Paula1 aFeng, QiPing1 aTaylor, Kent, D1 aLi, Guo1 aEvans, Daniel, S1 aSmith, Albert, V1 ade Keyser, Catherine, E1 aJohnson, Andrew, D1 ade Craen, Anton, J M1 aStott, David, J1 aBuckley, Brendan, M1 aFord, Ian1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aSattar, Naveed1 aMunroe, Patricia, B1 aSever, Peter1 aPoulter, Neil1 aStanton, Alice1 aShields, Denis, C1 aO'Brien, Eoin1 aShaw-Hawkins, Sue1 aChen, Y-D, Ida1 aNickerson, Deborah, A1 aSmith, Joshua, D1 aDubé, Marie, Pierre1 aBoekholdt, Matthijs1 aHovingh, Kees1 aKastelein, John, J P1 aMcKeigue, Paul, M1 aBetteridge, John1 aNeil, Andrew1 aDurrington, Paul, N1 aDoney, Alex1 aCarr, Fiona1 aMorris, Andrew1 aMcCarthy, Mark, I1 aGroop, Leif1 aAhlqvist, Emma1 aBis, Joshua, C1 aRice, Kenneth1 aSmith, Nicholas, L1 aLumley, Thomas1 aWhitsel, Eric, A1 aStürmer, Til1 aBoerwinkle, Eric1 aNgwa, Julius, S1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWei, Wei-Qi1 aWilke, Russell, A1 aLiu, Ching-Ti1 aSun, Fangui1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aPost, Wendy1 aSotoodehnia, Nona1 aArnold, Alice, M1 aStafford, Jeanette, M1 aDing, Jingzhong1 aHerrington, David, M1 aKritchevsky, Stephen, B1 aEiriksdottir, Gudny1 aLauner, Leonore, J1 aHarris, Tamara, B1 aChu, Audrey, Y1 aGiulianini, Franco1 aMacFadyen, Jean, G1 aBarratt, Bryan, J1 aNyberg, Fredrik1 aStricker, Bruno, H1 aUitterlinden, André, G1 aHofman, Albert1 aRivadeneira, Fernando1 aEmilsson, Valur1 aFranco, Oscar, H1 aRidker, Paul, M1 aGudnason, Vilmundur1 aLiu, Yongmei1 aDenny, Joshua, C1 aBallantyne, Christie, M1 aRotter, Jerome, I1 aCupples, Adrienne1 aPsaty, Bruce, M1 aPalmer, Colin, N A1 aTardif, Jean-Claude1 aColhoun, Helen, M1 aHitman, Graham1 aKrauss, Ronald, M1 aJukema, Wouter1 aCaulfield, Mark, J1 aWelcome Trust Case Control Consortium uhttps://chs-nhlbi.org/node/659103126nas a2200457 4500008004100000022001400041245011500055210007000170260001600240300001200256490000800268520184400276653000902120653002502129653002802154653001902182653002102201653000902222653001102231653001102242653000902253653001402262653001802276653003202294653002402326653001702350653001102367653001802378100002202396700002502418700002402443700002102467700002002488700001802508700001902526700002202545700002202567700001902589700002402608856003602632 2014 eng d a1475-266200aPlasma phospholipid and dietary α-linolenic acid, mortality, CHD and stroke: the Cardiovascular Health Study.0 aPlasma phospholipid and dietary αlinolenic acid mortality CHD an c2014 Oct 14 a1206-130 v1123 aPrevious studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18 : 3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged ≥ 65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0·73 (95 % CI 0·61, 0·88) and 0·64 (95 % CI 0·52, 0·80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.
10aAged10aalpha-Linolenic Acid10aCardiovascular Diseases10aCohort Studies10aCoronary Disease10aDiet10aFemale10aHumans10aMale10aMortality10aPhospholipids10aProportional Hazards Models10aProspective Studies10aRisk Factors10aStroke10aUnited States1 aFretts, Amanda, M1 aMozaffarian, Dariush1 aSiscovick, David, S1 aSitlani, Colleen1 aPsaty, Bruce, M1 aRimm, Eric, B1 aSong, Xiaoling1 aMcKnight, Barbara1 aSpiegelman, Donna1 aKing, Irena, B1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/656203179nas a2200529 4500008004100000022001400041245012900055210006900184260001600253300001000269490000800279520167700287653002101964653001601985653000902001653002202010653001502032653002802047653001902075653003202094653003102126653001102157653002202168653001802190653001102208653000902219653001402228653002402242653002002266653001702286653001802303653001702321653001802338100002402356700002102380700001902401700002102420700002002441700001902461700002502480700002202505700002002527700002402547700002402571700001802595856003602613 2014 eng d a1879-191300aPlasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study).0 aPlasmafree fatty acids fatty acidbinding protein 4 and mortality c2014 Sep 15 a843-80 v1143 aPlasma-free fatty acids (FFAs) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes, but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992 to 1993 as part of the Cardiovascular Health Study, an observational cohort of community-dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio [HR] per SD: 1.14, 95% confidence interval [CI] 1.09 to 1.18), but FABP4 levels were not (HR 1.04, 95% CI 0.98 to 1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death because of cardiovascular disease, dementia, infection, and respiratory causes but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p = 0.45), but FABP4 appeared to be associated with total mortality differentially in men and women (HR 1.17, 95% CI 1.08 to 1.26 for men; HR 1.02, 95% CI 0.96 to 1.07 for women, interaction p value <0.001). In conclusion, in a cohort of community-dwelling older subjects, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and noncardiovascular mortality.
10aAge Distribution10aAge Factors10aAged10aAged, 80 and over10aBiomarkers10aCardiovascular Diseases10aCause of Death10aFatty Acid-Binding Proteins10aFatty Acids, Nonesterified10aFemale10aFollow-Up Studies10aHealth Status10aHumans10aMale10aPrognosis10aProspective Studies10aRisk Assessment10aRisk Factors10aSurvival Rate10aTime Factors10aUnited States1 aMiedema, Michael, D1 aMaziarz, Marlena1 aBiggs, Mary, L1 aZieman, Susan, J1 aKizer, Jorge, R1 aIx, Joachim, H1 aMozaffarian, Dariush1 aTracy, Russell, P1 aPsaty, Bruce, M1 aSiscovick, David, S1 aMukamal, Kenneth, J1 aDjoussé, Luc uhttps://chs-nhlbi.org/node/658404219nas a2200913 4500008004100000022001400041245008500055210006900140260001300209300001100222490000700233520168500240653001601925653000901941653002201950653002101972653002501993653001902018653004002037653001102077653003802088653003402126653001302160653001102173653000902184653001602193653003602209653002402245653001702269653001402286653001602300653001102316100003002327700002002357700001902377700002202396700002002418700002002438700001502458700001602473700002102489700003002510700002202540700002002562700002102582700001802603700002102621700002002642700001602662700002302678700001902701700001802720700002202738700002002760700002102780700002102801700002302822700001702845700002602862700002402888700001602912700002602928700001902954700001902973700002802992700002403020700002303044700001603067700001803083700002003101700002103121700002003142700002003162700002203182700002003204700002303224700002203247856003603269 2014 eng d a1524-462800aPredicting stroke through genetic risk functions: the CHARGE Risk Score Project.0 aPredicting stroke through genetic risk functions the CHARGE Risk c2014 Feb a403-120 v453 aBACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.
METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.
RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).
CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.
10aAge Factors10aAged10aAged, 80 and over10aArea Under Curve10aCase-Control Studies10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aROC Curve10aSex Factors10aStroke1 aIbrahim-Verbaas, Carla, A1 aFornage, Myriam1 aBis, Joshua, C1 aChoi, Seung, Hoan1 aPsaty, Bruce, M1 aMeigs, James, B1 aRao, Madhu1 aNalls, Mike1 aFontes, João, D1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aEhret, Georg, B1 aFox, Caroline, S1 aMalik, Rainer1 aDichgans, Martin1 aSchmidt, Helena1 aLahti, Jari1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Kenneth1 aRotter, Jerome, I1 aTaylor, Kent, D1 aFolsom, Aaron, R1 aBoerwinkle, Eric1 aRosamond, Wayne, D1 aShahar, Eyal1 aGottesman, Rebecca, F1 aKoudstaal, Peter, J1 aAmin, Najaf1 aWieberdink, Renske, G1 aDehghan, Abbas1 aHofman, Albert1 aUitterlinden, André, G1 aDeStefano, Anita, L1 aDebette, Stephanie1 aXue, Luting1 aBeiser, Alexa1 aWolf, Philip, A1 aDeCarli, Charles1 aIkram, Arfan, M1 aSeshadri, Sudha1 aMosley, Thomas, H1 aLongstreth, W T1 aDuijn, Cornelia, M1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/622003265nas a2200457 4500008004100000022001400041245012300055210006900178260001300247300001300260490000700273520196100280653000902241653002202250653001002272653002502282653002602307653002402333653001102357653002202368653001602390653001102406653002002417653003102437653000902468653002102477653001402498653002402512653001702536653002702553100001902580700002402599700002002623700002302643700002302666700001802689700002002707700002202727700002202749856003602771 2014 eng d a1758-535X00aPrognostic implications of microvascular and macrovascular abnormalities in older adults: cardiovascular health study.0 aPrognostic implications of microvascular and macrovascular abnor c2014 Dec a1495-5020 v693 aBACKGROUND: Microvascular and macrovascular abnormalities are frequently found on noninvasive tests performed in older adults. Their prognostic implications on disability and life expectancy have not been collectively assessed.
METHODS: This prospective study included 2,452 adults (mean age: 79.5 years) with available measures of microvascular (brain, retina, kidney) and macrovascular abnormalities (brain, carotid, coronary, peripheral artery) in the Cardiovascular Health Study. The burden of microvascular and macrovascular abnormalities was examined in relation to total, activity-of-daily-living disability-free, and severe disability-free life expectancies in the next 10 years (1999-2009).
RESULTS: At 75 years, individuals with low burden of both abnormalities lived, on average, 8.71 years (95% confidence interval: 8.29, 9.12) of which 7.67 years (7.16, 8.17) were without disability. In comparison, individuals with high burden of both abnormalities had shortest total life expectancy (6.95 years [6.52, 7.37]; p < .001) and disability-free life expectancy (5.60 years [5.10, 6.11]; p < .001). Although total life expectancy was similarly reduced for those with high burden of either type of abnormalities (microvascular: 7.96 years [7.50, 8.42] vs macrovascular: 8.25 years [7.80, 8.70]; p = .10), microvascular abnormalities seemed to have larger impact than macrovascular abnormalities on disability-free life expectancy (6.45 years [5.90, 6.99] vs 6.96 years [6.43, 7.48]; p = .016). These results were consistent for severe disability-free life expectancy and in individuals without clinical cardiovascular disease.
CONCLUSIONS: Considering both microvascular and macrovascular abnormalities from multiple noninvasive tests may provide additional prognostic information on how older adults spend their remaining life. Optimal clinical use of this information remains to be determined.
10aAged10aAged, 80 and over10aAging10aAnkle Brachial Index10aDisability Evaluation10aElectrocardiography10aFemale10aFollow-Up Studies10aForecasting10aHumans10aLife Expectancy10aMagnetic Resonance Imaging10aMale10aMicrocirculation10aPrognosis10aProspective Studies10aRisk Factors10aVascular Malformations1 aKim, Dae, Hyun1 aGrodstein, Francine1 aNewman, Anne, B1 aChaves, Paulo, H M1 aOdden, Michelle, C1 aKlein, Ronald1 aSarnak, Mark, J1 aPatel, Kushang, V1 aLipsitz, Lewis, A uhttps://chs-nhlbi.org/node/636303227nas a2200505 4500008004100000022001400041245012600055210006900181260001600250300001200266490000700278520166100285653003501946653002301981653004002004653001002044653001102054653003202065653002102097653002602118100002002144700002002164700002302184700002402207700002902231700001802260700002502278700001902303700002602322700002302348700001702371700002202388700002202410700002002432700002402452700002502476700003002501700002502531700002102556700002002577700002402597700002602621710003802647856003602685 2014 eng d a1460-208300aQuantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.0 aQuantifying rare deleterious variation in 12 human cytochrome P4 c2014 Apr 15 a1957-630 v233 aThe study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
10aCytochrome P-450 Enzyme System10aDatabases, Genetic10aEuropean Continental Ancestry Group10aExome10aHumans10aPharmaceutical Preparations10aPharmacogenetics10aPolymorphism, Genetic1 aGordon, Adam, S1 aTabor, Holly, K1 aJohnson, Andrew, D1 aSnively, Beverly, M1 aAssimes, Themistocles, L1 aAuer, Paul, L1 aIoannidis, John, P A1 aPeters, Ulrike1 aRobinson, Jennifer, G1 aSucheston, Lara, E1 aWang, Danxin1 aSotoodehnia, Nona1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aJackson, Rebecca, D1 aHerrington, David, M1 aO'Donnell, Christopher, J1 aReiner, Alexander, P1 aRich, Stephen, S1 aRieder, Mark, J1 aBamshad, Michael, J1 aNickerson, Deborah, A1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/656503213nas a2200541 4500008004100000022001400041245011300055210006900168260001300237300001100250490000700261520163100268653001001899653003901909653000901948653002201957653001601979653003701995653002802032653001902060653001502079653004002094653001102134653003102145653001102176653002802187653000902215653001602224653001502240653003302255653001702288100001902305700002502324700001802349700002102367700002002388700001602408700002302424700002302447700001702470700001902487700001902506700002302525700002102548700001802569710004802587856003602635 2014 eng d a1523-175500aRelative risks of chronic kidney disease for mortality and end-stage renal disease across races are similar.0 aRelative risks of chronic kidney disease for mortality and endst c2014 Oct a819-270 v863 aSome suggest race-specific cutpoints for kidney measures to define and stage chronic kidney disease (CKD), but evidence for race-specific clinical impact is limited. To address this issue, we compared hazard ratios of estimated glomerular filtration rates (eGFR) and albuminuria across races using meta-regression in 1.1 million adults (75% Asians, 21% Whites, and 4% Blacks) from 45 cohorts. Results came mainly from 25 general population cohorts comprising 0.9 million individuals. The associations of lower eGFR and higher albuminuria with mortality and end-stage renal disease (ESRD) were largely similar across races. For example, in Asians, Whites, and Blacks, the adjusted hazard ratios (95% confidence interval) for eGFR 45-59 versus 90-104 ml/min per 1.73 m(2) were 1.3 (1.2-1.3), 1.1 (1.0-1.2), and 1.3 (1.1-1.7) for all-cause mortality, 1.6 (1.5-1.7), 1.4 (1.2-1.7), and 1.4 (0.7-2.9) for cardiovascular mortality, and 27.6 (11.1-68.7), 11.2 (6.0-20.9), and 4.1 (2.2-7.5) for ESRD, respectively. The corresponding hazard ratios for urine albumin-to-creatinine ratio 30-299 mg/g or dipstick 1+ versus an albumin-to-creatinine ratio under 10 or dipstick negative were 1.6 (1.4-1.8), 1.7 (1.5-1.9), and 1.8 (1.7-2.1) for all-cause mortality, 1.7 (1.4-2.0), 1.8 (1.5-2.1), and 2.8 (2.2-3.6) for cardiovascular mortality, and 7.4 (2.0-27.6), 4.0 (2.8-5.9), and 5.6 (3.4-9.2) for ESRD, respectively. Thus, the relative mortality or ESRD risks of lower eGFR and higher albuminuria were largely similar among three major races, supporting similar clinical approach to CKD definition and staging, across races.
10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aAlbuminuria10aAsian Continental Ancestry Group10aCardiovascular Diseases10aCohort Studies10aCreatinine10aEuropean Continental Ancestry Group10aFemale10aGlomerular Filtration Rate10aHumans10aKidney Failure, Chronic10aMale10aMiddle Aged10aOdds Ratio10aRenal Insufficiency, Chronic10aRisk Factors1 aWen, Chi, Pang1 aMatsushita, Kunihiro1 aCoresh, Josef1 aIseki, Kunitoshi1 aIslam, Muhammad1 aKatz, Ronit1 aMcClellan, William1 aPeralta, Carmen, A1 aWang, Haiyan1 ade Zeeuw, Dick1 aAstor, Brad, C1 aGansevoort, Ron, T1 aLevey, Andrew, S1 aLevin, Adeera1 aChronic Kidney Disease Prognosis Consortium uhttps://chs-nhlbi.org/node/629503245nas a2200517 4500008004100000022001400041245011100055210006900166260001300235300001100248490000800259520180600267653000902073653002202082653001902104653002302123653002802146653002102174653002102195653002702216653002202243653001102265653001102276653001702287653001102304653002002315653001102335653000902346653003102355653001202386653002202398653001702420100002302437700002402460700002402484700001602508700002502524700002102549700001902570700002002589700002402609700001802633700002002651700002002671856003602691 2014 eng d a1879-148400aRisk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study.0 aRisk factors for cardiovascular disease across the spectrum of o c2014 Nov a336-420 v2373 aOBJECTIVE: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age.
METHODS: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP).
RESULTS: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45).
CONCLUSIONS: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.
10aAged10aAged, 80 and over10aBlood Pressure10aC-Reactive Protein10aCardiovascular Diseases10aCholesterol, HDL10aCholesterol, LDL10aDiabetes Complications10aDiabetes Mellitus10aFemale10aHumans10aInflammation10aKidney10aKidney Diseases10aLipids10aMale10aNatriuretic Peptide, Brain10aObesity10aPeptide Fragments10aRisk Factors1 aOdden, Michelle, C1 aShlipak, Michael, G1 aWhitson, Heather, E1 aKatz, Ronit1 aKearney, Patricia, M1 adeFilippi, Chris1 aShastri, Shani1 aSarnak, Mark, J1 aSiscovick, David, S1 aCushman, Mary1 aPsaty, Bruce, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/658803375nas a2200541 4500008004100000022001400041245007300055210006900128260001600197300001200213490000700225520189700232653000902129653002202138653002002160653002002180653001902200653001602219653001102235653001102246653001402257653002902271653000902300653001602309653002402325653003002349653002002379653001702399653001102416100002002427700002502447700002602472700002502498700002402523700001902547700001702566700002602583700002002609700002002629700002402649700002002673700002002693700001902713700002102732700002402753700002002777856003602797 2014 eng d a1526-632X00aSeparate prediction of intracerebral hemorrhage and ischemic stroke.0 aSeparate prediction of intracerebral hemorrhage and ischemic str c2014 May 20 a1804-120 v823 aOBJECTIVES: To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).
METHODS: We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions' performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.
RESULTS: High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross-validation. Models were well calibrated in all cohorts. Correlations between 10-year ICH and IS risks were moderate in each cohort.
CONCLUSIONS: We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual's stroke risk.
10aAged10aAged, 80 and over10aAtherosclerosis10aBody Mass Index10aBrain Ischemia10aCholesterol10aFemale10aHumans10aIncidence10aIntracranial Hemorrhages10aMale10aMiddle Aged10aModels, Statistical10aPredictive Value of Tests10aRisk Assessment10aRisk Factors10aStroke1 aFerket, Bart, S1 avan Kempen, Bob, J H1 aWieberdink, Renske, G1 aSteyerberg, Ewout, W1 aKoudstaal, Peter, J1 aHofman, Albert1 aShahar, Eyal1 aGottesman, Rebecca, F1 aRosamond, Wayne1 aKizer, Jorge, R1 aKronmal, Richard, A1 aPsaty, Bruce, M1 aLongstreth, W T1 aMosley, Thomas1 aFolsom, Aaron, R1 aHunink, M, G Myriam1 aIkram, Arfan, M uhttps://chs-nhlbi.org/node/633802820nas a2200349 4500008004100000022001400041245018500055210006900240260000900309300001200318490000600330520176400336653001002100653001902110653001902129653001002148653001102158653002202169100002402191700001902215700002002234700002002254700001902274700001802293700001702311700002202328700002102350700002002371700002602391700001702417856003602434 2014 eng d a1932-620300aSequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study.0 aSequence analysis of six blood pressure candidate regions in 417 c2014 ae1091550 v93 aBACKGROUND: Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).
METHODS AND RESULTS: Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.
CONCLUSION: Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
10aAging10aBlood Pressure10aCohort Studies10aHeart10aHumans10aSequence Analysis1 aMorrison, Alanna, C1 aBis, Joshua, C1 aHwang, Shih-Jen1 aEhret, Georg, B1 aLumley, Thomas1 aRice, Kenneth1 aMuzny, Donna1 aGibbs, Richard, A1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aChakravarti, Aravinda1 aLevy, Daniel uhttps://chs-nhlbi.org/node/661803673nas a2200529 4500008004100000022001400041245019500055210006900250260001300319300001100332490000600343520199700349653000902346653002202355653001002377653002002387653004302407653001902450653004002469653001102509653002202520653003402542653001302576653001102589653000902600653001602609653003602625653002702661653005202688100001902740700002202759700002302781700002002804700002002824700001702844700002202861700001902883700001802902700001902920700002102939700002002960700001902980700002502999700003003024710005303054856003603107 2014 eng d a1942-326800aSequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aSequencing of 2 subclinical atherosclerosis candidate regions in c2014 Jun a359-640 v73 aBACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).
METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).
CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.
10aAged10aAged, 80 and over10aAging10aAtherosclerosis10aClass Ib Phosphatidylinositol 3-Kinase10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA10aSodium-Phosphate Cotransporter Proteins, Type I1 aBis, Joshua, C1 aWhite, Charles, C1 aFranceschini, Nora1 aBrody, Jennifer1 aZhang, Xiaoling1 aMuzny, Donna1 aSantibanez, Jireh1 aGibbs, Richard1 aLiu, Xiaoming1 aLin, Honghuang1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aNorth, Kari, E1 aCupples, Adrienne, L1 aO'Donnell, Christopher, J1 aCHARGE Subclinical Atherosclerosis Working Group uhttps://chs-nhlbi.org/node/654704324nas a2200793 4500008004100000022001400041245017800055210006900233260001300302300001100315490000600326520200100332653001002333653000902343653002202352653001002374653001902384653001102403653002202414653003402436653001302470653002802483653001902511653001102530653000902541653001602550653004002566653003602606653002702642100002202669700002302691700001902714700001902733700001902752700001702771700001802788700002402806700001602830700002002846700001902866700001902885700002302904700001902927700002402946700002502970700002202995700002403017700001903041700002903060700003003089700002403119700002403143700002003167700002203187700002203209700002203231700002203253700002103275700002003296700002103316700002103337700002103358700002003379700002203399710002203421710004103443710001003484856003603494 2014 eng d a1942-326800aSequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.0 aSequencing of SCN5A identifies rare and common variants associat c2014 Jun a365-730 v73 aBACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.
METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).
CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.
10aAdult10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Conduction System10aHeart Diseases10aHumans10aMale10aMiddle Aged10aNAV1.5 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aMagnani, Jared, W1 aBrody, Jennifer, A1 aPrins, Bram, P1 aArking, Dan, E1 aLin, Honghuang1 aYin, Xiaoyan1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aZhang, Feng1 aSpector, Tim, D1 aAlonso, Alvaro1 aBis, Joshua, C1 aHeckbert, Susan, R1 aLumley, Thomas1 aSitlani, Colleen, M1 aCupples, Adrienne, L1 aLubitz, Steven, A1 aSoliman, Elsayed, Z1 aPulit, Sara, L1 aNewton-Cheh, Christopher1 aO'Donnell, Christopher, J1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aMuzny, Donna, M1 aGibbs, Richard, A1 aSantibanez, Jireh1 aTaylor, Herman, A1 aRotter, Jerome, I1 aLange, Leslie, A1 aPsaty, Bruce, M1 aJackson, Rebecca1 aRich, Stephen, S1 aBoerwinkle, Eric1 aJamshidi, Yalda1 aSotoodehnia, Nona1 aCHARGE Consortium1 aNHLBI Exome Sequencing Project (ESP)1 aUK10K uhttps://chs-nhlbi.org/node/658304329nas a2200781 4500008004100000022001400041245012500055210006900180260001300249300001000262490000700272520197700279653001902256653002802275653003702303653003802340653003402378653001102412653001402423653003602437653003102473653001702504653001102521100002102532700001802553700002002571700002102591700001902612700002702631700002502658700002502683700002902708700002202737700003002759700002002789700002802809700002002837700002802857700002002885700002202905700001902927700002002946700002802966700002002994700002203014700002203036700002003058700002003078700002103098700001903119700002403138700002203162700001903184700002303203700002203226700001803248700002303266700002003289700002003309700002203329700002003351700002403371710002603395710002603421710001903447710004503466856003603511 2014 eng d a1524-462800aShared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.0 aShared genetic susceptibility to ischemic stroke and coronary ar c2014 Jan a24-360 v453 aBACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.
RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).
CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
10aBrain Ischemia10aCoronary Artery Disease10aData Interpretation, Statistical10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPhenotype10aPolymorphism, Single Nucleotide10aReproducibility of Results10aRisk Factors10aStroke1 aDichgans, Martin1 aMalik, Rainer1 aKönig, Inke, R1 aRosand, Jonathan1 aClarke, Robert1 aGretarsdottir, Solveig1 aThorleifsson, Gudmar1 aMitchell, Braxton, D1 aAssimes, Themistocles, L1 aLevi, Christopher1 aO'Donnell, Christopher, J1 aFornage, Myriam1 aThorsteinsdottir, Unnur1 aPsaty, Bruce, M1 aHengstenberg, Christian1 aSeshadri, Sudha1 aErdmann, Jeanette1 aBis, Joshua, C1 aPeters, Annette1 aBoncoraglio, Giorgio, B1 aMärz, Winfried1 aMeschia, James, F1 aKathiresan, Sekar1 aIkram, Arfan, M1 aMcPherson, Ruth1 aStefansson, Kari1 aSudlow, Cathie1 aReilly, Muredach, P1 aThompson, John, R1 aSharma, Pankaj1 aHopewell, Jemma, C1 aChambers, John, C1 aWatkins, Hugh1 aRothwell, Peter, M1 aRoberts, Robert1 aMarkus, Hugh, S1 aSamani, Nilesh, J1 aFarrall, Martin1 aSchunkert, Heribert1 aMETASTROKE Consortium1 aCARDIoGRAM consortium1 aC4D Consortium1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/637003487nas a2200505 4500008004100000022001400041245012900055210006900184260001300253300001100266490000700277520205800284653000902342653002202351653001502373653002302388653001902411653001102430653001102441653001702452653004602469653001902515653001802534653001402552653000902566653004502575653001702620100001902637700001802656700001802674700002102692700001702713700001702730700002102747700002202768700001702790700001702807700002002824700001702844700002502861700001902886700002002905700002002925856003602945 2014 eng d a1758-535X00aSimple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults.0 aSimple biologically informed inflammatory index of two serum cyt c2014 Feb a165-730 v693 aBACKGROUND: Individual measurements of inflammation have been utilized to assess adverse outcomes risk in older adults with varying degrees of success. This study was designed to identify biologically informed, aggregate measures of inflammation for optimal risk assessment and to inform further biological study of inflammatory pathways.
METHODS: In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI.
RESULTS: The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index (hazards ratio = 1.62; 95% CI: 1.54, 1.70) compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study (hazards ratio 1.33; 95% CI: 1.17-1.52). Stratification by sex and CVD status further strengthened the association of inflammation index score with mortality.
CONCLUSION: A simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.
10aAged10aAged, 80 and over10aBiomarkers10aC-Reactive Protein10aCohort Studies10aFemale10aHumans10aInflammation10aInterleukin 1 Receptor Antagonist Protein10aInterleukin-1810aInterleukin-610aLongevity10aMale10aReceptors, Tumor Necrosis Factor, Type I10aRisk Factors1 aVaradhan, Ravi1 aYao, Wenliang1 aMatteini, Amy1 aBeamer, Brock, A1 aXue, Qian-Li1 aYang, Huanle1 aManwani, Bhavish1 aReiner, Alexander1 aJenny, Nancy1 aParekh, Neel1 aFallin, Daniele1 aNewman, Anne1 aBandeen-Roche, Karen1 aTracy, Russell1 aFerrucci, Luigi1 aWalston, Jeremy uhttps://chs-nhlbi.org/node/660803530nas a2200565 4500008004100000022001400041245010700055210006900162260001300231300001100244490000700255520189800262653001802160653002102178653002002199653002802219653003002247653004002277653001202317653001102329653003802340653002202378653001302400653002402413653002602437653001102463653002302474653000902497653001602506653003602522653001702558653001002575653003102585653001702616653001802633100001802651700002402669700001902693700002302712700001902735700002302754700002502777700002002802700002002822700002402842700002502866700001902891700001802910856003602928 2014 eng d a1432-042800aSleep duration does not mediate or modify association of common genetic variants with type 2 diabetes.0 aSleep duration does not mediate or modify association of common c2014 Feb a339-460 v573 aAIMS/HYPOTHESIS: Short and long sleep duration are associated with increased risk of type 2 diabetes. We aimed to investigate whether genetic variants for fasting glucose or type 2 diabetes associate with short or long sleep duration and whether sleep duration modifies the association of genetic variants with these traits.
METHODS: We examined the cross-sectional relationship between self-reported habitual sleep duration and prevalence of type 2 diabetes in individuals of European descent participating in five studies included in the Candidate Gene Association Resource (CARe), totalling 1,474 cases and 8,323 controls. We tested for association of 16 fasting glucose-associated variants, 27 type 2 diabetes-associated variants and aggregate genetic risk scores with continuous and dichotomised (≤5 h or ≥9 h) sleep duration using regression models adjusted for age, sex and BMI. Finally, we tested whether a gene × behaviour interaction of variants with sleep duration had an impact on fasting glucose or type 2 diabetes risk.
RESULTS: Short sleep duration was significantly associated with type 2 diabetes in CARe (OR 1.32; 95% CI 1.08, 1.61; p = 0.008). Variants previously associated with fasting glucose or type 2 diabetes and genetic risk scores were not associated with sleep duration. Furthermore, no study-wide significant interaction was observed between sleep duration and these variants on glycaemic traits. Nominal interactions were observed for sleep duration and PPARG rs1801282, CRY2 rs7943320 and HNF1B rs4430796 in influencing risk of type 2 diabetes (p < 0.05).
CONCLUSIONS/INTERPRETATION: Our findings suggest that differences in habitual sleep duration do not mediate or modify the relationship between common variants underlying glycaemic traits (including in circadian rhythm genes) and diabetes.
10aBlood Glucose10aBody Composition10aBody Mass Index10aCross-Sectional Studies10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFasting10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aGlucose Intolerance10aGlycated Hemoglobin A10aHumans10aInsulin Resistance10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aSleep10aSurveys and Questionnaires10aTime Factors10aUnited States1 aTare, Archana1 aLane, Jacqueline, M1 aCade, Brian, E1 aGrant, Struan, F A1 aChen, Ting-Hsu1 aPunjabi, Naresh, M1 aLauderdale, Diane, S1 aZee, Phyllis, C1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aScheer, Frank, A J L1 aRedline, Susan1 aSaxena, Richa uhttps://chs-nhlbi.org/node/627003990nas a2200757 4500008004100000022001400041245017100055210006900226260001300295300001100308490000600319520184400325653001002169653000902179653002202188653001002210653001902220653001102239653002202250653003402272653001302306653001902319653001102338653000902349653001602358653003602374653002002410653002702430100001902457700001402476700002302490700001902513700001902532700001902551700002202570700002102592700002402613700002102637700001802658700001802676700002002694700002302714700003002737700002302767700001602790700001702806700001902823700001402842700001602856700002402872700001902896700002402915700001802939700002202957700001902979700001702998700002403015700002403039700002303063700002003086700002003106700002503126700002403151700002103175856003603196 2014 eng d a1942-326800aStrategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aStrategies to design and analyze targeted sequencing data cohort c2014 Jun a335-430 v73 aBACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.
METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.
CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.
10aAdult10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aResearch Design10aSequence Analysis, DNA1 aLin, Honghuang1 aWang, Min1 aBrody, Jennifer, A1 aBis, Joshua, C1 aDupuis, Josée1 aLumley, Thomas1 aMcKnight, Barbara1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aReid, Jeffrey, G1 aBressler, Jan1 aLiu, Xiaoming1 aDavis, Brian, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aKovar, Christie, L1 aDinh, Huyen1 aWu, Yuanqing1 aNewsham, Irene1 aChen, Han1 aBroka, Andi1 aDeStefano, Anita, L1 aGupta, Mayetri1 aLunetta, Kathryn, L1 aLiu, Ching-Ti1 aWhite, Charles, C1 aXing, Chuanhua1 aZhou, Yanhua1 aBenjamin, Emelia, J1 aSchnabel, Renate, B1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aMuzny, Donna, M1 aCupples, Adrienne, L1 aMorrison, Alanna, C1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/657802829nas a2200421 4500008004100000022001400041245017500055210006900230260001300299300001100312490000700323520157500330653003101905653003901936653000901975653002201984653001902006653002802025653001302053653004002066653001102106653002202117653000902139653001502148653001102163653001402174653002502188653000902213653001702222653001802239653001202257100002302269700001602292700002002308700002002328700002302348856003602371 2014 eng d a1524-456300aSystolic and diastolic blood pressure, incident cardiovascular events, and death in elderly persons: the role of functional limitation in the Cardiovascular Health Study.0 aSystolic and diastolic blood pressure incident cardiovascular ev c2014 Sep a472-800 v643 aWhether limitation in the ability to perform activities of daily living (ADL) or gait speed can identify elders in whom the association of systolic and diastolic blood pressure (DBP) with cardiovascular events (CVDs) and death differs is unclear. We evaluated whether limitation in ADL or gait speed modifies the association of systolic blood pressure or DBP with incident CVD (n=2358) and death (n=3547) in the Cardiovascular Health Study. Mean age was 78±5 and 21% reported limitation in ≥1 ADL. There were 778 CVD and 1289 deaths over 9 years. Among persons without and those with ADL limitation, systolic blood pressure was associated with incident CVD: hazard ratio [HR] (per 10-mm Hg increase) 1.08 (95% confidence interval, 1.03, 1.13) and 1.06 (0.97, 1.17), respectively. ADL modified the association of DBP with incident CVD. Among those without ADL limitation, DBP was weakly associated with incident CVD, HR 1.04 (0.79, 1.37) for DBP >80, compared with <65 mm Hg. Among those with ADL limitation, DBP was inversely associated with CVD: HR 0.65 (0.44, 0.96) for DBP 66 to 80 mm Hg and HR 0.49 (0.25, 0.94) for DBP >80, compared with DBP ≤65. Among people with ADL limitation, a DBP of 66 to 80 had the lowest risk of death, HR 0.72 (0.57, 0.91), compared with a DBP of ≤65. Associations did not vary by 15-feet walking speed. ADL can identify elders in whom diastolic hypotension is associated with higher cardiovascular risk and death. Functional status, rather than chronologic age alone, should inform design of hypertension trials in elders.
10aActivities of Daily Living10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aBlood Pressure10aCardiovascular Diseases10aDiastole10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGait10aHeart Rate10aHumans10aIncidence10aLongitudinal Studies10aMale10aRisk Factors10aSurvival Rate10aSystole1 aPeralta, Carmen, A1 aKatz, Ronit1 aNewman, Anne, B1 aPsaty, Bruce, M1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/639803677nas a2200613 4500008004100000022001400041245016900055210006900224260001300293300001000306490000700316520181200323653000902135653002402144653001102168653003802179653002202217653003402239653002502273653001102298653002702309653000902336653001602345653003602361653002902397100001902426700002202445700002302467700001902490700002402509700002202533700002202555700002202577700002202599700002202621700002202643700002102665700002002686700002202706700001902728700002202747700001702769700002302786700002402809700001902833700002102852700001902873700002302892700001902915700002402934700002402958710004502982856003603027 2014 eng d a1556-387100aTargeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.0 aTargeted sequencing in candidate genes for atrial fibrillation t c2014 Mar a452-70 v113 aBACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.
OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.
METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.
RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).
CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
10aAged10aAtrial Fibrillation10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHomeodomain Proteins10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-61 aLin, Honghuang1 aSinner, Moritz, F1 aBrody, Jennifer, A1 aArking, Dan, E1 aLunetta, Kathryn, L1 aRienstra, Michiel1 aLubitz, Steven, A1 aMagnani, Jared, W1 aSotoodehnia, Nona1 aMcKnight, Barbara1 aMcManus, David, D1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aBis, Joshua, C1 aGibbs, Richard, A1 aMuzny, Donna1 aKovar, Christie, L1 aMorrison, Alanna, C1 aGupta, Mayetri1 aFolsom, Aaron, R1 aKääb, Stefan1 aHeckbert, Susan, R1 aAlonso, Alvaro1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aCHARGE Atrial Fibrillation Working Group uhttps://chs-nhlbi.org/node/614903375nas a2200565 4500008004100000022001400041245012200055210006900177260001300246300001200259490000600271520178500277653001602062653000902078653001002087653002402097653001502121653003202136653002402168653002802192653001102220653003802231653001102269653001402280653001502294653000902309653001402318653003602332653002402368653002002392653001702412653001502429653001302444653001702457100002202474700002302496700002002519700002802539700001402567700001602581700001302597700002202610700002002632700002502652700002802677700002202705700002302727700002302750856003602773 2014 eng d a1941-308400aTelomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.0 aTelomere length and the risk of atrial fibrillation insights int c2014 Dec a1026-320 v73 aBACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.
METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.
CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.
10aAge Factors10aAged10aAging10aAtrial Fibrillation10aCalifornia10aCardiac Surgical Procedures10aCellular Senescence10aCross-Sectional Studies10aFemale10aGenetic Predisposition to Disease10aHumans10aIncidence10aLeukocytes10aMale10aPhenotype10aPolymorphism, Single Nucleotide10aProspective Studies10aRisk Assessment10aRisk Factors10aTelomerase10aTelomere10aTime Factors1 aRoberts, Jason, D1 aDewland, Thomas, A1 aLongoria, James1 aFitzpatrick, Annette, L1 aZiv, Elad1 aHu, Donglei1 aLin, Jue1 aGlidden, David, V1 aPsaty, Bruce, M1 aBurchard, Esteban, G1 aBlackburn, Elizabeth, H1 aOlgin, Jeffrey, E1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/659404315nas a2200901 4500008004100000022001400041245006300055210006000118260001600178300001200194490000700206520174600213653002201959653003701981653001802018653004002036653001802076653003402094653001302128653001102141653002002152653001502172653002702187653001402214653003602228653002802264100002302292700002502315700002002340700002602360700002302386700002002409700002102429700002202450700002002472700002002492700002302512700002202535700001902557700002002576700002502596700001802621700001902639700002102658700002102679700002402700700002102724700001602745700001402761700002102775700002302796700002002819700002202839700002102861700001902882700001502901700001902916700002102935700001902956700002802975700002303003700002103026700001803047700002503065700002003090700002303110700002503133700002203158700003003180700002303210700002103233700002203254700001903276710002203295710001103317710004903328856003603377 2014 eng d a1460-208300aTrans-ethnic meta-analysis of white blood cell phenotypes.0 aTransethnic metaanalysis of white blood cell phenotypes c2014 Dec 20 a6944-600 v233 aWhite blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.
10aAfrican Americans10aAsian Continental Ancestry Group10aBayes Theorem10aEuropean Continental Ancestry Group10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLeukocyte Count10aLeukocytes10aLinkage Disequilibrium10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aKeller, Margaux, F1 aReiner, Alexander, P1 aOkada, Yukinori1 avan Rooij, Frank, J A1 aJohnson, Andrew, D1 aChen, Ming-Huei1 aSmith, Albert, V1 aMorris, Andrew, P1 aTanaka, Toshiko1 aFerrucci, Luigi1 aZonderman, Alan, B1 aLettre, Guillaume1 aHarris, Tamara1 aGarcia, Melissa1 aBandinelli, Stefania1 aQayyum, Rehan1 aYanek, Lisa, R1 aBecker, Diane, M1 aBecker, Lewis, C1 aKooperberg, Charles1 aKeating, Brendan1 aReis, Jared1 aTang, Hua1 aBoerwinkle, Eric1 aKamatani, Yoichiro1 aMatsuda, Koichi1 aKamatani, Naoyuki1 aNakamura, Yusuke1 aKubo, Michiaki1 aLiu, Simin1 aDehghan, Abbas1 aFelix, Janine, F1 aHofman, Albert1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aFranco, Oscar, H1 aLongo, Dan, L1 aSingleton, Andrew, B1 aPsaty, Bruce, M1 aEvans, Michelle, K1 aCupples, Adrienne, L1 aRotter, Jerome, I1 aO'Donnell, Christopher, J1 aTakahashi, Atsushi1 aWilson, James, G1 aGanesh, Santhi, K1 aNalls, Mike, A1 aCHARGE Hematology1 aCOGENT1 aBioBank Japan Project (RIKEN) Working Groups uhttps://chs-nhlbi.org/node/657303118nas a2200373 4500008004100000022001400041245016800055210006900223260001300292300001600305490000700321520198600328653000902314653002802323653003502351653002102386653001602407653001102423653001102434653001402445653002502459653000902484653003102493653001702524653003202541653001102573653001802584100002202602700002002624700002102644700002302665700002002688856003602708 2014 eng d a1097-679500aWhat do carotid intima-media thickness and plaque add to the prediction of stroke and cardiovascular disease risk in older adults? The cardiovascular health study.0 aWhat do carotid intimamedia thickness and plaque add to the pred c2014 Sep a998-1005.e20 v273 aBACKGROUND: The aim of this study was to evaluate whether the addition of ultrasound carotid intima-media thickness (CIMT) measurements and risk categories of plaque help predict incident stroke and cardiovascular disease (CVD) in older adults.
METHODS: Carotid ultrasound studies were recorded in the multicenter Cardiovascular Health Study. CVD was defined as coronary heart disease plus heart failure plus stroke. Ten-year risk prediction Cox proportional-hazards models for stroke and CVD were calculated using Cardiovascular Health Study-specific coefficients for Framingham risk score factors. Categories of CIMT and CIMT plus plaque were added to Framingham risk score prediction models, and categorical net reclassification improvement (NRI) and Harrell's c-statistic were calculated.
RESULTS: In 4,384 Cardiovascular Health Study participants (61% women, 14% black; mean baseline age, 72 ± 5 years) without CVD at baseline, higher CIMT category and the presence of plaque were both associated with higher incidence rates for stroke and CVD. The addition of CIMT improved the ability of Framingham risk score-type risk models to discriminate cases from noncases of incident stroke and CVD (NRI = 0.062, P = .015, and NRI = 0.027, P < .001, respectively), with no further improvement by adding plaque. For both outcomes, NRI was driven by down-classifying those without incident disease. Although the addition of plaque to CIMT did not result in a significant NRI for either outcome, it was significant among those without incident disease.
CONCLUSIONS: In older adults, the addition of CIMT modestly improves 10-year risk prediction for stroke and CVD beyond a traditional risk factor model, mainly by down-classifying risk in those without stroke or CVD; the addition of plaque to CIMT adds no statistical benefit in the overall cohort, although there is evidence of down-classification in those without events.
10aAged10aCardiovascular Diseases10aCarotid Intima-Media Thickness10aCarotid Stenosis10aComorbidity10aFemale10aHumans10aIncidence10aLongitudinal Studies10aMale10aReproducibility of Results10aRisk Factors10aSensitivity and Specificity10aStroke10aSurvival Rate1 aGardin, Julius, M1 aBartz, Traci, M1 aPolak, Joseph, F1 aO'Leary, Daniel, H1 aWong, Nathan, D uhttps://chs-nhlbi.org/node/656405955nas a2201657 4500008004100000022001400041245011000055210006900165260001600234300001100250490000700261520138800268653001001656653000901666653002201675653002101697653001901718653001801737653001001755653001101765653002201776653001901798653001701817653003401834653001301868653001101881653001101892653000901903653001601912653001401928653003601942653002801978653002702006653001902033653002702052653002602079100002102105700001402126700001402140700001602154700002202170700002202192700001702214700002002231700002102251700002102272700001302293700002002306700001702326700001502343700001702358700002002375700001402395700002702409700001802436700002202454700001602476700001902492700001702511700002102528700002302549700002002572700001802592700002202610700001802632700001502650700001202665700001702677700001502694700001802709700001902727700001902746700001902765700002502784700002602809700002102835700002502856700002102881700001902902700002502921700001702946700002502963700001202988700002303000700002003023700002603043700002903069700002303098700002803121700001803149700002003167700002303187700002103210700001903231700001803250700002803268700001903296700002403315700002303339700002803362700001703390700002203407700002203429700002403451700002403475700002003499700002303519700002203542700001603564700001703580700002403597700002003621700001803641700002003659700002103679700001603700700001903716700002203735700002803757700002303785700003003808700001903838700001903857700002503876700002103901700002003922700002103942700002203963700001603985700002004001700002504021700002404046700002104070700002604091700002504117700002104142700002204163700002304185710005304208856003604261 2014 eng d a1537-660500aWhole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.0 aWholeexome sequencing identifies rare and lowfrequency coding va c2014 Feb 06 a233-450 v943 aElevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
10aAdult10aAged10aApolipoproteins E10aCholesterol, LDL10aCohort Studies10aDyslipidemias10aExome10aFemale10aFollow-Up Studies10aGene Frequency10aGenetic Code10aGenome-Wide Association Study10aGenotype10aHumans10aLipase10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aProprotein Convertase 910aProprotein Convertases10aReceptors, LDL10aSequence Analysis, DNA10aSerine Endopeptidases1 aLange, Leslie, A1 aHu, Youna1 aZhang, He1 aXue, Chenyi1 aSchmidt, Ellen, M1 aTang, Zheng-Zheng1 aBizon, Chris1 aLange, Ethan, M1 aSmith, Joshua, D1 aTurner, Emily, H1 aJun, Goo1 aKang, Hyun, Min1 aPeloso, Gina1 aAuer, Paul1 aLi, Kuo-Ping1 aFlannick, Jason1 aZhang, Ji1 aFuchsberger, Christian1 aGaulton, Kyle1 aLindgren, Cecilia1 aLocke, Adam1 aManning, Alisa1 aSim, Xueling1 aRivas, Manuel, A1 aHolmen, Oddgeir, L1 aGottesman, Omri1 aLu, Yingchang1 aRuderfer, Douglas1 aStahl, Eli, A1 aDuan, Qing1 aLi, Yun1 aDurda, Peter1 aJiao, Shuo1 aIsaacs, Aaron1 aHofman, Albert1 aBis, Joshua, C1 aCorrea, Adolfo1 aGriswold, Michael, E1 aJakobsdottir, Johanna1 aSmith, Albert, V1 aSchreiner, Pamela, J1 aFeitosa, Mary, F1 aZhang, Qunyuan1 aHuffman, Jennifer, E1 aCrosby, Jacy1 aWassel, Christina, L1 aDo, Ron1 aFranceschini, Nora1 aMartin, Lisa, W1 aRobinson, Jennifer, G1 aAssimes, Themistocles, L1 aCrosslin, David, R1 aRosenthal, Elisabeth, A1 aTsai, Michael1 aRieder, Mark, J1 aFarlow, Deborah, N1 aFolsom, Aaron, R1 aLumley, Thomas1 aFox, Ervin, R1 aCarlson, Christopher, S1 aPeters, Ulrike1 aJackson, Rebecca, D1 aDuijn, Cornelia, M1 aUitterlinden, André, G1 aLevy, Daniel1 aRotter, Jerome, I1 aTaylor, Herman, A1 aGudnason, Vilmundur1 aSiscovick, David, S1 aFornage, Myriam1 aBorecki, Ingrid, B1 aHayward, Caroline1 aRudan, Igor1 aChen, Eugene1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSætrom, Pål1 aHveem, Kristian1 aBoehnke, Michael1 aGroop, Leif1 aMcCarthy, Mark1 aMeitinger, Thomas1 aBallantyne, Christie, M1 aGabriel, Stacey, B1 aO'Donnell, Christopher, J1 aPost, Wendy, S1 aNorth, Kari, E1 aReiner, Alexander, P1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aAltshuler, David1 aKathiresan, Sekar1 aLin, Dan-Yu1 aJarvik, Gail, P1 aCupples, Adrienne, L1 aKooperberg, Charles1 aWilson, James, G1 aNickerson, Deborah, A1 aAbecasis, Goncalo, R1 aRich, Stephen, S1 aTracy, Russell, P1 aWiller, Cristen, J1 aNHLBI Grand Opportunity Exome Sequencing Project uhttps://chs-nhlbi.org/node/657703390nas a2200517 4500008004100000022001400041245012400055210006900179260001300248300001000261490000700271520190100278653000902179653002402188653001002212653002102222653002802243653002702271653002402298653001102322653001602333653001902349653001102368653001802379653003102397653000902428653001602437653003002453653002402483653002402507653001702531653002202548100001802570700002002588700002002608700001902628700002102647700002302668700002202691700002602713700002302739700002402762700002602786700002402812856003602836 2015 eng d a1524-462800aAssociation between left atrial abnormality on ECG and vascular brain injury on MRI in the Cardiovascular Health Study.0 aAssociation between left atrial abnormality on ECG and vascular c2015 Mar a711-60 v463 aBACKGROUND AND PURPOSE: Emerging evidence suggests that atrial disease is associated with vascular brain injury in the absence of atrial fibrillation.
METHODS: The Cardiovascular Health Study prospectively enrolled community-dwelling adults aged ≥65 years. Among participants who underwent MRI, we examined associations of ECG left atrial abnormality with brain infarcts and leukoaraiosis. P-wave terminal force in lead V1 was the primary measure of left atrial abnormality; P-wave area and duration were secondary predictors. We excluded participants with atrial fibrillation before or on their index ECG. Primary outcomes were incident infarcts and worsening leukoaraiosis from initial to follow-up scan ≈5 years later. Secondary outcomes were prevalent infarcts and degree of leukoaraiosis on initial MRI. Relative risk (RR) and linear regression models were adjusted for vascular risk factors.
RESULTS: Among 3129 participants with ≥1 scan, each SD increase in P-wave terminal force in lead V1 was associated with a 0.05-point (95% confidence interval [CI], 0.0003-0.10) higher baseline white matter grade on a 10-point scale. P-wave terminal force in lead V1 was associated with prevalent infarcts of any type (RR per SD, 1.09; 95% CI, 1.04-1.16) and more so with prevalent nonlacunar infarcts (RR per SD, 1.22; 95% CI, 1.08-1.38). Among 1839 participants with 2 scans, P-wave terminal force in lead V1 was associated with worsening leukoaraiosis (RR per SD, 1.09; 95% CI, 1.01-1.18), but not with incident infarcts (RR per SD, 1.06; 95% CI, 0.93-1.20). Sensitivity analyses adjusting for incident atrial fibrillation found similar results. P-wave area and duration were not associated with outcomes.
CONCLUSIONS: ECG left atrial abnormality is associated with vascular brain injury in the absence of documented atrial fibrillation.
10aAged10aAtrial Fibrillation10aBrain10aBrain Infarction10aCardiovascular Diseases10aCerebrovascular Trauma10aElectrocardiography10aFemale10aHeart Atria10aHeart Diseases10aHumans10aLinear Models10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPredictive Value of Tests10aProspective Studies10aRegression Analysis10aRisk Factors10aTreatment Outcome1 aKamel, Hooman1 aBartz, Traci, M1 aLongstreth, W T1 aOkin, Peter, M1 aThacker, Evan, L1 aPatton, Kristen, K1 aStein, Phyllis, K1 aGottesman, Rebecca, F1 aHeckbert, Susan, R1 aKronmal, Richard, A1 aElkind, Mitchell, S V1 aSoliman, Elsayed, Z uhttps://chs-nhlbi.org/node/666803495nas a2200505 4500008004100000022001400041245014400055210006900199260000900268300000700277490000700284520210500291653001002396653000902406653001902415653002802434653002502462653001102487653002202498653001102520653002502531653000902556653001802565653003602583653001602619653002102635653003602656653001402692100001702706700001102723700001402734700001902748700001202767700001502779700001202794700001702806700001702823700001502840700001802855700001502873700001602888700002502904710002402929856003602953 2015 eng d a1465-993X00aAssociation of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study.0 aAssociation of 25Hydroxyvitamin D status and genetic variation i c2015 a810 v163 aBACKGROUND: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.
METHODS: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.
RESULTS: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09).
CONCLUSIONS: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.
10aAdult10aAged10aCohort Studies10aCross-Sectional Studies10aDNA-Binding Proteins10aFemale10aGenetic Variation10aHumans10aLongitudinal Studies10aMale10aMassachusetts10aMetabolic Networks and Pathways10aMiddle Aged10aNuclear Proteins10aPolymorphism, Single Nucleotide10aVitamin D1 aHansen, J, G1 aGao, W1 aDupuis, J1 aO'Connor, G, T1 aTang, W1 aKowgier, M1 aSood, A1 aGharib, S, A1 aPalmer, L, J1 aFornage, M1 aHeckbert, S R1 aPsaty, B M1 aBooth, S, L1 aCassano, Patricia, A1 aSUNLIGHT Consortium uhttps://chs-nhlbi.org/node/685103472nas a2200781 4500008004100000022001400041245008200055210006900137260001300206300001500219490000700234520128200241653001001523653001201533653002201545653002201567653001001589653001101599653003401610653001601644653001101660653003101671653000901702653001501711653003601726653000901762653004101771100002001812700002201832700001901854700002101873700001201894700002801906700002601934700002501960700002601985700002102011700001502032700001602047700002102063700002002084700002102104700001902125700002202144700002802166700002202194700002302216700002102239700002002260700002302280700002202303700002202325700002202347700001902369700002102388700002402409700002302433700002202456700002202478700002702500700002202527700002002549700002202569700002002591700002002611700002302631856003602654 2015 eng d a1558-149700aAssociation of Alzheimer's disease GWAS loci with MRI markers of brain aging.0 aAssociation of Alzheimers disease GWAS loci with MRI markers of c2015 Apr a1765.e7-160 v363 aWhether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.
10aAging10aAlleles10aAlzheimer Disease10aApolipoproteins E10aBrain10aFemale10aGenome-Wide Association Study10aHippocampus10aHumans10aMagnetic Resonance Imaging10aMale10aOrgan Size10aPolymorphism, Single Nucleotide10aRisk10aSialic Acid Binding Ig-like Lectin 31 aChauhan, Ganesh1 aAdams, Hieab, H H1 aBis, Joshua, C1 aWeinstein, Galit1 aYu, Lei1 aTöglhofer, Anna, Maria1 aSmith, Albert, Vernon1 avan der Lee, Sven, J1 aGottesman, Rebecca, F1 aThomson, Russell1 aWang, Jing1 aYang, Qiong1 aNiessen, Wiro, J1 aLopez, Oscar, L1 aBecker, James, T1 aPhan, Thanh, G1 aBeare, Richard, J1 aArfanakis, Konstantinos1 aFleischman, Debra1 aVernooij, Meike, W1 aMazoyer, Bernard1 aSchmidt, Helena1 aSrikanth, Velandai1 aKnopman, David, S1 aJack, Clifford, R1 aAmouyel, Philippe1 aHofman, Albert1 aDeCarli, Charles1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aBennett, David, A1 aSchmidt, Reinhold1 aLongstreth, William, T1 aMosley, Thomas, H1 aFornage, Myriam1 aLauner, Lenore, J1 aSeshadri, Sudha1 aIkram, Arfan, M1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/681506729nas a2201369 4500008004100000022001400041245006600055210006500121260001500186300001000201490000800211520297400219653001003193653000903203653001603212653002203228653001103250653001103261653002003272653000903292653001603301653001403317653002603331653001703357653001103374110004003385700003003425700002103455700001903476700001903495700002503514700002103539700002303560700001303583700002003596700002103616700002303637700001903660700002103679700002003700700002403720700002303744700002803767700002003795700001603815700002403831700002103855700002003876700002203896700002103918700002003939700002203959700003003981700001804011700002204029700002304051700002904074700002004103700002104123700001504144700002504159700002104184700002304205700002104228700002204249700002504271700001804296700001604314700002304330700002504353700001804378700002004396700001904416700001904435700001704454700001904471700002404490700002304514700002604537700002104563700002204584700001804606700002104624700001904645700002504664700002204689700002204711700002504733700001904758700002104777700002004798700001804818700002204836700002204858700002004880700002004900700002104920700001804941700002404959700001904983700002205002700001905024700002105043700001805064700002505082700002105107700002105128700001605149700003205165700002205197700002305219700002205242700001905264700002305283700001705306856003605323 2015 eng d a1538-359800aAssociation of Cardiometabolic Multimorbidity With Mortality.0 aAssociation of Cardiometabolic Multimorbidity With Mortality c2015 Jul 7 a52-600 v3143 aIMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing.
OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.
DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.
EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).
MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy.
RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.
CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
10aAdult10aAged10aComorbidity10aDiabetes Mellitus10aFemale10aHumans10aLife Expectancy10aMale10aMiddle Aged10aMortality10aMyocardial Infarction10aRisk Factors10aStroke1 aEmerging Risk Factors Collaboration1 aDi Angelantonio, Emanuele1 aKaptoge, Stephen1 aWormser, David1 aWilleit, Peter1 aButterworth, Adam, S1 aBansal, Narinder1 aO'Keeffe, Linda, M1 aGao, Pei1 aWood, Angela, M1 aBurgess, Stephen1 aFreitag, Daniel, F1 aPennells, Lisa1 aPeters, Sanne, A1 aHart, Carole, L1 aHåheim, Lise, Lund1 aGillum, Richard, F1 aNordestgaard, Børge, G1 aPsaty, Bruce, M1 aYeap, Bu, B1 aKnuiman, Matthew, W1 aNietert, Paul, J1 aKauhanen, Jussi1 aSalonen, Jukka, T1 aKuller, Lewis, H1 aSimons, Leon, A1 aSchouw, Yvonne, T1 aBarrett-Connor, Elizabeth1 aSelmer, Randi1 aCrespo, Carlos, J1 aRodriguez, Beatriz1 aVerschuren, W, M Monique1 aSalomaa, Veikko1 aSvärdsudd, Kurt1 aHarst, Pim1 aBjörkelund, Cecilia1 aWilhelmsen, Lars1 aWallace, Robert, B1 aBrenner, Hermann1 aAmouyel, Philippe1 aBarr, Elizabeth, L M1 aIso, Hiroyasu1 aOnat, Altan1 aTrevisan, Maurizio1 aD'Agostino, Ralph, B1 aCooper, Cyrus1 aKavousi, Maryam1 aWelin, Lennart1 aRoussel, Ronan1 aHu, Frank, B1 aSato, Shinichi1 aDavidson, Karina, W1 aHoward, Barbara, V1 aLeening, Maarten, J G1 aLeening, Maarten1 aRosengren, Annika1 aDörr, Marcus1 aDeeg, Dorly, J H1 aKiechl, Stefan1 aStehouwer, Coen, D A1 aNissinen, Aulikki1 aGiampaoli, Simona1 aDonfrancesco, Chiara1 aKromhout, Daan1 aPrice, Jackie, F1 aPeters, Annette1 aMeade, Tom, W1 aCasiglia, Edoardo1 aLawlor, Debbie, A1 aGallacher, John1 aNagel, Dorothea1 aFranco, Oscar, H1 aAssmann, Gerd1 aDagenais, Gilles, R1 aJukema, Wouter1 aSundström, Johan1 aWoodward, Mark1 aBrunner, Eric, J1 aKhaw, Kay-Tee1 aWareham, Nicholas, J1 aWhitsel, Eric, A1 aNjølstad, Inger1 aHedblad, Bo1 aWassertheil-Smoller, Sylvia1 aEngström, Gunnar1 aRosamond, Wayne, D1 aSelvin, Elizabeth1 aSattar, Naveed1 aThompson, Simon, G1 aDanesh, John uhttps://chs-nhlbi.org/node/681104486nas a2200901 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520184700254653001002101653002202111653002302133653002802156653001902184653004002203653001002243653001102253653001902264653003802283653003402321653003802355653001102393653000902404653001102413653003602424653002902460653001702489100002202506700001802528700001902546700001902565700001402584700002102598700002102619700002002640700002402660700001902684700002802703700002002731700002202751700001202773700002402785700002402809700002102833700002002854700002102874700001902895700002102914700001602935700002002951700001502971700001902986700002003005700001803025700002103043700001803064700002203082700002403104700002303128700002303151700001903174700002603193700002203219700001903241700001903260700002103279700002103300700002403321700002403345700002003369700002003389710006503409710007403474856003603548 2015 eng d a1460-208300aAssociation of exome sequences with plasma C-reactive protein levels in >9000 participants.0 aAssociation of exome sequences with plasma Creactive protein lev c2015 Jan 15 a559-710 v243 aC-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.
10aAdult10aAfrican Americans10aC-Reactive Protein10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aExome10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHepatocyte Nuclear Factor 1-alpha10aHumans10aMale10aPlasma10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-610aRisk Factors1 aSchick, Ursula, M1 aAuer, Paul, L1 aBis, Joshua, C1 aLin, Honghuang1 aWei, Peng1 aPankratz, Nathan1 aLange, Leslie, A1 aBrody, Jennifer1 aStitziel, Nathan, O1 aKim, Daniel, S1 aCarlson, Christopher, S1 aFornage, Myriam1 aHaessler, Jeffery1 aHsu, Li1 aJackson, Rebecca, D1 aKooperberg, Charles1 aLeal, Suzanne, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aTracy, Russell1 aArdissino, Diego1 aShah, Svati1 aWiller, Cristen1 aLoos, Ruth1 aMelander, Olle1 aMcPherson, Ruth1 aHovingh, Kees1 aReilly, Muredach1 aWatkins, Hugh1 aGirelli, Domenico1 aFontanillas, Pierre1 aChasman, Daniel, I1 aGabriel, Stacey, B1 aGibbs, Richard1 aNickerson, Deborah, A1 aKathiresan, Sekar1 aPeters, Ulrike1 aDupuis, Josée1 aWilson, James, G1 aRich, Stephen, S1 aMorrison, Alanna, C1 aBenjamin, Emelia, J1 aGross, Myron, D1 aReiner, Alex, P1 aCohorts for Heart and Aging Research in Genomic Epidemiology1 aNational Heart, Lung, and Blood Institute GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659703022nas a2200481 4500008004100000022001400041245011800055210006900173260001300242300001000255490000600265520167500271653001001946653002201956653001201978653002101990653004002011653001102051653001402062653002802076653001102104653000902115653001302124100001302137700002102150700001702171700002902188700002202217700001902239700002302258700002102281700002402302700002102326700002402347700001902371700001902390700002102409700002002430700001902450700001402469700002102483856003602504 2015 eng d a1942-326800aAssociation of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.0 aAssociation of Rare LossOfFunction Alleles in HAL Serum Histidin c2015 Apr a351-50 v83 aBACKGROUND: Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.
METHODS AND RESULTS: By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2×10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2×10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9×10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.
CONCLUSIONS: Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.
10aAdult10aAfrican Americans10aAlleles10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aHistidine10aHistidine Ammonia-Lyase10aHumans10aMale10aMutation1 aYu, Bing1 aLi, Alexander, H1 aMuzny, Donna1 aVeeraraghavan, Narayanan1 ade Vries, Paul, S1 aBis, Joshua, C1 aMusani, Solomon, K1 aAlexander, Danny1 aMorrison, Alanna, C1 aFranco, Oscar, H1 aUitterlinden, Andre1 aHofman, Albert1 aDehghan, Abbas1 aWilson, James, G1 aPsaty, Bruce, M1 aGibbs, Richard1 aWei, Peng1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/668903082nas a2200409 4500008004100000022001400041245012400055210006900179260001300248300001000261490000700271520181300278653000902091653001802100653001902118653003002137653001102167653001102178653004902189653004902238653003302287653000902320653002602329100002502355700002902380700002602409700002102435700002402456700002802480700002002508700002102528700002002549700002002569700002502589700002202614856003602636 2015 eng d a1532-541500aChanges in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults.0 aChanges in insulinlike growth factorI and its binding proteins a c2015 May a902-90 v633 aOBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period.
DESIGN: Retrospective analysis of a cohort study.
SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania.
PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897).
MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06).
RESULTS: At baseline, mean age was 76.3±3.6, and 18.5% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3% for IGF-I, 59.7% for IGFBP-1, -13.4% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7% for IGF-I, 25.6% for IGFBP-1, -6.4% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up.
CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.
10aAged10aBlood Glucose10aCohort Studies10aDiabetes Mellitus, Type 210aFemale10aHumans10aInsulin-Like Growth Factor Binding Protein 110aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aRetrospective Studies1 aAneke-Nash, Chino, S1 aParrinello, Christina, M1 aRajpathak, Swapnil, N1 aRohan, Thomas, E1 aStrotmeyer, Elsa, S1 aKritchevsky, Stephen, B1 aPsaty, Bruce, M1 aBůzková, Petra1 aKizer, Jorge, R1 aNewman, Anne, B1 aStrickler, Howard, D1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/673704590nas a2200889 4500008004100000022001400041245009700055210006900152260001500221300001100236490000700247520195700254653003502211653002102246653003202267653002202299653001102321653003602332100002502368700001702393700002202410700001702432700002202449700002202471700002102493700002902514700002402543700002102567700001702588700002002605700002002625700002502645700001702670700002002687700002302707700002402730700001902754700002302773700002202796700002102818700002202839700002202861700002002883700001902903700002302922700002302945700002402968700002202992700002003014700001603034700001903050700002303069700002503092700002703117700002503144700001603169700002303185700002203208700002803230700002003258700001803278700001803296700002503314700002103339700002103360700001603381700002003397700002003417700002103437700002403458710002603482710002103508710003803529710005203567710004503619856003603664 2015 ENG d a1526-632X00aCommon variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.0 aCommon variation in COL4A1COL4A2 is associated with sporadic cer c2015 Mar 3 a918-260 v843 aOBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.
METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).
RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.
CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
10aCerebral Small Vessel Diseases10aCollagen Type IV10aGenetic Association Studies10aGenetic Variation10aHumans10aPolymorphism, Single Nucleotide1 aRannikmae, Kristiina1 aDavies, Gail1 aThomson, Pippa, A1 aBevan, Steve1 aDevan, William, J1 aFalcone, Guido, J1 aTraylor, Matthew1 aAnderson, Christopher, D1 aBattey, Thomas, W K1 aRadmanesh, Farid1 aDeka, Ranjan1 aWoo, Jessica, G1 aMartin, Lisa, J1 aJimenez-Conde, Jordi1 aSelim, Magdy1 aBrown, Devin, L1 aSilliman, Scott, L1 aKidwell, Chelsea, S1 aMontaner, Joan1 aLangefeld, Carl, D1 aSlowik, Agnieszka1 aHansen, Bjorn, M1 aLindgren, Arne, G1 aMeschia, James, F1 aFornage, Myriam1 aBis, Joshua, C1 aDebette, Stephanie1 aIkram, Mohammad, A1 aLongstreth, Will, T1 aSchmidt, Reinhold1 aZhang, Cathy, R1 aYang, Qiong1 aSharma, Pankaj1 aKittner, Steven, J1 aMitchell, Braxton, D1 aHolliday, Elizabeth, G1 aLevi, Christopher, R1 aAttia, John1 aRothwell, Peter, M1 aPoole, Deborah, L1 aBoncoraglio, Giorgio, B1 aPsaty, Bruce, M1 aMalik, Rainer1 aRost, Natalia1 aWorrall, Bradford, B1 aDichgans, Martin1 aVan Agtmael, Tom1 aWoo, Daniel1 aMarkus, Hugh, S1 aSeshadri, Sudha1 aRosand, Jonathan1 aSudlow, Cathie, L M1 aMETASTROKE Consortium1 aCHARGE WMH Group1 aISGC ICH GWAS Study Collaboration1 aWMH in Ischemic Stroke GWAS Study Collaboration1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/686405848nas a2201069 4500008004100000022001400041245018600055210006900241260001300310300001200323490000800335520268400343653001803027653001903045653003203064653003803096653003403134653001103168653001803179653002003197653001203217653002303229653002803252653000903280653001803289653001603307653003603323653001703359100002203376700002003398700002703418700002403445700002003469700002403489700003203513700002003545700002803565700002303593700001603616700002003632700002903652700001903681700003203700700002503732700001803757700002003775700001903795700002303814700002103837700002203858700002003880700002303900700002403923700002103947700002103968700002603989700002104015700002004036700002104056700001804077700002504095700001704120700002004137700002304157700002404180700002204204700001904226700001604245700002004261700002104281700002404302700002104326700001704347700002104364700002804385700002004413700002104433700002004454700002504474700002304499700002004522700002104542700001904563700002304582700002504605700002104630700002204651700002504673700002004698700002404718856003604742 2015 eng d a1938-320700aConsumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians.0 aConsumption of meat is associated with higher fasting glucose an c2015 Nov a1266-780 v1023 aBACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.
OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.
DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.
RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.
CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
10aBlood Glucose10aCohort Studies10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHyperglycemia10aHyperinsulinism10aInsulin10aInsulin Resistance10aInsulin-Secreting Cells10aMeat10aMeat Products10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aFretts, Amanda, M1 aFollis, Jack, L1 aNettleton, Jennifer, A1 aLemaitre, Rozenn, N1 aNgwa, Julius, S1 aWojczynski, Mary, K1 aKalafati, Ioanna, Panagiota1 aVarga, Tibor, V1 aFrazier-Wood, Alexis, C1 aHouston, Denise, K1 aLahti, Jari1 aEricson, Ulrika1 avan den Hooven, Edith, H1 aMikkilä, Vera1 ade Jong, Jessica, C Kiefte-1 aMozaffarian, Dariush1 aRice, Kenneth1 aRenstrom, Frida1 aNorth, Kari, E1 aMcKeown, Nicola, M1 aFeitosa, Mary, F1 aKanoni, Stavroula1 aSmith, Caren, E1 aGarcia, Melissa, E1 aTiainen, Anna-Maija1 aSonestedt, Emily1 aManichaikul, Ani1 avan Rooij, Frank, J A1 aDimitriou, Maria1 aRaitakari, Olli1 aPankow, James, S1 aDjoussé, Luc1 aProvince, Michael, A1 aHu, Frank, B1 aLai, Chao-Qiang1 aKeller, Margaux, F1 aPerälä, Mia-Maria1 aRotter, Jerome, I1 aHofman, Albert1 aGraff, Misa1 aKähönen, Mika1 aMukamal, Kenneth1 aJohansson, Ingegerd1 aOrdovas, Jose, M1 aLiu, Yongmei1 aMännistö, Satu1 aUitterlinden, André, G1 aDeloukas, Panos1 aSeppälä, Ilkka1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aBorecki, Ingrid, B1 aFranks, Paul, W1 aArnett, Donna, K1 aNalls, Mike, A1 aEriksson, Johan, G1 aOrho-Melander, Marju1 aFranco, Oscar, H1 aLehtimäki, Terho1 aDedoussis, George, V1 aMeigs, James, B1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/684403184nas a2200421 4500008004100000022001400041245012600055210006900181260001300250300001000263490000600273520201000279653000902289653002102298653001902319653000902338653001102347653001802358653001102376653001402387653000902401653001902410653001202429653003202441653002402473653001702497653002402514653001202538653001802550100002402568700002302592700002102615700002102636700002402657700002002681700002502701856003602726 2015 eng d a2213-178700aContribution of Major Lifestyle Risk Factors for Incident Heart Failure in Older Adults: The Cardiovascular Health Study.0 aContribution of Major Lifestyle Risk Factors for Incident Heart c2015 Jul a520-80 v33 aOBJECTIVES: The goal of this study was to determine the relative contribution of major lifestyle factors on the development of heart failure (HF) in older adults.
BACKGROUND: HF incurs high morbidity, mortality, and health care costs among adults ≥65 years of age, which is the most rapidly growing segment of the U.S.
METHODS: We prospectively investigated separate and combined associations of lifestyle risk factors with incident HF (1,380 cases) over 21.5 years among 4,490 men and women in the Cardiovascular Health Study, which is a community-based cohort of older adults. Lifestyle factors included 4 dietary patterns (Alternative Healthy Eating Index, Dietary Approaches to Stop Hypertension, an American Heart Association 2020 dietary goals score, and a Biologic pattern, which was constructed using previous knowledge of cardiovascular disease dietary risk factors), 4 physical activity metrics (exercise intensity, walking pace, energy expended in leisure activity, and walking distance), alcohol intake, smoking, and obesity.
RESULTS: No dietary pattern was associated with developing HF (p > 0.05). Walking pace and leisure activity were associated with a 26% and 22% lower risk of HF, respectively (pace >3 mph vs. <2 mph; hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.63 to 0.86; leisure activity ≥845 kcal/week vs. <845 kcal/week; HR: 0.78; 95% CI: 0.69 to 0.87). Modest alcohol intake, maintaining a body mass index <30 kg/m(2), and not smoking were also independently associated with a lower risk of HF. Participants with ≥4 healthy lifestyle factors had a 45% (HR: 0.55; 95% CI: 0.42 to 0.74) lower risk of HF. Heterogeneity by age, sex, cardiovascular disease, hypertension medication use, and diabetes was not observed.
CONCLUSIONS: Among older U.S. adults, physical activity, modest alcohol intake, avoiding obesity, and not smoking, but not dietary patterns, were associated with a lower risk of HF.
10aAged10aAlcohol Drinking10aCohort Studies10aDiet10aFemale10aHeart Failure10aHumans10aIncidence10aMale10aMotor Activity10aObesity10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSedentary Lifestyle10aSmoking10aUnited States1 aDel Gobbo, Liana, C1 aKalantarian, Shadi1 aImamura, Fumiaki1 aLemaitre, Rozenn1 aSiscovick, David, S1 aPsaty, Bruce, M1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/676903409nas a2200625 4500008004100000022001400041245006700055210006500122260001300187300001100200490000700211520169000218653001201908653002101920653003101941653003401972653001102006653001502017653001302032653001702045653001302062653002502075100002102100700002302121700001702144700002002161700001802181700002402199700002102223700001902244700002002263700001602283700002002299700002202319700001702341700002002358700002102378700002302399700001902422700002002441700001702461700002402478700002802502700001402530700002402544700002202568700002402590700002002614700002402634700002302658700002402681700002402705700001802729856003602747 2015 eng d a1468-624400aDCAF4, a novel gene associated with leucocyte telomere length.0 aDCAF4 a novel gene associated with leucocyte telomere length c2015 Mar a157-620 v523 aBACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).
RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24).
CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.
10aAlleles10aCarrier Proteins10aGene Expression Regulation10aGenome-Wide Association Study10aHumans10aLeukocytes10aMelanoma10aRisk Factors10aTelomere10aTelomere Homeostasis1 aMangino, Massimo1 aChristiansen, Lene1 aStone, Rivka1 aHunt, Steven, C1 aHorvath, Kent1 aEisenberg, Dan, T A1 aKimura, Masayuki1 aPetersen, Inge1 aKark, Jeremy, D1 aHerbig, Utz1 aReiner, Alex, P1 aBenetos, Athanase1 aCodd, Veryan1 aNyholt, Dale, R1 aSinnreich, Ronit1 aChristensen, Kaare1 aNassar, Hisham1 aHwang, Shih-Jen1 aLevy, Daniel1 aBataille, Veronique1 aFitzpatrick, Annette, L1 aChen, Wei1 aBerenson, Gerald, S1 aSamani, Nilesh, J1 aMartin, Nicholas, G1 aTishkoff, Sarah1 aSchork, Nicholas, J1 aKyvik, Kirsten Ohm1 aDalgård, Christine1 aSpector, Timothy, D1 aAviv, Abraham uhttps://chs-nhlbi.org/node/681703702nas a2200529 4500008004100000022001400041245011600055210006900171260001500240300001100255490000700266520220700273653001602480653000902496653002202505653001602527653003402543653001502577653002202592653001102614653003102625653001802656653001102674653000902685653003202694653002402726653003302750653001702783653001602800653001202816653001102828100001802839700001602857700002002873700002302893700002002916700002402936700002002960700001902980700002402999700002203023700002803045700002003073700002403093700001903117856003603136 2015 eng d a1555-905X00aDevelopment and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD.0 aDevelopment and validation of a model to predict 5year risk of d c2015 Mar 6 a363-710 v103 aBACKGROUND AND OBJECTIVES: CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study.
RESULTS: The development cohort included 828 participants who had a mean age of 80 (±5.6) years and an eGFR of 47 (±11) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-51) mg/g. The validation cohort included 789 participants who had a mean age of 74 (±2.8) years and an eGFR of 50 (±9) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-42) mg/g. The final model for 5-year mortality risk included age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8% among participants with the lowest scores to 83.6% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95% confidence interval, 0.64 to 0.74).
CONCLUSIONS: A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making.
10aAge Factors10aAged10aAged, 80 and over10aAlbuminuria10aContinental Population Groups10aCreatinine10aDiabetes Mellitus10aFemale10aGlomerular Filtration Rate10aHeart Failure10aHumans10aMale10aProportional Hazards Models10aRegression Analysis10aRenal Insufficiency, Chronic10aRisk Factors10aSex Factors10aSmoking10aStroke1 aBansal, Nisha1 aKatz, Ronit1 ade Boer, Ian, H1 aPeralta, Carmen, A1 aFried, Linda, F1 aSiscovick, David, S1 aRifkin, Dena, E1 aHirsch, Calvin1 aCummings, Steven, R1 aHarris, Tamara, B1 aKritchevsky, Stephen, B1 aSarnak, Mark, J1 aShlipak, Michael, G1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/665903799nas a2200757 4500008004100000022001400041245019200055210006900247260001300316300001200329490000700341520158600348653002301934653002101957653004101978653001902019653000902038653002602047653002602073653002502099653002702124653001602151653002502167653001102192653001102203653000902214653001602223653003602239100002002275700002002295700002702315700001902342700001802361700001302379700002002392700002302412700001502435700001902450700002002469700002002489700002502509700002502534700001902559700002202578700002102600700001802621700002002639700001802659700002202677700002102699700002502720700002202745700001702767700002302784700002002807700002102827700001902848700001202867700001302879700001902892700002502911700002402936700002102960700002402981856003603005 2015 eng d a1613-413300aDietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium.0 aDietary fatty acids modulate associations between genetic varian c2015 Jul a1373-830 v593 aSCOPE: Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid.
METHODS AND RESULTS: We conducted meta-analyses (N = 11 668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid.
CONCLUSION: Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.
10aAcetyltransferases10aAcyltransferases10aAdaptor Proteins, Signal Transducing10aCarboxy-Lyases10aDiet10aDocosahexaenoic Acids10aEicosapentaenoic Acid10aErythrocyte Membrane10aFatty Acid Desaturases10aFatty Acids10aFatty Acids, Omega-310aFemale10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aSmith, Caren, E1 aFollis, Jack, L1 aNettleton, Jennifer, A1 aFoy, Millennia1 aH Y Wu, Jason1 aMa, Yiyi1 aTanaka, Toshiko1 aManichakul, Ani, W1 aWu, Hongyu1 aChu, Audrey, Y1 aSteffen, Lyn, M1 aFornage, Myriam1 aMozaffarian, Dariush1 aKabagambe, Edmond, K1 aFerruci, Luigi1 aChen, Yii-Der Ida1 aRich, Stephen, S1 aDjoussé, Luc1 aRidker, Paul, M1 aTang, Weihong1 aMcKnight, Barbara1 aTsai, Michael, Y1 aBandinelli, Stefania1 aRotter, Jerome, I1 aHu, Frank, B1 aChasman, Daniel, I1 aPsaty, Bruce, M1 aArnett, Donna, K1 aKing, Irena, B1 aSun, Qi1 aWang, Lu1 aLumley, Thomas1 aChiuve, Stephanie, E1 aSiscovick, David, S1 aOrdovas, Jose, M1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/668705255nas a2200949 4500008004100000022001400041245015700055210006900212260000900281300001300290490000700303520251800310653002202828653000902850653002802859653002802887653004002915653001102955653003402966653001103000653001703011653001403028653000903042653001603051653003603067653002203103100001903125700002103144700001603165700002203181700002603203700001603229700002103245700002303266700001603289700002003305700002203325700002203347700002103369700002303390700002303413700002003436700002203456700002303478700002103501700002203522700002003544700002103564700002203585700001803607700002003625700002503645700002203670700002303692700001703715700002103732700002303753700002403776700002003800700002103820700002203841700002503863700002803888700002203916700001403938700001903952700001903971700002003990700002604010700002404036700002704060700001904087700002404106700002204130700001604152700001904168700002304187700002104210700002004231700001804251856003604269 2015 eng d a1932-620300aDrug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.0 aDrugGene Interactions of Antihypertensive Medications and Risk o c2015 ae01404960 v103 aBACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.
10aAfrican Americans10aAged10aAntihypertensive Agents10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aHypertension10aIncidence10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTreatment Outcome1 aBis, Joshua, C1 aSitlani, Colleen1 aIrvin, Ryan1 aAvery, Christy, L1 aSmith, Albert, Vernon1 aSun, Fangui1 aEvans, Daniel, S1 aMusani, Solomon, K1 aLi, Xiaohui1 aTrompet, Stella1 aKrijthe, Bouwe, P1 aHarris, Tamara, B1 aQuibrera, Miguel1 aBrody, Jennifer, A1 aDemissie, Serkalem1 aDavis, Barry, R1 aWiggins, Kerri, L1 aTranah, Gregory, J1 aLange, Leslie, A1 aSotoodehnia, Nona1 aStott, David, J1 aFranco, Oscar, H1 aLauner, Lenore, J1 aStürmer, Til1 aTaylor, Kent, D1 aCupples, Adrienne, L1 aEckfeldt, John, H1 aSmith, Nicholas, L1 aLiu, Yongmei1 aWilson, James, G1 aHeckbert, Susan, R1 aBuckley, Brendan, M1 aIkram, Arfan, M1 aBoerwinkle, Eric1 aChen, Yii-Der Ida1 ade Craen, Anton, J M1 aUitterlinden, André, G1 aRotter, Jerome, I1 aFord, Ian1 aHofman, Albert1 aSattar, Naveed1 aSlagboom, Eline1 aWestendorp, Rudi, G J1 aGudnason, Vilmundur1 aVasan, Ramachandran, S1 aLumley, Thomas1 aCummings, Steven, R1 aTaylor, Herman, A1 aPost, Wendy1 aJukema, Wouter1 aStricker, Bruno, H1 aWhitsel, Eric, A1 aPsaty, Bruce, M1 aArnett, Donna uhttps://chs-nhlbi.org/node/687506191nas a2201513 4500008004100000022001400041245010300055210006900158260001500227300001000242490000800252520194100260653001602201653001702217653001202234653002202246653002502268653002102293653002802314653001002342653001102352653003802363653002502401653001702426653001102443653000902454653001602463653001302479653002602492653005302518653001902571653001802590653001802608100001202626700002402638700001802662700002902680700001802709700002802727700001702755700002002772700001502792700001202807700002002819700002102839700002102860700002002881700001802901700002202919700002302941700002302964700002202987700002003009700002803029700002103057700001703078700002403095700002803119700001803147700002303165700002203188700002403210700002203234700001903256700002203275700001903297700001803316700002903334700001503363700002203378700002003400700002003420700002203440700001503462700002303477700001603500700001903516700001703535700001703552700002903569700001903598700002003617700002103637700002203658700002303680700002003703700001903723700002203742700001203764700002103776700002003797700002403817700002003841700002503861700002103886700002103907700002403928700002203952700002503974700002103999700002404020700002104044700001904065700002004084700002204104700002204126700002004148700002004168700002804188700002404216700002404240700002104264700002004285700002504305700002404330700002004354700002604374700002504400700001804425700002604443700002104469700002304490700003004513700002104543700002004564700002204584710003504606856003604641 2015 eng d a1476-468700aExome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.0 aExome sequencing identifies rare LDLR and APOA5 alleles conferri c2015 Feb 5 a102-60 v5183 aMyocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
10aAge Factors10aAge of Onset10aAlleles10aApolipoproteins A10aCase-Control Studies10aCholesterol, LDL10aCoronary Artery Disease10aExome10aFemale10aGenetic Predisposition to Disease10aGenetics, Population10aHeterozygote10aHumans10aMale10aMiddle Aged10aMutation10aMyocardial Infarction10aNational Heart, Lung, and Blood Institute (U.S.)10aReceptors, LDL10aTriglycerides10aUnited States1 aDo, Ron1 aStitziel, Nathan, O1 aWon, Hong-Hee1 aJørgensen, Anders, Berg1 aDuga, Stefano1 aMerlini, Pier, Angelica1 aKiezun, Adam1 aFarrall, Martin1 aGoel, Anuj1 aZuk, Or1 aGuella, Illaria1 aAsselta, Rosanna1 aLange, Leslie, A1 aPeloso, Gina, M1 aAuer, Paul, L1 aGirelli, Domenico1 aMartinelli, Nicola1 aFarlow, Deborah, N1 aDePristo, Mark, A1 aRoberts, Robert1 aStewart, Alexander, F R1 aSaleheen, Danish1 aDanesh, John1 aEpstein, Stephen, E1 aSivapalaratnam, Suthesh1 aHovingh, Kees1 aKastelein, John, J1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aShah, Svati, H1 aKraus, William, E1 aDavies, Robert1 aNikpay, Majid1 aJohansen, Christopher, T1 aWang, Jian1 aHegele, Robert, A1 aHechter, Eliana1 aMärz, Winfried1 aKleber, Marcus, E1 aHuang, Jie1 aJohnson, Andrew, D1 aLi, Mingyao1 aBurke, Greg, L1 aGross, Myron1 aLiu, Yongmei1 aAssimes, Themistocles, L1 aHeiss, Gerardo1 aLange, Ethan, M1 aFolsom, Aaron, R1 aTaylor, Herman, A1 aOlivieri, Oliviero1 aHamsten, Anders1 aClarke, Robert1 aReilly, Dermot, F1 aYin, Wu1 aRivas, Manuel, A1 aDonnelly, Peter1 aRossouw, Jacques, E1 aPsaty, Bruce, M1 aHerrington, David, M1 aWilson, James, G1 aRich, Stephen, S1 aBamshad, Michael, J1 aTracy, Russell, P1 aCupples, Adrienne, L1 aRader, Daniel, J1 aReilly, Muredach, P1 aSpertus, John, A1 aCresci, Sharon1 aHartiala, Jaana1 aTang, W, H Wilson1 aHazen, Stanley, L1 aAllayee, Hooman1 aReiner, Alex, P1 aCarlson, Christopher, S1 aKooperberg, Charles1 aJackson, Rebecca, D1 aBoerwinkle, Eric1 aLander, Eric, S1 aSchwartz, Stephen, M1 aSiscovick, David, S1 aMcPherson, Ruth1 aTybjaerg-Hansen, Anne1 aAbecasis, Goncalo, R1 aWatkins, Hugh1 aNickerson, Deborah, A1 aArdissino, Diego1 aSunyaev, Shamil, R1 aO'Donnell, Christopher, J1 aAltshuler, David1 aGabriel, Stacey1 aKathiresan, Sekar1 aNHLBI Exome Sequencing Project uhttps://chs-nhlbi.org/node/669104825nas a2201141 4500008004100000022001400041245010700055210007000162260001600232300001200248490000700260520164000267653001001907653002001917653002501937653001801962653002301980653004002003653001102043653001702054653003402071653001102105653000902116653001202125653003602137100002702173700002002200700002002220700002002240700001902260700002002279700002402299700002002323700002402343700002302367700002402390700002302414700002402437700001402461700002102475700002102496700002202517700001802539700001902557700001902576700002402595700001902619700002302638700002402661700002002685700001702705700001602722700001702738700002502755700001502780700001802795700001902813700002002832700001402852700002002866700002102886700002102907700002102928700001602949700002002965700002102985700002603006700002003032700001703052700002003069700001803089700001903107700001903126700001903145700002303164700001903187700002803206700002403234700002103258700002503279700002003304700002303324700001603347700002803363700002303391700002503414700001103439700002003450700002503470700002503495700002003520700002203540700002003562700002503582700002003607700002003627856003603647 2015 eng d a1460-208300aGene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry.0 aGene × dietary pattern interactions in obesity analysis of up to c2015 Aug 15 a4728-380 v243 aObesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.
10aAdult10aBody Mass Index10aCase-Control Studies10aDiet, Western10aEpistasis, Genetic10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aObesity10aPolymorphism, Single Nucleotide1 aNettleton, Jennifer, A1 aFollis, Jack, L1 aNgwa, Julius, S1 aSmith, Caren, E1 aAhmad, Shafqat1 aTanaka, Toshiko1 aWojczynski, Mary, K1 aVoortman, Trudy1 aLemaitre, Rozenn, N1 aKristiansson, Kati1 aNuotio, Marja-Liisa1 aHouston, Denise, K1 aPerälä, Mia-Maria1 aQi, Qibin1 aSonestedt, Emily1 aManichaikul, Ani1 aKanoni, Stavroula1 aGanna, Andrea1 aMikkilä, Vera1 aNorth, Kari, E1 aSiscovick, David, S1 aHarald, Kennet1 aMcKeown, Nicola, M1 aJohansson, Ingegerd1 aRissanen, Harri1 aLiu, Yongmei1 aLahti, Jari1 aHu, Frank, B1 aBandinelli, Stefania1 aRukh, Gull1 aRich, Stephen1 aBooij, Lisanne1 aDmitriou, Maria1 aAx, Erika1 aRaitakari, Olli1 aMukamal, Kenneth1 aMännistö, Satu1 aHallmans, Göran1 aJula, Antti1 aEricson, Ulrika1 aJacobs, David, R1 avan Rooij, Frank, J A1 aDeloukas, Panos1 aSjogren, Per1 aKähönen, Mika1 aDjoussé, Luc1 aPerola, Markus1 aBarroso, Inês1 aHofman, Albert1 aStirrups, Kathleen1 aViikari, Jorma1 aUitterlinden, André, G1 aKalafati, Ioanna, P1 aFranco, Oscar, H1 aMozaffarian, Dariush1 aSalomaa, Veikko1 aBorecki, Ingrid, B1 aKnekt, Paul1 aKritchevsky, Stephen, B1 aEriksson, Johan, G1 aDedoussis, George, V1 aQi, Lu1 aFerrucci, Luigi1 aOrho-Melander, Marju1 aZillikens, Carola, M1 aIngelsson, Erik1 aLehtimäki, Terho1 aRenstrom, Frida1 aCupples, Adrienne, L1 aLoos, Ruth, J F1 aFranks, Paul, W uhttps://chs-nhlbi.org/node/680203195nas a2200577 4500008004100000022001400041245014300055210006900198260001300267300001100280490000700291520150000298653001001798653002201808653000901830653004001839653001601879653001101895653001701906653003401923653001101957653000901968653003501977653001602012653003602028653002702064653002602091100001802117700001802135700001702153700002102170700002102191700001602212700002202228700002402250700001702274700002102291700002402312700001802336700002202354700002102376700002302397700002302420700001802443700002102461700003002482700002302512700002502535700002102560856003602581 2015 eng d a1096-865200aGene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.0 aGenecentric approach identifies new and known loci for FVIII act c2015 Jun a534-400 v903 aCoagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.
10aAdult10aAfrican Americans10aAged10aEuropean Continental Ancestry Group10aFactor VIII10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMethionine Adenosyltransferase10aMiddle Aged10aPolymorphism, Single Nucleotide10aVenous Thromboembolism10avon Willebrand Factor1 aTang, Weihong1 aCushman, Mary1 aGreen, David1 aRich, Stephen, S1 aLange, Leslie, A1 aYang, Qiong1 aTracy, Russell, P1 aTofler, Geoffrey, H1 aBasu, Saonli1 aWilson, James, G1 aKeating, Brendan, J1 aWeng, Lu-Chen1 aTaylor, Herman, A1 aJacobs, David, R1 aDelaney, Joseph, A1 aPalmer, Cameron, D1 aYoung, Taylor1 aPankow, James, S1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aReiner, Alexander, P1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/737604354nas a2200661 4500008004100000022001400041245008900055210006900144260001300213300001200226490000700238520241500245653001002660653001202670653001802682653005302700653001902753653003002772653002502802653004002827653001202867653001102879653003302890653001102923653002302934653000902957653001602966653003302982653003503015653001403050653003603064653001003100653002403110100002203134700002003156700002003176700002003196700002003216700002403236700001703260700002103277700003203298700002503330700002503355700002003380700001903400700002403419700002803443700002803471700002403499700001803523700001803541700002403559700001903583700002103602710003303623856003603656 2015 eng d a1935-554800aGene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits.0 aGeneEnvironment Interactions of CircadianRelated Genes for Cardi c2015 Aug a1456-660 v383 aOBJECTIVE: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations.
RESEARCH DESIGN AND METHODS: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
RESULTS: We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h).
CONCLUSIONS: Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.
10aAdult10aAlleles10aBlood Glucose10aCircadian Rhythm Signaling Peptides and Proteins10aCohort Studies10aDiabetes Mellitus, Type 210aDiet, Fat-Restricted10aEuropean Continental Ancestry Group10aFasting10aFemale10aGene-Environment Interaction10aHumans10aInsulin Resistance10aMale10aMiddle Aged10aMulticenter Studies as Topic10aObservational Studies as Topic10aPhenotype10aPolymorphism, Single Nucleotide10aSleep10aWaist Circumference1 aDashti, Hassan, S1 aFollis, Jack, L1 aSmith, Caren, E1 aTanaka, Toshiko1 aGaraulet, Marta1 aGottlieb, Daniel, J1 aHruby, Adela1 aJacques, Paul, F1 ade Jong, Jessica, C Kiefte-1 aLamon-Fava, Stefania1 aScheer, Frank, A J L1 aBartz, Traci, M1 aKovanen, Leena1 aWojczynski, Mary, K1 aFrazier-Wood, Alexis, C1 aAhluwalia, Tarunveer, S1 aPerälä, Mia-Maria1 aJonsson, Anna1 aMuka, Taulant1 aKalafati, Ioanna, P1 aMikkilä, Vera1 aOrdovas, Jose, M1 aCHARGE Nutrition Study Group uhttps://chs-nhlbi.org/node/692702719nas a2200469 4500008004100000022001400041245010800055210006900163260001600232300001100248490000700259520132600266653000901592653001001601653002801611653001901639653002401658653002801682653003401710653003301744653002201777653001801799653003401817653001101851653002501862653002701887653002001914653002101934653002001955653001801975100002401993700002102017700001902038700002202057700002502079700002202104700002102126700002502147700002102172700002002193856003602213 2015 eng d a1097-025800aGeneralized estimating equations for genome-wide association studies using longitudinal phenotype data.0 aGeneralized estimating equations for genomewide association stud c2015 Jan 15 a118-300 v343 aMany longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.
10aAged10aAging10aCardiovascular Diseases10aCohort Studies10aComputer Simulation10aCross-Sectional Studies10aEpidemiologic Research Design10aGene-Environment Interaction10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aMeta-Analysis as Topic10aModels, Genetic10aPharmacogenetics10aRisk Assessment10aUnited States1 aSitlani, Colleen, M1 aRice, Kenneth, M1 aLumley, Thomas1 aMcKnight, Barbara1 aCupples, Adrienne, L1 aAvery, Christy, L1 aNoordam, Raymond1 aStricker, Bruno, H C1 aWhitsel, Eric, A1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/660203799nas a2200637 4500008004100000022001400041245010600055210006900161260001300230300001000243490000700253520205800260653000902318653002202327653001202349653001002361653001402371653001302385653001102398653003402409653001102443653002602454653000902480653003602489653000902525653002102534653001702555653001702572653003502589653001702624100002002641700001602661700002102677700002902698700002702727700002002754700001702774700001702791700002002808700001802828700001902846700002102865700001602886700002002902700002002922700002302942700001902965700001902984700002203003700002003025700002303045700001603068700001803084700002303102856003603125 2015 eng d a1524-462800aGenes from a translational analysis support a multifactorial nature of white matter hyperintensities.0 aGenes from a translational analysis support a multifactorial nat c2015 Feb a341-70 v463 aBACKGROUND AND PURPOSE: White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative.
METHODS: We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE.
RESULTS: Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1).
CONCLUSIONS: Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.
10aAged10aAlzheimer Disease10aAnimals10aBrain10aCausality10aDementia10aFemale10aGenome-Wide Association Study10aHumans10aLeukoencephalopathies10aMale10aPolymorphism, Single Nucleotide10aRats10aRats, Inbred SHR10aRats, Wistar10aRisk Factors10aTranslational Medical Research10aWhite Matter1 aLopez, Lorna, M1 aHill, David1 aHarris, Sarah, E1 aHernandez, Maria, Valdes1 aManiega, Susana, Munoz1 aBastin, Mark, E1 aBailey, Emma1 aSmith, Colin1 aMcBride, Martin1 aMcClure, John1 aGraham, Delyth1 aDominiczak, Anna1 aYang, Qiong1 aFornage, Myriam1 aIkram, Arfan, M1 aDebette, Stephanie1 aLauner, Lenore1 aBis, Joshua, C1 aSchmidt, Reinhold1 aSeshadri, Sudha1 aPorteous, David, J1 aStarr, John1 aDeary, Ian, J1 aWardlaw, Joanna, M uhttps://chs-nhlbi.org/node/681806452nas a2201885 4500008004100000022001400041245015700055210006900212260001300281300001100294490000700305520181900312653000902131653002202140653002002162653001402182653002402196653001902220653001102239653003802250653003402288653001802322653001102340653000902351653001602360653002902376653001402405653003602419653001302455100001402468700001702482700001302499700001602512700001602528700001702544700001302561700002602574700001302600700001302613700002202626700001802648700001102666700001802677700001702695700001502712700001502727700001602742700001802758700001502776700001402791700001202805700001002817700001302827700001202840700001402852700001702866700001502883700001802898700001502916700001302931700001202944700001202956700001502968700001802983700001003001700001703011700001403028700001203042700001503054700001803069700001803087700001603105700001403121700001903135700001503154700001903169700001603188700001503204700001203219700002003231700001903251700001603270700001603286700001303302700001403315700001903329700001503348700001903363700001403382700001803396700001503414700001703429700001103446700001003457700001203467700001803479700001603497700002103513700001703534700001703551700001603568700001403584700001603598700001503614700001703629700001403646700001603660700001503676700001503691700001503706700001803721700001603739700001503755700001403770700002003784700001603804700001603820700001603836700002203852700001703874700001503891700001503906700002203921700001703943700001303960700001803973700001703991700001604008700001704024700001204041700001404053700001604067700001804083700001504101700002104116700001504137700001604152700002004168700001704188700001904205700001904224700001604243700001304259700001804272700001504290700002004305700001604325700001604341700001604357700001504373700001604388700001704404700001404421700002204435700001604457700001704473700001604490710002404506856003604530 2015 eng d a1476-557800aGenetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).0 aGenetic contributions to variation in general cognitive function c2015 Feb a183-920 v203 aGeneral cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
10aAged10aAged, 80 and over10aAtherosclerosis10aCognition10aCognition Disorders10aCohort Studies10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHMGN1 Protein10aHumans10aMale10aMiddle Aged10aNeuropsychological Tests10aPhenotype10aPolymorphism, Single Nucleotide10aScotland1 aDavies, G1 aArmstrong, N1 aBis, J C1 aBressler, J1 aChouraki, V1 aGiddaluru, S1 aHofer, E1 aIbrahim-Verbaas, C, A1 aKirin, M1 aLahti, J1 avan der Lee, S, J1 aLe Hellard, S1 aLiu, T1 aMarioni, R, E1 aOldmeadow, C1 aPostmus, I1 aSmith, A V1 aSmith, J, A1 aThalamuthu, A1 aThomson, R1 aVitart, V1 aWang, J1 aYu, L1 aZgaga, L1 aZhao, W1 aBoxall, R1 aHarris, S, E1 aHill, W, D1 aLiewald, D, C1 aLuciano, M1 aAdams, H1 aAmes, D1 aAmin, N1 aAmouyel, P1 aAssareh, A, A1 aAu, R1 aBecker, J, T1 aBeiser, A1 aBerr, C1 aBertram, L1 aBoerwinkle, E1 aBuckley, B, M1 aCampbell, H1 aCorley, J1 aDe Jager, P, L1 aDufouil, C1 aEriksson, J, G1 aEspeseth, T1 aFaul, J, D1 aFord, I1 aGottesman, R, F1 aGriswold, M, E1 aGudnason, V1 aHarris, T B1 aHeiss, G1 aHofman, A1 aHolliday, E, G1 aHuffman, J1 aKardia, S, L R1 aKochan, N1 aKnopman, D, S1 aKwok, J, B1 aLambert, J-C1 aLee, T1 aLi, G1 aLi, S-C1 aLoitfelder, M1 aLopez, O, L1 aLundervold, A, J1 aLundqvist, A1 aMather, K, A1 aMirza, S, S1 aNyberg, L1 aOostra, B A1 aPalotie, A1 aPapenberg, G1 aPattie, A1 aPetrovic, K1 aPolasek, O1 aPsaty, B M1 aRedmond, P1 aReppermund, S1 aRotter, J I1 aSchmidt, H1 aSchuur, M1 aSchofield, P, W1 aScott, R, J1 aSteen, V, M1 aStott, D, J1 avan Swieten, J, C1 aTaylor, K, D1 aTrollor, J1 aTrompet, S1 aUitterlinden, A G1 aWeinstein, G1 aWiden, E1 aWindham, B, G1 aJukema, J, W1 aWright, A F1 aWright, M, J1 aYang, Q1 aAmieva, H1 aAttia, J, R1 aBennett, D, A1 aBrodaty, H1 ade Craen, A, J M1 aHayward, C1 aIkram, M, A1 aLindenberger, U1 aNilsson, L-G1 aPorteous, D, J1 aRäikkönen, K1 aReinvang, I1 aRudan, I1 aSachdev, P, S1 aSchmidt, R1 aSchofield, P, R1 aSrikanth, V1 aStarr, J, M1 aTurner, S T1 aWeir, D, R1 aWilson, J F1 avan Duijn, C1 aLauner, L1 aFitzpatrick, A, L1 aSeshadri, S1 aMosley, T, H1 aDeary, I, J1 aGeneration Scotland uhttps://chs-nhlbi.org/node/681602945nas a2200589 4500008004100000022001400041245009400055210006900149260001300218300001100231490000700242520132000249653001901569653001601588653001701604653002201621653003401643653001101677100002401688700001901712700002501731700001801756700002201774700002101796700001701817700001201834700002301846700001901869700001301888700001701901700002401918700002101942700002101963700002001984700001802004700002102022700001802043700001802061700001502079700002202094700001902116700002102135700002102156700002502177700001702202700001802219700001702237700002002254700002002274700002502294856003602319 2015 eng d a1539-726200aGenetic loci associated with circulating levels of very long-chain saturated fatty acids.0 aGenetic loci associated with circulating levels of very longchai c2015 Jan a176-840 v563 aVery long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.
10aCohort Studies10aFatty Acids10aGenetic Loci10aGenetic Variation10aGenome-Wide Association Study10aHumans1 aLemaitre, Rozenn, N1 aKing, Irena, B1 aKabagambe, Edmond, K1 aH Y Wu, Jason1 aMcKnight, Barbara1 aManichaikul, Ani1 aGuan, Weihua1 aSun, Qi1 aChasman, Daniel, I1 aFoy, Millennia1 aWang, Lu1 aZhu, Jingwen1 aSiscovick, David, S1 aTsai, Michael, Y1 aArnett, Donna, K1 aPsaty, Bruce, M1 aDjoussé, Luc1 aChen, Yii-der, I1 aTang, Weihong1 aWeng, Lu-Chen1 aWu, Hongyu1 aJensen, Majken, K1 aChu, Audrey, Y1 aJacobs, David, R1 aRich, Stephen, S1 aMozaffarian, Dariush1 aSteffen, Lyn1 aRimm, Eric, B1 aHu, Frank, B1 aRidker, Paul, M1 aFornage, Myriam1 aFriedlander, Yechiel uhttps://chs-nhlbi.org/node/661504501nas a2200649 4500008004100000022001400041245015600055210006900211260001300280300001200293490000800305520259500313653002202908653002102930653002002951653001502971653004002986653002503026653001903051653003203070653001703102653002603119653001103145653001803156653003603174653002203210100002503232700002503257700002603282700002403308700002103332700001203353700001903365700001303384700001903397700002503416700002103441700001503462700002203477700002303499700001903522700002003541700001703561700001903578700002203597700002003619700001803639700001903657700001803676700002403694700002003718700002103738700001803759700001703777700002103794856003603815 2015 eng d a1938-320700aGenetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.0 aGenetic loci associated with circulating phospholipid trans fatt c2015 Feb a398-4060 v1013 aBACKGROUND: Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health.
OBJECTIVE: The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers.
DESIGN: We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts.
RESULTS: Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (β = 0.0035, P = 4.90 × 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (β = 0.0053, P = 1.05 × 10(-6)) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 × 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans.
CONCLUSIONS: Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.
10aAfrican Americans10aArachidonic Acid10aAsian Americans10aBiomarkers10aEuropean Continental Ancestry Group10aFatty Acids, Omega-610aGene Frequency10aGenetic Association Studies10aGenetic Loci10aGenotyping Techniques10aHumans10aPhospholipids10aPolymorphism, Single Nucleotide10aTrans Fatty Acids1 aMozaffarian, Dariush1 aKabagambe, Edmond, K1 aJohnson, Catherine, O1 aLemaitre, Rozenn, N1 aManichaikul, Ani1 aSun, Qi1 aFoy, Millennia1 aWang, Lu1 aWiener, Howard1 aIrvin, Marguerite, R1 aRich, Stephen, S1 aWu, Hongyu1 aJensen, Majken, K1 aChasman, Daniel, I1 aChu, Audrey, Y1 aFornage, Myriam1 aSteffen, Lyn1 aKing, Irena, B1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aDjoussé, Luc1 aChen, Ida, Y-D1 aH Y Wu, Jason1 aSiscovick, David, S1 aRidker, Paul, M1 aTsai, Michael, Y1 aRimm, Eric, B1 aHu, Frank, B1 aArnett, Donna, K uhttps://chs-nhlbi.org/node/668504154nas a2200829 4500008004100000022001400041245006800055210006700123260001300190300001000203490000700213520178300220653001202003653002002015653003502035653001902070653003702089653001302126653003402139653001302173653001102186653001302197653001802210653002702228653001402255653003602269653001102305100002702316700002102343700001802364700001702382700001902399700002302418700002002441700002202461700001902483700002102502700002802523700001902551700001802570700002002588700002002608700002002628700001602648700002302664700001902687700002102706700002202727700002202749700001902771700002702790700002302817700002002840700002302860700002002883700002102903700001902924700001902943700002202962700002502984700002103009700002503030700002103055700002003076700002203096700001603118700001903134710004503153710004503198710004503243856003603288 2015 eng d a1524-462800aGenetic overlap between diagnostic subtypes of ischemic stroke.0 aGenetic overlap between diagnostic subtypes of ischemic stroke c2015 Mar a615-90 v463 aBACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.
METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.
RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.
CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
10aAlleles10aAtherosclerosis10aCerebral Small Vessel Diseases10aCohort Studies10aData Interpretation, Statistical10aEmbolism10aGenome-Wide Association Study10aGenotype10aHumans10aIschemia10aLinear Models10aMeta-Analysis as Topic10aPhenotype10aPolymorphism, Single Nucleotide10aStroke1 aHolliday, Elizabeth, G1 aTraylor, Matthew1 aMalik, Rainer1 aBevan, Steve1 aFalcone, Guido1 aHopewell, Jemma, C1 aCheng, Yu-Ching1 aCotlarciuc, Ioana1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBoncoraglio, Giorgio, B1 aClarke, Robert1 aCole, John, W1 aFornage, Myriam1 aFurie, Karen, L1 aIkram, Arfan, M1 aJannes, Jim1 aKittner, Steven, J1 aLincz, Lisa, F1 aMaguire, Jane, M1 aMeschia, James, F1 aMosley, Thomas, H1 aNalls, Mike, A1 aOldmeadow, Christopher1 aParati, Eugenio, A1 aPsaty, Bruce, M1 aRothwell, Peter, M1 aSeshadri, Sudha1 aScott, Rodney, J1 aSharma, Pankaj1 aSudlow, Cathie1 aWiggins, Kerri, L1 aWorrall, Bradford, B1 aRosand, Jonathan1 aMitchell, Braxton, D1 aDichgans, Martin1 aMarkus, Hugh, S1 aLevi, Christopher1 aAttia, John1 aWray, Naomi, R1 aAustralian Stroke Genetics Collaborative1 aWellcome Trust Case Control Consortium 21 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/668804013nas a2201093 4500008004100000022001400041245012400055210006900179260000900248300000900257490000600266520085300272653003801125653001601163653001901179653003201198653001101230653002301241653001601264100003001280700002401310700001801334700001801352700002801370700001801398700002701416700002001443700001801463700001801481700002801499700002501527700002201552700002101574700002001595700002101615700002001636700002001656700002001676700002101696700002301717700002001740700002101760700002701781700002601808700002401834700001901858700002601877700001901903700001901922700002101941700002401962700002001986700002502006700001602031700001902047700002202066700002302088700001902111700002202130700002402152700002302176700001902199700002202218700002602240700002002266700001502286700002102301700002102322700002202343700001902365700002202384700001602406700002002422700002102442700002002463700002302483700002502506700002002531700002202551700001902573700001502592700002302607700002402630700002802654700002202682700002702704700002502731700002002756700002302776700002002799700002302819710004102842856003602883 2015 eng d a2041-172300aGenome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.0 aGenome of The Netherlands populationspecific imputations identif c2015 a60650 v63 aVariants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
10aATP-Binding Cassette Transporters10aCholesterol10aGene Frequency10aGenetic Association Studies10aHumans10aMutation, Missense10aNetherlands1 avan Leeuwen, Elisabeth, M1 aKarssen, Lennart, C1 aDeelen, Joris1 aIsaacs, Aaron1 aMedina-Gómez, Carolina1 aMbarek, Hamdi1 aKanterakis, Alexandros1 aTrompet, Stella1 aPostmus, Iris1 aVerweij, Niek1 avan Enckevort, David, J1 aHuffman, Jennifer, E1 aWhite, Charles, C1 aFeitosa, Mary, F1 aBartz, Traci, M1 aManichaikul, Ani1 aJoshi, Peter, K1 aPeloso, Gina, M1 aDeelen, Patrick1 avan Dijk, Freerk1 aWillemsen, Gonneke1 ade Geus, Eco, J1 aMilaneschi, Yuri1 aPenninx, Brenda, W J H1 aFrancioli, Laurent, C1 aMenelaou, Androniki1 aPulit, Sara, L1 aRivadeneira, Fernando1 aHofman, Albert1 aOostra, Ben, A1 aFranco, Oscar, H1 aLeach, Irene, Mateo1 aBeekman, Marian1 ade Craen, Anton, J M1 aUh, Hae-Won1 aTrochet, Holly1 aHocking, Lynne, J1 aPorteous, David, J1 aSattar, Naveed1 aPackard, Chris, J1 aBuckley, Brendan, M1 aBrody, Jennifer, A1 aBis, Joshua, C1 aRotter, Jerome, I1 aMychaleckyj, Josyf, C1 aCampbell, Harry1 aDuan, Qing1 aLange, Leslie, A1 aWilson, James, F1 aHayward, Caroline1 aPolasek, Ozren1 aVitart, Veronique1 aRudan, Igor1 aWright, Alan, F1 aRich, Stephen, S1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aKearney, Patricia, M1 aStott, David, J1 aCupples, Adrienne1 aJukema, Wouter1 aHarst, Pim1 aSijbrands, Eric, J1 aHottenga, Jouke-Jan1 aUitterlinden, André, G1 aSwertz, Morris, A1 avan Ommen, Gert-Jan, B1 ade Bakker, Paul, I W1 aSlagboom, Eline1 aBoomsma, Dorret, I1 aWijmenga, Cisca1 aDuijn, Cornelia, M1 aGenome of the Netherlands Consortium uhttps://chs-nhlbi.org/node/668202703nas a2200445 4500008004100000022001400041245008300055210006900138260001300207300001100220490000700231520140200238653001001640653002201650653003501672653002001707653003401727653001101761653001401772653003601786653002801822100002101850700002201871700002001893700002501913700002101938700002101959700001901980700002401999700001702023700002302040700002102063700002402084700002402108700002302132700002102155700002502176700002002201856003602221 2015 ENG d a1758-535X00aGenome-Wide Association Study and Linkage Analysis of the Healthy Aging Index.0 aGenomeWide Association Study and Linkage Analysis of the Healthy c2015 Aug a1003-80 v703 aBACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.
METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.
RESULTS: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.
CONCLUSIONS: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.
10aAging10aApolipoproteins E10aForkhead Transcription Factors10aGenetic Linkage10aGenome-Wide Association Study10aHumans10aLongevity10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aMinster, Ryan, L1 aSanders, Jason, L1 aSingh, Jatinder1 aKammerer, Candace, M1 aBarmada, Michael1 aMatteini, Amy, M1 aZhang, Qunyuan1 aWojczynski, Mary, K1 aDaw, Warwick1 aBrody, Jennifer, A1 aArnold, Alice, M1 aLunetta, Kathryn, L1 aMurabito, Joanne, M1 aChristensen, Kaare1 aPerls, Thomas, T1 aProvince, Michael, A1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/670307237nas a2202149 4500008004100000022001400041245010100055210006900156260001300225300001100238490000700249520180600256653004102062653006402103653003802167653001102205653002802216653001602244653003402260653001102294653001402305653003602319110004402355700001802399700001602417700001202433700001602445700001302461700001502474700001602489700001202505700001502517700001602532700001502548700001502563700001602578700001602594700001402610700001002624700002102634700001302655700001902668700002102687700001502708700001502723700001702738700001302755700001602768700001902784700001602803700001702819700001402836700001402850700001202864700001102876700001302887700001702900700001702917700001202934700001702946700001502963700002202978700001903000700001403019700001603033700001403049700001603063700001903079700002203098700002203120700001503142700001703157700001103174700001603185700001403201700001303215700001503228700001603243700002103259700001403280700001003294700001703304700001503321700001703336700001703353700001603370700001203386700001603398700002003414700001403434700001403448700001403462700001603476700001503492700001803507700001803525700001703543700001803560700001503578700001903593700001503612700001503627700001503642700001603657700002103673700001403694700001703708700001703725700001603742700001503758700001403773700001603787700001803803700001903821700001803840700001503858700001603873700001403889700001703903700001803920700001103938700001403949700001503963700001603978700002003994700001404014700001804028700001904046700001504065700001604080700001604096700001604112700001604128700001704144700001404161700001604175700001404191700001904205700001604224700001804240700001904258700001504277700001404292700001504306700001404321700001704335700002004352700002004372700001704392700001904409700001604428700001704444700001304461700001504474700001804489700001804507700001704525700001704542700002004559700001604579700001604595700002004611700002604631700001204657700001604669700001904685700001804704700001704722700001604739700001504755700001304770700001604783700001604799700001704815700002004832700001804852700001704870710006604887710005504953710004305008856003605051 2015 ENG d a1476-557800aGenome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.0 aGenomewide metaanalysis identifies six novel loci associated wit c2015 May a647-560 v203 aCoffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.
10aAdaptor Proteins, Signal Transducing10aBasic Helix-Loop-Helix Leucine Zipper Transcription Factors10aBrain-Derived Neurotrophic Factor10aCoffea10aCytochrome P-450 CYP1A210aFood Habits10aGenome-Wide Association Study10aHumans10aPhenotype10aPolymorphism, Single Nucleotide1 aCoffee and Caffeine Genetics Consortium1 aCornelis, M C1 aByrne, E, M1 aEsko, T1 aNalls, M, A1 aGanna, A1 aPaynter, N1 aMonda, K, L1 aAmin, N1 aFischer, K1 aRenstrom, F1 aNgwa, J, S1 aHuikari, V1 aCavadino, A1 aNolte, I, M1 aTeumer, A1 aYu, K1 aMarques-Vidal, P1 aRawal, R1 aManichaikul, A1 aWojczynski, M, K1 aVink, J, M1 aZhao, J, H1 aBurlutsky, G1 aLahti, J1 aMikkilä, V1 aLemaitre, R, N1 aEriksson, J1 aMusani, S, K1 aTanaka, T1 aGeller, F1 aLuan, J1 aHui, J1 aMägi, R1 aDimitriou, M1 aGarcia, M, E1 aHo, W-K1 aWright, M, J1 aRose, L, M1 aMagnusson, P, K E1 aPedersen, N, L1 aCouper, D1 aOostra, B A1 aHofman, A1 aIkram, M, A1 aTiemeier, H, W1 aUitterlinden, A G1 avan Rooij, F, J A1 aBarroso, I1 aJohansson, I1 aXue, L1 aKaakinen, M1 aMilani, L1 aPower, C1 aSnieder, H1 aStolk, R, P1 aBaumeister, S, E1 aBiffar, R1 aGu, F1 aBastardot, F1 aKutalik, Z1 aJacobs, D, R1 aForouhi, N G1 aMihailov, E1 aLind, L1 aLindgren, C1 aMichaëlsson, K1 aMorris, A1 aJensen, M1 aKhaw, K-T1 aLuben, R, N1 aWang, J, J1 aMännistö, S1 aPerälä, M-M1 aKähönen, M1 aLehtimäki, T1 aViikari, J1 aMozaffarian, D1 aMukamal, K1 aPsaty, B M1 aDöring, A1 aHeath, A, C1 aMontgomery, G, W1 aDahmen, N1 aCarithers, T1 aTucker, K, L1 aFerrucci, L1 aBoyd, H, A1 aMelbye, M1 aTreur, J, L1 aMellström, D1 aHottenga, J, J1 aProkopenko, I1 aTönjes, A1 aDeloukas, P1 aKanoni, S1 aLorentzon, M1 aHouston, D, K1 aLiu, Y1 aDanesh, J1 aRasheed, A1 aMason, M, A1 aZonderman, A, B1 aFranke, L1 aKristal, B, S1 aKarjalainen, J1 aReed, D, R1 aWestra, H-J1 aEvans, M, K1 aSaleheen, D1 aHarris, T B1 aDedoussis, G1 aCurhan, G1 aStumvoll, M1 aBeilby, J1 aPasquale, L, R1 aFeenstra, B1 aBandinelli, S1 aOrdovás, J, M1 aChan, A, T1 aPeters, U1 aOhlsson, C1 aGieger, C1 aMartin, N, G1 aWaldenberger, M1 aSiscovick, D, S1 aRaitakari, O1 aEriksson, J, G1 aMitchell, P1 aHunter, D, J1 aKraft, P1 aRimm, E, B1 aBoomsma, D, I1 aBorecki, I, B1 aLoos, R, J F1 aWareham, N J1 aVollenweider, P1 aCaporaso, N1 aGrabe, H, J1 aNeuhouser, M, L1 aWolffenbuttel, B, H R1 aHu, F B1 aHypponen, E1 aJärvelin, M-R1 aCupples, L, A1 aFranks, P, W1 aRidker, P M1 aDuijn, C M1 aHeiss, G1 aMetspalu, A1 aNorth, K, E1 aIngelsson, E1 aNettleton, J, A1 avan Dam, R, M1 aChasman, D I1 aInternational Parkinson's Disease Genomics Consortium (IPDGC)1 aNorth American Brain Expression Consortium (NABEC)1 aUK Brain Expression Consortium (UKBEC) uhttps://chs-nhlbi.org/node/660607065nas a2201873 4500008004100000022001400041245015900055210006900214260001600283300001100299490000700310520180500317653000902122653002202131653001002153653002202163653001402185653001902199653001102218653003402229653001302263653001102276653000902287653002102296653001602317653003602333653001302369653001802382653002402400653002202424653002002446100002302466700003002489700001802519700001902537700001802556700001902574700001702593700002102610700002402631700002102655700001602676700002402692700003202716700002302748700001602771700001902787700002302806700001702829700001202846700002202858700002202880700002102902700002002923700002002943700002002963700002002983700001503003700001703018700001803035700001903053700002103072700002203093700001203115700001903127700001903146700002703165700001703192700002003209700002503229700001403254700001903268700001603287700001903303700002303322700002403345700001603369700001803385700002003403700001403423700002203437700001903459700002503478700002603503700002203529700002403551700001603575700001603591700001903607700002703626700002103653700002203674700002003696700001303716700002103729700002403750700002203774700001503796700002403811700002203835700002003857700001703877700001903894700001903913700002003932700001403952700002103966700002503987700002404012700002304036700002204059700002104081700001904102700001904121700002304140700002204163700002504185700002304210700001804233700001904251700002404270700002304294700002304317700002004340700001604360700002804376700002204404700003004426700002104456700002304477700002004500700002004520700001904540700002004559700002004579700002104599700002304620700002604643700002204669700002704691700002204718700002004740700001704760700002304777700002404800700002804824700002404852700003104876700002204907700002004929700001804949700002304967700001904990700002805009700002005037700002205057710007605079856003605155 2015 eng d a1873-240200aGenome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.0 aGenomewide studies of verbal declarative memory in nondemented o c2015 Apr 15 a749-630 v773 aBACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
10aAged10aAged, 80 and over10aAging10aApolipoproteins E10aClaudin-510aCohort Studies10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMemory Disorders10aMiddle Aged10aPolymorphism, Single Nucleotide10aProteins10aProteoglycans10aRegression Analysis10aSulfotransferases10aVerbal Learning1 aDebette, Stephanie1 aVerbaas, Carla, A Ibrahim1 aBressler, Jan1 aSchuur, Maaike1 aSmith, Albert1 aBis, Joshua, C1 aDavies, Gail1 aWolf, Christiane1 aGudnason, Vilmundur1 aChibnik, Lori, B1 aYang, Qiong1 aDeStefano, Anita, L1 ade Quervain, Dominique, J F1 aSrikanth, Velandai1 aLahti, Jari1 aGrabe, Hans, J1 aSmith, Jennifer, A1 aPriebe, Lutz1 aYu, Lei1 aKarbalai, Nazanin1 aHayward, Caroline1 aWilson, James, F1 aCampbell, Harry1 aPetrovic, Katja1 aFornage, Myriam1 aChauhan, Ganesh1 aYeo, Robin1 aBoxall, Ruth1 aBecker, James1 aStegle, Oliver1 aMather, Karen, A1 aChouraki, Vincent1 aSun, Qi1 aRose, Lynda, M1 aResnick, Susan1 aOldmeadow, Christopher1 aKirin, Mirna1 aWright, Alan, F1 aJonsdottir, Maria, K1 aAu, Rhoda1 aBecker, Albert1 aAmin, Najaf1 aNalls, Mike, A1 aTurner, Stephen, T1 aKardia, Sharon, L R1 aOostra, Ben1 aWindham, Gwen1 aCoker, Laura, H1 aZhao, Wei1 aKnopman, David, S1 aHeiss, Gerardo1 aGriswold, Michael, E1 aGottesman, Rebecca, F1 aVitart, Veronique1 aHastie, Nicholas, D1 aZgaga, Lina1 aRudan, Igor1 aPolasek, Ozren1 aHolliday, Elizabeth, G1 aSchofield, Peter1 aChoi, Seung, Hoan1 aTanaka, Toshiko1 aAn, Yang1 aPerry, Rodney, T1 aKennedy, Richard, E1 aSale, Michèle, M1 aWang, Jing1 aWadley, Virginia, G1 aLiewald, David, C1 aRidker, Paul, M1 aGow, Alan, J1 aPattie, Alison1 aStarr, John, M1 aPorteous, David1 aLiu, Xuan1 aThomson, Russell1 aArmstrong, Nicola, J1 aEiriksdottir, Gudny1 aAssareh, Arezoo, A1 aKochan, Nicole, A1 aWiden, Elisabeth1 aPalotie, Aarno1 aHsieh, Yi-Chen1 aEriksson, Johan, G1 aVogler, Christian1 avan Swieten, John, C1 aShulman, Joshua, M1 aBeiser, Alexa1 aRotter, Jerome1 aSchmidt, Carsten, O1 aHoffmann, Wolfgang1 aNöthen, Markus, M1 aFerrucci, Luigi1 aAttia, John1 aUitterlinden, André, G1 aAmouyel, Philippe1 aDartigues, Jean-François1 aAmieva, Hélène1 aRäikkönen, Katri1 aGarcia, Melissa1 aWolf, Philip, A1 aHofman, Albert1 aLongstreth, W T1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aDeJager, Philip, L1 aSachdev, Perminder, S1 aSchmidt, Reinhold1 aBreteler, Monique, M B1 aTeumer, Alexander1 aLopez, Oscar, L1 aCichon, Sven1 aChasman, Daniel, I1 aGrodstein, Francine1 aMüller-Myhsok, Bertram1 aTzourio, Christophe1 aPapassotiropoulos, Andreas1 aBennett, David, A1 aIkram, Arfan, M1 aDeary, Ian, J1 aDuijn, Cornelia, M1 aLauner, Lenore1 aFitzpatrick, Annette, L1 aSeshadri, Sudha1 aMosley, Thomas, H1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium uhttps://chs-nhlbi.org/node/668404127nas a2200877 4500008004100000022001400041245007800055210006900133260001300202300001000215490000700225520166400232653000901896653002201905653002201927653002801949653001901977653001101996653002802007653003502035653003402070653001102104653001402115653000902129653001602138653003602154653002702190100001702217700002102234700001802255700002102273700002102294700002402315700002202339700002302361700002102384700002002405700001202425700002102437700001902458700002402477700002402501700002402525700002002549700002302569700001902592700002202611700002402633700002102657700001902678700002002697700001802717700002002735700002602755700002202781700002002803700002202823700002202845700002802867700001402895700002502909700002202934700002002956700002402976700002203000700001903022700002203041700002103063700002003084700002303104700001903127700002003146700002303166700002403189856003603213 2015 eng d a1758-535X00aGWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.0 aGWAS of longevity in CHARGE consortium confirms APOE and FOXO3 c c2015 Jan a110-80 v703 aBACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.
METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.
RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).
CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.
10aAged10aAged, 80 and over10aApolipoproteins E10aCell Adhesion Molecules10aCohort Studies10aFemale10aForkhead Box Protein O310aForkhead Transcription Factors10aGenome-Wide Association Study10aHumans10aLongevity10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Kainic Acid1 aBroer, Linda1 aBuchman, Aron, S1 aDeelen, Joris1 aEvans, Daniel, S1 aFaul, Jessica, D1 aLunetta, Kathryn, L1 aSebastiani, Paola1 aSmith, Jennifer, A1 aSmith, Albert, V1 aTanaka, Toshiko1 aYu, Lei1 aArnold, Alice, M1 aAspelund, Thor1 aBenjamin, Emelia, J1 aDe Jager, Philip, L1 aEirkisdottir, Gudny1 aEvans, Denis, A1 aGarcia, Melissa, E1 aHofman, Albert1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKiel, Douglas, P1 aOostra, Ben, A1 aOrwoll, Eric, S1 aParimi, Neeta1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSeshadri, Sudha1 aSingleton, Andrew1 aTiemeier, Henning1 aUitterlinden, André, G1 aZhao, Wei1 aBandinelli, Stefania1 aBennett, David, A1 aFerrucci, Luigi1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aKarasik, David1 aLauner, Lenore, J1 aPerls, Thomas, T1 aSlagboom, Eline1 aTranah, Gregory, J1 aWeir, David, R1 aNewman, Anne, B1 aDuijn, Cornelia, M1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/655005324nas a2201021 4500008004100000022001400041245012300055210006900178260001300247300001100260490000800271520242700279653001002706653002002716653001902736653001902755653002802774653000902802653002102811653001802832653004002850653002902890653001102919653003302930653003802963653001103001653000903012653001603021653001203037653003603049653001003085653001603095100002203111700002003133700002003153700002003173700001903193700002403212700001703236700002103253700002503274700002103299700001803320700002503338700001903363700002003382700002403402700001803426700002803444700003103472700001903503700001903522700002403541700001603565700002303581700001503604700001903619700002203638700002303660700001903683700002003702700002003722700001803742700002503760700002403785700002003809700002203829700002403851700002303875700002303898700002203921700002003943700002403963700002503987700002104012700002104033700001904054700002004073700002004093700002304113700002504136700001904161700002104180700002204201700002204223700002104245856003604266 2015 eng d a1938-320700aHabitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants.0 aHabitual sleep duration is associated with BMI and macronutrient c2015 Jan a135-430 v1013 aBACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake.
OBJECTIVES: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations.
DESIGN: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.
RESULTS: We observed a significant association between sleep duration and lower BMI (β ± SE = 0.16 ± 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 ± 0.06%, P = 0.03; women: 0.10 ± 0.05%, P = 0.04) and with lower carbohydrate (-0.31 ± 0.12%, P < 0.01), higher total fat (0.18 ± 0.09%, P = 0.05), and higher PUFA (0.05 ± 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake.
CONCLUSIONS: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile.
10aAdult10aBody Mass Index10aCLOCK Proteins10aCohort Studies10aCross-Sectional Studies10aDiet10aDietary Proteins10aEnergy Intake10aEuropean Continental Ancestry Group10aFatty Acids, Unsaturated10aFemale10aGene-Environment Interaction10aGenetic Predisposition to Disease10aHumans10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aSleep10aYoung Adult1 aDashti, Hassan, S1 aFollis, Jack, L1 aSmith, Caren, E1 aTanaka, Toshiko1 aCade, Brian, E1 aGottlieb, Daniel, J1 aHruby, Adela1 aJacques, Paul, F1 aLamon-Fava, Stefania1 aRichardson, Kris1 aSaxena, Richa1 aScheer, Frank, A J L1 aKovanen, Leena1 aBartz, Traci, M1 aPerälä, Mia-Maria1 aJonsson, Anna1 aFrazier-Wood, Alexis, C1 aKalafati, Ioanna-Panagiota1 aMikkilä, Vera1 aPartonen, Timo1 aLemaitre, Rozenn, N1 aLahti, Jari1 aHernandez, Dena, G1 aToft, Ulla1 aJohnson, Craig1 aKanoni, Stavroula1 aRaitakari, Olli, T1 aPerola, Markus1 aPsaty, Bruce, M1 aFerrucci, Luigi1 aGrarup, Niels1 aHighland, Heather, M1 aRallidis, Loukianos1 aKähönen, Mika1 aHavulinna, Aki, S1 aSiscovick, David, S1 aRäikkönen, Katri1 aJørgensen, Torben1 aRotter, Jerome, I1 aDeloukas, Panos1 aViikari, Jorma, S A1 aMozaffarian, Dariush1 aLinneberg, Allan1 aSeppälä, Ilkka1 aHansen, Torben1 aSalomaa, Veikko1 aGharib, Sina, A1 aEriksson, Johan, G1 aBandinelli, Stefania1 aPedersen, Oluf1 aRich, Stephen, S1 aDedoussis, George1 aLehtimäki, Terho1 aOrdovas, Jose, M uhttps://chs-nhlbi.org/node/661403293nas a2200541 4500008004100000022001400041245011700055210006900172260001300241300001200254490000800266520179700274653001602071653001602087653000902103653002202112653001002134653002402144653001502168653001102183653001102194653001402205653001802219653000902237653002602246653003102272653002202303653001402325653003202339653002402371653002002395653001702415653001702432653001802449653001802467100001902485700002002504700001802524700001902542700002402561700002102585700002402606700002202630700002302652700002002675700002002695856003602715 2015 eng d a1468-201X00aHigher circulating adiponectin levels are associated with increased risk of atrial fibrillation in older adults.0 aHigher circulating adiponectin levels are associated with increa c2015 Sep a1368-740 v1013 aBACKGROUND: Adiponectin has cardioprotective properties, suggesting that lower levels seen in obesity and diabetes could heighten risk of atrial fibrillation (AF). Among older adults, however, higher adiponectin has been linked to greater incidence of adverse outcomes associated with AF, although recent reports have shown this association to be U-shaped. We postulated that higher adiponectin would be linked to increased risk for AF in older adults in a U-shaped manner.
METHODS: We examined the associations of total and high-molecular-weight (HMW) adiponectin with incident AF among individuals free of prevalent cardiovascular disease (CVD) participating in a population-based cohort study of older adults (n=3190; age=74±5 years).
RESULTS: During median follow-up of 11.4 years, there were 886 incident AF events. Adjusted cubic splines showed a positive and linear association between adiponectin and incident AF. After adjusting for potential confounders, including amino-terminal pro-B-type natriuretic peptide 1-76, the HR (95% CI) for AF per SD increase in total adiponectin was 1.14 (1.05 to 1.24), while that for HMW adiponectin was 1.17 (1.08 to 1.27). Additional adjustment for putative mediators, including subclinical CVD, diabetes, lipids and inflammation, did not significantly affect these estimates.
CONCLUSIONS: The present findings demonstrate that higher, not lower, levels of adiponectin are independently associated with increased risk of AF in older adults despite its documented cardiometabolic benefits. Additional work is necessary to determine if adiponectin is a marker of failed counter-regulatory pathways or whether this hormone is directly harmful in the setting of or as a result of advanced age.
10aAdiponectin10aAge Factors10aAged10aAged, 80 and over10aAging10aAtrial Fibrillation10aBiomarkers10aFemale10aHumans10aIncidence10aLinear Models10aMale10aMultivariate Analysis10aNatriuretic Peptide, Brain10aPeptide Fragments10aPrognosis10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aTime Factors10aUnited States10aUp-Regulation1 aMacheret, Fima1 aBartz, Traci, M1 aDjoussé, Luc1 aIx, Joachim, H1 aMukamal, Kenneth, J1 aZieman, Susan, J1 aSiscovick, David, S1 aTracy, Russell, P1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/680108133nas a2201957 4500008004100000022001400041245012800055210006900183260001600252300001100268490000800279520256000287653000902847653002002856653001602876653002102892653002102913653003002934653001102964653002002975653001102995653004103006653005103047653000903098653001603107653003603123653004203159653001703201100002403218700001803242700003103260700002303291700002503314700001503339700001803354700002003372700002303392700002103415700002103436700001803457700002203475700001503497700002803512700002103540700001703561700002203578700001403600700001803614700001903632700002203651700001903673700001503692700001703707700002003724700002603744700002103770700002203791700002503813700002103838700003103859700002203890700002403912700002503936700002103961700002303982700002404005700001904029700002304048700002304071700002104094700002504115700002004140700001904160700001804179700002104197700001404218700001904232700002604251700002404277700002004301700001504321700002004336700003404356700002104390700002304411700002604434700002204460700002604482700001804508700001904526700001904545700002204564700002204586700002304608700002004631700002004651700002104671700002104692700002304713700002104736700002004757700002404777700002104801700002304822700002004845700002204865700001904887700001904906700003704925700002104962700002104983700002205004700002305026700002205049700002405071700002105095700002505116700002005141700002405161700001805185700001805203700002105221700002905242700001905271700002105290700002305311700002005334700002305354700001905377700001805396700001705414700001505431700001905446700002205465700002305487700001505510700002105525700002605546700002305572700002205595700001805617700001805635700002505653700002005678700002105698700002205719700002105741700002405762700002405786700001905810700002505829700002405854700002705878700002105905700001805926700001905944700002105963700002005984700002406004700002406028700001906052710002306071710002106094710002406115856003606139 2015 eng d a1474-547X00aHMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.0 aHMGcoenzyme A reductase inhibition type 2 diabetes and bodyweigh c2015 Jan 24 a351-610 v3853 aBACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).
INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
FUNDING: The funding sources are cited at the end of the paper.
10aAged10aBody Mass Index10aBody Weight10aCholesterol, HDL10aCholesterol, LDL10aDiabetes Mellitus, Type 210aFemale10aGenetic Testing10aHumans10aHydroxymethylglutaryl CoA Reductases10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRandomized Controlled Trials as Topic10aRisk Factors1 aSwerdlow, Daniel, I1 aPreiss, David1 aKuchenbaecker, Karoline, B1 aHolmes, Michael, V1 aEngmann, Jorgen, E L1 aShah, Tina1 aSofat, Reecha1 aStender, Stefan1 aJohnson, Paul, C D1 aScott, Robert, A1 aLeusink, Maarten1 aVerweij, Niek1 aSharp, Stephen, J1 aGuo, Yiran1 aGiambartolomei, Claudia1 aChung, Christina1 aPeasey, Anne1 aAmuzu, Antoinette1 aLi, KaWah1 aPalmen, Jutta1 aHoward, Philip1 aCooper, Jackie, A1 aDrenos, Fotios1 aLi, Yun, R1 aLowe, Gordon1 aGallacher, John1 aStewart, Marlene, C W1 aTzoulaki, Ioanna1 aBuxbaum, Sarah, G1 avan der A, Daphne, L1 aForouhi, Nita, G1 aOnland-Moret, Charlotte, N1 aSchouw, Yvonne, T1 aSchnabel, Renate, B1 aHubacek, Jaroslav, A1 aKubinova, Ruzena1 aBaceviciene, Migle1 aTamosiunas, Abdonas1 aPajak, Andrzej1 aTopor-Madry, Roman1 aStepaniak, Urszula1 aMalyutina, Sofia1 aBaldassarre, Damiano1 aSennblad, Bengt1 aTremoli, Elena1 ade Faire, Ulf1 aVeglia, Fabrizio1 aFord, Ian1 aJukema, Wouter1 aWestendorp, Rudi, G J1 ade Borst, Gert, Jan1 ade Jong, Pim, A1 aAlgra, Ale1 aSpiering, Wilko1 avan der Zee, Anke, H Maitland1 aKlungel, Olaf, H1 ade Boer, Anthonius1 aDoevendans, Pieter, A1 aEaton, Charles, B1 aRobinson, Jennifer, G1 aDuggan, David1 aKjekshus, John1 aDowns, John, R1 aGotto, Antonio, M1 aKeech, Anthony, C1 aMarchioli, Roberto1 aTognoni, Gianni1 aSever, Peter, S1 aPoulter, Neil, R1 aWaters, David, D1 aPedersen, Terje, R1 aAmarenco, Pierre1 aNakamura, Haruo1 aMcMurray, John, J V1 aLewsey, James, D1 aChasman, Daniel, I1 aRidker, Paul, M1 aMaggioni, Aldo, P1 aTavazzi, Luigi1 aRay, Kausik, K1 aSeshasai, Sreenivasa, Rao Kondap1 aManson, JoAnn, E1 aPrice, Jackie, F1 aWhincup, Peter, H1 aMorris, Richard, W1 aLawlor, Debbie, A1 aSmith, George Davey1 aBen-Shlomo, Yoav1 aSchreiner, Pamela, J1 aFornage, Myriam1 aSiscovick, David, S1 aCushman, Mary1 aKumari, Meena1 aWareham, Nick, J1 aVerschuren, W, M Monique1 aRedline, Susan1 aPatel, Sanjay, R1 aWhittaker, John, C1 aHamsten, Anders1 aDelaney, Joseph, A1 aDale, Caroline1 aGaunt, Tom, R1 aWong, Andrew1 aKuh, Diana1 aHardy, Rebecca1 aKathiresan, Sekar1 aCastillo, Berta, A1 aHarst, Pim1 aBrunner, Eric, J1 aTybjaerg-Hansen, Anne1 aMarmot, Michael, G1 aKrauss, Ronald, M1 aTsai, Michael1 aCoresh, Josef1 aHoogeveen, Ronald, C1 aPsaty, Bruce, M1 aLange, Leslie, A1 aHakonarson, Hakon1 aDudbridge, Frank1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aKivimaki, Mika1 aTimpson, Nicholas, J1 aLangenberg, Claudia1 aAsselbergs, Folkert, W1 aVoevoda, Mikhail1 aBobak, Martin1 aPikhart, Hynek1 aWilson, James, G1 aReiner, Alex, P1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aSattar, Naveed1 aDIAGRAM Consortium1 aMAGIC Consortium1 aInterAct Consortium uhttps://chs-nhlbi.org/node/686304486nas a2200925 4500008004100000022001400041245007500055210006900130260001500199300001200214490000700226520186200233653002302095653001202118653002302130653004002153653003802193653003402231653001302265653001102278653001802289653000902307653000902316653003602325653000902361653001402370653003602384653002402420100002002444700001802464700002602482700002502508700001902533700002002552700002302572700001902595700002102614700001602635700001802651700001902669700001902688700002502707700001902732700002702751700002102778700001602799700002402815700002602839700002602865700002402891700001702915700002202932700002002954700002302974700001802997700001903015700001803034700002103052700001903073700001903092700002303111700002303134700002603157700001903183700001703202700002703219700002403246700002003270700002503290700001903315700001903334700002203353700002003375700001703395700002203412700002103434700002503455710004403480856003603524 2015 eng d a1460-208300aIntegrative pathway genomics of lung function and airflow obstruction.0 aIntegrative pathway genomics of lung function and airflow obstru c2015 Dec 1 a6836-480 v243 aChronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.
10aAirway Obstruction10aAnimals10aCell Proliferation10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenomics10aHumans10aImmune System10aLung10aMale10aMetabolic Networks and Pathways10aMice10aPhenotype10aPolymorphism, Single Nucleotide10aSignal Transduction1 aGharib, Sina, A1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aBirkland, Timothy, P1 aWilk, Jemma, B1 aWain, Louise, V1 aBrody, Jennifer, A1 aObeidat, Ma'en1 aHancock, Dana, B1 aTang, Wenbo1 aRawal, Rajesh1 aBoezen, Marike1 aImboden, Medea1 aHuffman, Jennifer, E1 aLahousse, Lies1 aAlves, Alexessander, C1 aManichaikul, Ani1 aHui, Jennie1 aMorrison, Alanna, C1 aRamasamy, Adaikalavan1 aSmith, Albert, Vernon1 aGudnason, Vilmundur1 aSurakka, Ida1 aVitart, Veronique1 aEvans, David, M1 aStrachan, David, P1 aDeary, Ian, J1 aHofman, Albert1 aGläser, Sven1 aWilson, James, F1 aNorth, Kari, E1 aZhao, Jing Hua1 aHeckbert, Susan, R1 aJarvis, Deborah, L1 aProbst-Hensch, Nicole1 aSchulz, Holger1 aBarr, Graham1 aJarvelin, Marjo-Riitta1 aO'Connor, George, T1 aKähönen, Mika1 aCassano, Patricia, A1 aHysi, Pirro, G1 aDupuis, Josée1 aHayward, Caroline1 aPsaty, Bruce, M1 aHall, Ian, P1 aParks, William, C1 aTobin, Martin, D1 aLondon, Stephanie, J1 aCHARGE Consortium; SpiroMeta Consortium uhttps://chs-nhlbi.org/node/686009013nas a2202797 4500008004100000022001400041245011400055210006900169260000900238300000900247490000600256520115900262653003901421653001801460653003001478653004001508653001001548653001201558653003201570653001701602653003801619653002201657653003701679653002601716653001101742653001201753653001801765653004401783653003601827100002101863700001901884700002101903700001601924700002301940700002301963700001801986700002502004700002402029700002202053700002002075700001502095700002502110700001302135700001802148700003102166700001802197700002102215700001102236700002602247700002502273700002002298700001902318700001702337700002302354700002002377700002302397700002302420700001702443700001602460700001802476700002602494700002102520700002002541700001202561700002002573700002102593700002402614700001902638700002502657700002502682700002302707700002102730700002102751700002202772700002302794700002502817700002002842700002002862700002302882700001602905700002402921700001402945700002302959700002502982700002103007700002303028700002203051700001903073700001703092700001903109700002003128700001903148700002203167700001903189700002003208700002403228700002203252700002503274700002303299700002203322700002303344700002403367700001503391700002003406700002003426700002303446700001403469700002103483700001703504700001803521700002303539700002303562700002503585700002303610700002403633700001903657700002403676700001903700700002203719700002003741700001403761700001803775700001703793700001703810700001603827700001703843700002503860700002103885700002203906700002203928700002003950700002203970700002003992700002704012700001704039700002304056700002104079700002004100700001904120700002604139700001804165700001904183700002104202700002004223700001404243700002004257700002004277700002704297700002304324700002004347700002804367700001804395700002304413700002304436700002704459700001704486700002104503700002704524700001804551700001904569700001904588700002104607700001904628700002004647700002504667700001904692700002004711700002204731700002004753700002304773700002004796700002004816700002104836700002104857700002204878700001704900700002604917700001904943700002404962700002204986700002005008700002005028700002105048700002005069700002205089700002405111700002005135700002205155700002605177700002205203700001905225700002405244700002405268700002205292700001705314700001905331700003005350700002305380700002505403700002105428700001905449700002505468700002105493700002005514700001605534700002505550700002005575700002805595700001705623700001805640700001805658700002405676700001905700700002305719700002305742700001905765700002005784700001905804700002305823700002505846700002405871700002105895700002005916700002005936700002005956700002105976700002505997700002406022700001906046700002206065700002006087700002106107700002206128710002906150856003606179 2015 eng d a2041-172300aLow-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.0 aLowfrequency and rare exome chip variants associate with fasting c2015 a58970 v63 aFasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
10aAfrican Continental Ancestry Group10aBlood Glucose10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aExome10aFasting10aGenetic Association Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGlucagon-Like Peptide-1 Receptor10aGlucose-6-Phosphatase10aHumans10aInsulin10aMutation Rate10aOligonucleotide Array Sequence Analysis10aPolymorphism, Single Nucleotide1 aWessel, Jennifer1 aChu, Audrey, Y1 aWillems, Sara, M1 aWang, Shuai1 aYaghootkar, Hanieh1 aBrody, Jennifer, A1 aDauriz, Marco1 aHivert, Marie-France1 aRaghavan, Sridharan1 aLipovich, Leonard1 aHidalgo, Bertha1 aFox, Keolu1 aHuffman, Jennifer, E1 aAn, Ping1 aLu, Yingchang1 aRasmussen-Torvik, Laura, J1 aGrarup, Niels1 aEhm, Margaret, G1 aLi, Li1 aBaldridge, Abigail, S1 aStančáková, Alena1 aAbrol, Ravinder1 aBesse, Céline1 aBoland, Anne1 aBork-Jensen, Jette1 aFornage, Myriam1 aFreitag, Daniel, F1 aGarcia, Melissa, E1 aGuo, Xiuqing1 aHara, Kazuo1 aIsaacs, Aaron1 aJakobsdottir, Johanna1 aLange, Leslie, A1 aLayton, Jill, C1 aLi, Man1 aZhao, Jing, Hua1 aMeidtner, Karina1 aMorrison, Alanna, C1 aNalls, Mike, A1 aPeters, Marjolein, J1 aSabater-Lleal, Maria1 aSchurmann, Claudia1 aSilveira, Angela1 aSmith, Albert, V1 aSoutham, Lorraine1 aStoiber, Marcus, H1 aStrawbridge, Rona, J1 aTaylor, Kent, D1 aVarga, Tibor, V1 aAllin, Kristine, H1 aAmin, Najaf1 aAponte, Jennifer, L1 aAung, Tin1 aBarbieri, Caterina1 aBihlmeyer, Nathan, A1 aBoehnke, Michael1 aBombieri, Cristina1 aBowden, Donald, W1 aBurns, Sean, M1 aChen, Yuning1 aChen, Yii-DerI1 aCheng, Ching-Yu1 aCorrea, Adolfo1 aCzajkowski, Jacek1 aDehghan, Abbas1 aEhret, Georg, B1 aEiriksdottir, Gudny1 aEscher, Stefan, A1 aFarmaki, Aliki-Eleni1 aFrånberg, Mattias1 aGambaro, Giovanni1 aGiulianini, Franco1 aGoddard, William, A1 aGoel, Anuj1 aGottesman, Omri1 aGrove, Megan, L1 aGustafsson, Stefan1 aHai, Yang1 aHallmans, Göran1 aHeo, Jiyoung1 aHoffmann, Per1 aIkram, Mohammad, K1 aJensen, Richard, A1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKaraleftheri, Maria1 aKhor, Chiea, C1 aKirkpatrick, Andrea1 aKraja, Aldi, T1 aKuusisto, Johanna1 aLange, Ethan, M1 aLee, I, T1 aLee, Wen-Jane1 aLeong, Aaron1 aLiao, Jiemin1 aLiu, Chunyu1 aLiu, Yongmei1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aMalerba, Giovanni1 aMamakou, Vasiliki1 aMarouli, Eirini1 aMaruthur, Nisa, M1 aMatchan, Angela1 aMcKean-Cowdin, Roberta1 aMcLeod, Olga1 aMetcalf, Ginger, A1 aMohlke, Karen, L1 aMuzny, Donna, M1 aNtalla, Ioanna1 aPalmer, Nicholette, D1 aPasko, Dorota1 aPeter, Andreas1 aRayner, Nigel, W1 aRenstrom, Frida1 aRice, Ken1 aSala, Cinzia, F1 aSennblad, Bengt1 aSerafetinidis, Ioannis1 aSmith, Jennifer, A1 aSoranzo, Nicole1 aSpeliotes, Elizabeth, K1 aStahl, Eli, A1 aStirrups, Kathleen1 aTentolouris, Nikos1 aThanopoulou, Anastasia1 aTorres, Mina1 aTraglia, Michela1 aTsafantakis, Emmanouil1 aJavad, Sundas1 aYanek, Lisa, R1 aZengini, Eleni1 aBecker, Diane, M1 aBis, Joshua, C1 aBrown, James, B1 aCupples, Adrienne, L1 aHansen, Torben1 aIngelsson, Erik1 aKarter, Andrew, J1 aLorenzo, Carlos1 aMathias, Rasika, A1 aNorris, Jill, M1 aPeloso, Gina, M1 aSheu, Wayne, H-H1 aToniolo, Daniela1 aVaidya, Dhananjay1 aVarma, Rohit1 aWagenknecht, Lynne, E1 aBoeing, Heiner1 aBottinger, Erwin, P1 aDedoussis, George1 aDeloukas, Panos1 aFerrannini, Ele1 aFranco, Oscar, H1 aFranks, Paul, W1 aGibbs, Richard, A1 aGudnason, Vilmundur1 aHamsten, Anders1 aHarris, Tamara, B1 aHattersley, Andrew, T1 aHayward, Caroline1 aHofman, Albert1 aJansson, Jan-Håkan1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLevy, Daniel1 aOostra, Ben, A1 aO'Donnell, Christopher, J1 aO'Rahilly, Stephen1 aPadmanabhan, Sandosh1 aPankow, James, S1 aPolasek, Ozren1 aProvince, Michael, A1 aRich, Stephen, S1 aRidker, Paul, M1 aRudan, Igor1 aSchulze, Matthias, B1 aSmith, Blair, H1 aUitterlinden, André, G1 aWalker, Mark1 aWatkins, Hugh1 aWong, Tien, Y1 aZeggini, Eleftheria1 aLaakso, Markku1 aBorecki, Ingrid, B1 aChasman, Daniel, I1 aPedersen, Oluf1 aPsaty, Bruce, M1 aTai, Shyong, E1 aDuijn, Cornelia, M1 aWareham, Nicholas, J1 aWaterworth, Dawn, M1 aBoerwinkle, Eric1 aKao, Linda, W H1 aFlorez, Jose, C1 aLoos, Ruth, J F1 aWilson, James, G1 aFrayling, Timothy, M1 aSiscovick, David, S1 aDupuis, Josée1 aRotter, Jerome, I1 aMeigs, James, B1 aScott, Robert, A1 aGoodarzi, Mark, O1 aEPIC-InterAct Consortium uhttps://chs-nhlbi.org/node/668605080nas a2201129 4500008004100000022001400041245007200055210006900127260001600196300001100212490000700223520191200230653002502142653002102167653002802188653001102216653001902227653001302246653002602259653001102285653000902296653003702305653001602342653003602358653002002394653001802414100002302432700002702455700001902482700001902501700002502520700002702545700002202572700002502594700001702619700002402636700002302660700002602683700002802709700001602737700002102753700001502774700002002789700002802809700001502837700002102852700001802873700002102891700002602912700002602938700002202964700001902986700002103005700002203026700001803048700002003066700002103086700001903107700002403126700002103150700002603171700002203197700002403219700002103243700002203264700001903286700002403305700002003329700002103349700001803370700001803388700001803406700002003424700002103444700002103465700001803486700002403504700001903528700001803547700002003565700002103585700002103606700002503627700002103652700002503673700002003698700002403718700001903742700002203761700002103783700002203804700002403826700002403850700001903874710002103893856003603914 2015 eng d a1522-964500aMendelian randomization of blood lipids for coronary heart disease.0 aMendelian randomization of blood lipids for coronary heart disea c2015 Mar 01 a539-500 v363 aAIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.
METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).
CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
10aCase-Control Studies10aCholesterol, HDL10aCoronary Artery Disease10aFemale10aGene Frequency10aGenotype10aGenotyping Techniques10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Assessment10aTriglycerides1 aHolmes, Michael, V1 aAsselbergs, Folkert, W1 aPalmer, Tom, M1 aDrenos, Fotios1 aLanktree, Matthew, B1 aNelson, Christopher, P1 aDale, Caroline, E1 aPadmanabhan, Sandosh1 aFinan, Chris1 aSwerdlow, Daniel, I1 aTragante, Vinicius1 avan Iperen, Erik, P A1 aSivapalaratnam, Suthesh1 aShah, Sonia1 aElbers, Clara, C1 aShah, Tina1 aEngmann, Jorgen1 aGiambartolomei, Claudia1 aWhite, Jon1 aZabaneh, Delilah1 aSofat, Reecha1 aMcLachlan, Stela1 aDoevendans, Pieter, A1 aBalmforth, Anthony, J1 aHall, Alistair, S1 aNorth, Kari, E1 aAlmoguera, Berta1 aHoogeveen, Ron, C1 aCushman, Mary1 aFornage, Myriam1 aPatel, Sanjay, R1 aRedline, Susan1 aSiscovick, David, S1 aTsai, Michael, Y1 aKarczewski, Konrad, J1 aHofker, Marten, H1 aVerschuren, Monique1 aBots, Michiel, L1 aSchouw, Yvonne, T1 aMelander, Olle1 aDominiczak, Anna, F1 aMorris, Richard1 aBen-Shlomo, Yoav1 aPrice, Jackie1 aKumari, Meena1 aBaumert, Jens1 aPeters, Annette1 aThorand, Barbara1 aKoenig, Wolfgang1 aGaunt, Tom, R1 aHumphries, Steve, E1 aClarke, Robert1 aWatkins, Hugh1 aFarrall, Martin1 aWilson, James, G1 aRich, Stephen, S1 ade Bakker, Paul, I W1 aLange, Leslie, A1 aSmith, George, Davey1 aReiner, Alex, P1 aTalmud, Philippa, J1 aKivimaki, Mika1 aLawlor, Debbie, A1 aDudbridge, Frank1 aSamani, Nilesh, J1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aCasas, Juan, P1 aUCLEB consortium uhttps://chs-nhlbi.org/node/656804273nas a2200853 4500008004100000022001400041245012600055210006900181260001500250300001100265490000700276520176600283653003802049653003402087653001302121653001102134653002702145653003202172653001502204653001702219653002702236100002002263700002302283700002202306700001802328700002102346700001802367700002302385700002802408700002202436700001902458700001802477700002102495700002202516700003002538700002202568700001202590700002702602700002302629700002102652700002002673700001902693700002302712700002002735700001802755700001902773700002702792700002002819700002402839700003002863700001902893700002002912700001802932700001802950700002002968700003202988700002303020700002203043700001703065700002203082700002203104700001703126700002003143700002403163700002503187700002103212700001503233700002303248700003203271700002303303700002903326710002803355856003603383 2015 eng d a1537-660500aMeta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.0 aMetaanalysis of 65734 individuals identifies TSPAN15 and SLC44A2 c2015 Apr 2 a532-420 v963 aVenous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.
10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMembrane Glycoproteins10aMembrane Transport Proteins10aOdds Ratio10aTetraspanins10aVenous Thromboembolism1 aGermain, Marine1 aChasman, Daniel, I1 ade Haan, Hugoline1 aTang, Weihong1 aLindström, Sara1 aWeng, Lu-Chen1 ade Andrade, Mariza1 ade Visser, Marieke, C H1 aWiggins, Kerri, L1 aSuchon, Pierre1 aSaut, Noémie1 aSmadja, David, M1 aLe Gal, Grégoire1 aVlieg, Astrid, van Hylcka1 aDi Narzo, Antonio1 aHao, Ke1 aNelson, Christopher, P1 aRocanin-Arjo, Ares1 aFolkersen, Lasse1 aMonajemi, Ramin1 aRose, Lynda, M1 aBrody, Jennifer, A1 aSlagboom, Eline1 aAïssi, Dylan1 aGagnon, France1 aDeleuze, Jean-Francois1 aDeloukas, Panos1 aTzourio, Christophe1 aDartigues, Jean-François1 aBerr, Claudine1 aTaylor, Kent, D1 aCivelek, Mete1 aEriksson, Per1 aPsaty, Bruce, M1 aHouwing-Duitermaat, Jeanine1 aGoodall, Alison, H1 aCambien, Francois1 aKraft, Peter1 aAmouyel, Philippe1 aSamani, Nilesh, J1 aBasu, Saonli1 aRidker, Paul, M1 aRosendaal, Frits, R1 aKabrhel, Christopher1 aFolsom, Aaron, R1 aHeit, John1 aReitsma, Pieter, H1 aTrégouët, David-Alexandre1 aSmith, Nicholas, L1 aMorange, Pierre-Emmanuel1 aCardiogenics consortium uhttps://chs-nhlbi.org/node/668103753nas a2200601 4500008004100000022001400041245011800055210006900173260001300242300001100255490000700266520199300273653002202266653002502288653001902313653003802332653003402370653001102404653003602415653001702451653001102468100001902479700002002498700002002518700002202538700001802560700001602578700001902594700002302613700002102636700002102657700002302678700002202701700002302723700002302746700002202769700001702791700001602808700002002824700001702844700002202861700002102883700001802904700002002922700002502942700002002967700002402987700002203011700002503033700002003058710003703078856003603115 2015 eng d a1524-462800aMeta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.0 aMetaAnalysis of GenomeWide Association Studies Identifies Geneti c2015 Aug a2063-80 v463 aBACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.
METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.
RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.
CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.
10aAfrican Americans10aCase-Control Studies10aCohort Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke1 aCarty, Cara, L1 aKeene, Keith, L1 aCheng, Yu-Ching1 aMeschia, James, F1 aChen, Wei-Min1 aNalls, Mike1 aBis, Joshua, C1 aKittner, Steven, J1 aRich, Stephen, S1 aTajuddin, Salman1 aZonderman, Alan, B1 aEvans, Michele, K1 aLangefeld, Carl, D1 aGottesman, Rebecca1 aMosley, Thomas, H1 aShahar, Eyal1 aWoo, Daniel1 aYaffe, Kristine1 aLiu, Yongmei1 aSale, Michèle, M1 aDichgans, Martin1 aMalik, Rainer1 aLongstreth, W T1 aMitchell, Braxton, D1 aPsaty, Bruce, M1 aKooperberg, Charles1 aReiner, Alexander1 aWorrall, Bradford, B1 aFornage, Myriam1 aCOMPASS and METASTROKE Consortia uhttps://chs-nhlbi.org/node/681206153nas a2201525 4500008004100000022001400041245009600055210006900151260001300220300001200233490000600245520187500251653000902126653002202135653002302157653003402180653001102214653001702225653003402242653001102276653000902287653002702296653001602323653002002339653001102359653001702370100002902387700002302416700001902439700002302458700001802481700002002499700002302519700002002542700002002562700001902582700002402601700002602625700002102651700002402672700002402696700002302720700002702743700002002770700002102790700002202811700002102833700002202854700001602876700002002892700002902912700002202941700002502963700002202988700001803010700001803028700002403046700002003070700002603090700002003116700002403136700002603160700002503186700001903211700002303230700001903253700001703272700001703289700001903306700003003325700002203355700001903377700001703396700002403413700002203437700002203459700002403481700002003505700002103525700001603546700002003562700002103582700001903603700002003622700002103642700002203663700002703685700002003712700002503732700001903757700002303776700002503799700002003824700002203844700002503866700002203891700002803913700002103941700002003962700002303982700002404005700001604029700002804045700002304073700001804096700001804114700002304132700001804155700002404173700002104197700002304218700001604241700001404257700002004271700001904291700002004310700002404330700002204354700002204376700002004398700002404418700002304442700002204465700002204487700001904509700002304528700002004551700002004571856003604591 2015 eng d a1942-326800aMultiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.0 aMultiethnic genomewide association study of cerebral white matte c2015 Apr a398-4090 v83 aBACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
10aAged10aAged, 80 and over10aChromosomes, Human10aContinental Population Groups10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aModels, Genetic10aStroke10aWhite Matter1 aVerhaaren, Benjamin, F J1 aDebette, Stephanie1 aBis, Joshua, C1 aSmith, Jennifer, A1 aIkram, Kamran1 aAdams, Hieab, H1 aBeecham, Ashley, H1 aRajan, Kumar, B1 aLopez, Lorna, M1 aBarral, Sandra1 avan Buchem, Mark, A1 avan der Grond, Jeroen1 aSmith, Albert, V1 aHegenscheid, Katrin1 aAggarwal, Neelum, T1 ade Andrade, Mariza1 aAtkinson, Elizabeth, J1 aBeekman, Marian1 aBeiser, Alexa, S1 aBlanton, Susan, H1 aBoerwinkle, Eric1 aBrickman, Adam, M1 aBryan, Nick1 aChauhan, Ganesh1 aChen, Christopher, P L H1 aChouraki, Vincent1 ade Craen, Anton, J M1 aCrivello, Fabrice1 aDeary, Ian, J1 aDeelen, Joris1 aDe Jager, Philip, L1 aDufouil, Carole1 aElkind, Mitchell, S V1 aEvans, Denis, A1 aFreudenberger, Paul1 aGottesman, Rebecca, F1 aGuðnason, Vilmundur1 aHabes, Mohamad1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHilal, Saima1 aHofer, Edith1 aHofman, Albert1 aIbrahim-Verbaas, Carla, A1 aKnopman, David, S1 aLewis, Cora, E1 aLiao, Jiemin1 aLiewald, David, C M1 aLuciano, Michelle1 avan der Lugt, Aad1 aMartinez, Oliver, O1 aMayeux, Richard1 aMazoyer, Bernard1 aNalls, Mike1 aNauck, Matthias1 aNiessen, Wiro, J1 aOostra, Ben, A1 aPsaty, Bruce, M1 aRice, Kenneth, M1 aRotter, Jerome, I1 avon Sarnowski, Bettina1 aSchmidt, Helena1 aSchreiner, Pamela, J1 aSchuur, Maaike1 aSidney, Stephen, S1 aSigurdsson, Sigurdur1 aSlagboom, Eline1 aStott, David, J M1 avan Swieten, John, C1 aTeumer, Alexander1 aTöglhofer, Anna, Maria1 aTraylor, Matthew1 aTrompet, Stella1 aTurner, Stephen, T1 aTzourio, Christophe1 aUh, Hae-Won1 aUitterlinden, André, G1 aVernooij, Meike, W1 aWang, Jing, J1 aWong, Tien, Y1 aWardlaw, Joanna, M1 aWindham, Gwen1 aWittfeld, Katharina1 aWolf, Christiane1 aWright, Clinton, B1 aYang, Qiong1 aZhao, Wei1 aZijdenbos, Alex1 aJukema, Wouter1 aSacco, Ralph, L1 aKardia, Sharon, L R1 aAmouyel, Philippe1 aMosley, Thomas, H1 aLongstreth, W T1 aDeCarli, Charles, C1 aDuijn, Cornelia, M1 aSchmidt, Reinhold1 aLauner, Lenore, J1 aGrabe, Hans, J1 aSeshadri, Sudha, S1 aIkram, Arfan, M1 aFornage, Myriam uhttps://chs-nhlbi.org/node/668304596nas a2201333 4500008004100000022001400041245010600055210006900161260001300230300001100243490000700254520134600261653001001607653002201617653000901639653001501648653004001663653001101703653003201714653003401746653001101780653000901791653001601800653003601816653001601852653001001868100001901878700001101897700001401908700001701922700002001939700001601959700001601975700001601991700001802007700001502025700001602040700001602056700001302072700001002085700001802095700001402113700002002127700001602147700001502163700001502178700001702193700001502210700001502225700001902240700001402259700001402273700001602287700001202303700001602315700001902331700001302350700001602363700001502379700001802394700001502412700001602427700001602443700001702459700001402476700001802490700001702508700001702525700001702542700001702559700001102576700001302587700001702600700002102617700001502638700001402653700002102667700001502688700001602703700001402719700001302733700001302746700001702759700001502776700001502791700001602806700001502822700001702837700001402854700002202868700001402890700001302904700001702917700001302934700001302947700001102960700001602971700001802987700001603005700001003021700001503031700001703046700001903063700001603082700001403098700001503112700001703127700001803144700001903162700001503181700001403196700001603210856003603226 2015 eng d a1476-557800aNovel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.0 aNovel loci associated with usual sleep duration the CHARGE Conso c2015 Oct a1232-90 v203 aUsual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
10aAdult10aAfrican Americans10aAged10aDyssomnias10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSelf Report10aSleep1 aGottlieb, D, J1 aHek, K1 aChen, T-H1 aWatson, N, F1 aEiriksdottir, G1 aByrne, E, M1 aCornelis, M1 aWarby, S, C1 aBandinelli, S1 aCherkas, L1 aEvans, D, S1 aGrabe, H, J1 aLahti, J1 aLi, M1 aLehtimäki, T1 aLumley, T1 aMarciante, K, D1 aPérusse, L1 aPsaty, B M1 aRobbins, J1 aTranah, G, J1 aVink, J, M1 aWilk, J, B1 aStafford, J, M1 aBellis, C1 aBiffar, R1 aBouchard, C1 aCade, B1 aCurhan, G C1 aEriksson, J, G1 aEwert, R1 aFerrucci, L1 aFülöp, T1 aGehrman, P, R1 aGoodloe, R1 aHarris, T B1 aHeath, A, C1 aHernandez, D1 aHofman, A1 aHottenga, J-J1 aHunter, D, J1 aJensen, M, K1 aJohnson, A D1 aKähönen, M1 aKao, L1 aKraft, P1 aLarkin, E, K1 aLauderdale, D, S1 aLuik, A, I1 aMedici, M1 aMontgomery, G, W1 aPalotie, A1 aPatel, S, R1 aPistis, G1 aPorcu, E1 aQuaye, L1 aRaitakari, O1 aRedline, S1 aRimm, E, B1 aRotter, J I1 aSmith, A V1 aSpector, T D1 aTeumer, A1 aUitterlinden, A G1 aVohl, M-C1 aWiden, E1 aWillemsen, G1 aYoung, T1 aZhang, X1 aLiu, Y1 aBlangero, J1 aBoomsma, D, I1 aGudnason, V1 aHu, F1 aMangino, M1 aMartin, N, G1 aO'Connor, G, T1 aStone, K, L1 aTanaka, T1 aViikari, J1 aGharib, S, A1 aPunjabi, N, M1 aRäikkönen, K1 aVölzke, H1 aMignot, E1 aTiemeier, H uhttps://chs-nhlbi.org/node/656603861nas a2200565 4500008004100000022001400041245010700055210006900162260001500231300001100246490000700257520230700264653001602571653000902587653001002596653001502606653001502621653002402636653001102660653003102671653001102702653001402713653001102727653001802738653002502756653000902781653003102790653002202821653003002843653001402873653003202887653002402919653003302943653001702976653001702993653001503010653001803025653001803043100001803061700001603079700002203095700001703117700002703134700002203161700001703183700001703200700002103217700002103238856003603259 2015 eng d a1555-905X00aNT-proBNP and troponin T and risk of rapid kidney function decline and incident CKD in elderly adults.0 aNTproBNP and troponin T and risk of rapid kidney function declin c2015 Feb 6 a205-140 v103 aBACKGROUND AND OBJECTIVES: Elevations in N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T are associated with poor cardiovascular outcomes. Whether elevations in these cardiac biomarkers are associated with decline in kidney function was evaluated.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline in 3752 participants free of heart failure in the Cardiovascular Health Study. eGFR was determined from the Chronic Kidney Disease Epidemiology Collaboration equation using serum cystatin C. Rapid decline in kidney function was defined as decline in serum cystatin C eGFR≥30%, and incident CKD was defined as the onset of serum cystatin C eGFR<60 among those without CKD at baseline (n=2786). Cox regression models were used to examine the associations of each biomarker with kidney function decline adjusting for demographics, baseline serum cystatin C eGFR, diabetes, and other CKD risk factors.
RESULTS: In total, 503 participants had rapid decline in serum cystatin C eGFR over a mean follow-up time of 6.41 (1.81) years, and 685 participants developed incident CKD over a mean follow-up time of 6.41 (1.74) years. Participants in the highest quartile of N-terminal pro-B-type natriuretic peptide (>237 pg/ml) had an 67% higher risk of rapid decline and 38% higher adjusted risk of incident CKD compared with participants in the lowest quartile (adjusted hazard ratio for serum cystatin C eGFR rapid decline, 1.67; 95% confidence interval, 1.25 to 2.23; hazard ratio for incident CKD, 1.38; 95% confidence interval, 1.08 to 1.76). Participants in the highest category of troponin T (>10.58 pg/ml) had 80% greater risk of rapid decline compared with participants in the lowest category (adjusted hazard ratio, 1.80; 95% confidence interval, 1.35 to 2.40). The association of troponin T with incident CKD was not statistically significant (hazard ratio, 1.17; 95% confidence interval, 0.92 to 1.50).
CONCLUSIONS: Elevated N-terminal pro-B-type natriuretic peptide and troponin T are associated with rapid decline of kidney function and incident CKD. Additional studies are needed to evaluate the mechanisms that may explain this association.
10aAge Factors10aAged10aAging10aBiomarkers10aCystatin C10aDisease Progression10aFemale10aGlomerular Filtration Rate10aHumans10aIncidence10aKidney10aLinear Models10aLongitudinal Studies10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aPrognosis10aProportional Hazards Models10aProspective Studies10aRenal Insufficiency, Chronic10aRisk Factors10aTime Factors10aTroponin T10aUnited States10aUp-Regulation1 aBansal, Nisha1 aKatz, Ronit1 aDalrymple, Lorien1 ade Boer, Ian1 aDeFilippi, Christopher1 aKestenbaum, Bryan1 aPark, Meyeon1 aSarnak, Mark1 aSeliger, Stephen1 aShlipak, Michael uhttps://chs-nhlbi.org/node/666103704nas a2200589 4500008004100000022001400041245013900055210007000194260001300264300001200277490000700289520197000296653001002266653002202276653002102298653000902319653002802328653001902356653002802375653001102403653003802414653003402452653001102486653001402497653004102511653002602552653000902578653001602587653003602603653003202639653002402671653002002695653002102715653002202736100001702758700002102775700002002796700001902816700002602835700002502861700001202886700002002898700002202918700002002940700002002960700001702980700001802997700002003015700002203035700002103057856003603078 2015 eng d a1524-463600aPlasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan.0 aPlasma Levels of Soluble Interleukin2 Receptor α Associations Wi c2015 Oct a2246-530 v353 aOBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.
APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5×10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31×10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.
CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.
10aAdult10aAfrican Americans10aAge Distribution10aAged10aCardiovascular Diseases10aCohort Studies10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aIncidence10aInterleukin-2 Receptor alpha Subunit10aKaplan-Meier Estimate10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aSex Distribution10aSurvival Analysis1 aDurda, Peter1 aSabourin, Jeremy1 aLange, Ethan, M1 aNalls, Mike, A1 aMychaleckyj, Josyf, C1 aJenny, Nancy, Swords1 aLi, Jin1 aWalston, Jeremy1 aHarris, Tamara, B1 aPsaty, Bruce, M1 aValdar, William1 aLiu, Yongmei1 aCushman, Mary1 aReiner, Alex, P1 aTracy, Russell, P1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/680902458nas a2200457 4500008004100000022001400041245012100055210006900176260000900245300001300254490000700267520116800274653002001442653001701462653001101479653001701490653002401507653003601531100001301567700001301580700001801593700001901611700001701630700002001647700002401667700001801691700002101709700001901730700002101749700002301770700001601793700002501809700002001834700001701854700001201871700002201883700001701905700002101922700002101943856003601964 2015 eng d a1932-620300aPopulation genomic analysis of 962 whole genome sequences of humans reveals natural selection in non-coding regions.0 aPopulation genomic analysis of 962 whole genome sequences of hum c2015 ae01216440 v103 aWhole genome analysis in large samples from a single population is needed to provide adequate power to assess relative strengths of natural selection across different functional components of the genome. In this study, we analyzed next-generation sequencing data from 962 European Americans, and found that as expected approximately 60% of the top 1% of positive selection signals lie in intergenic regions, 33% in intronic regions, and slightly over 1% in coding regions. Several detailed functional annotation categories in intergenic regions showed statistically significant enrichment in positively selected loci when compared to the null distribution of the genomic span of ENCODE categories. There was a significant enrichment of purifying selection signals detected in enhancers, transcription factor binding sites, microRNAs and target sites, but not on lincRNA or piRNAs, suggesting different evolutionary constraints for these domains. Loci in "repressed or low activity regions" and loci near or overlapping the transcription start site were the most significantly over-represented annotations among the top 1% of signals for positive selection.
10aDNA, Intergenic10aGenetic Loci10aHumans10aMetagenomics10aOpen Reading Frames10aPolymorphism, Single Nucleotide1 aYu, Fuli1 aLu, Jian1 aLiu, Xiaoming1 aGazave, Elodie1 aChang, Diana1 aRaj, Srilakshmi1 aHunter-Zinck, Haley1 aBlekhman, Ran1 aArbiza, Leonardo1 aVan Hout, Cris1 aMorrison, Alanna1 aJohnson, Andrew, D1 aBis, Joshua1 aCupples, Adrienne, L1 aPsaty, Bruce, M1 aMuzny, Donna1 aYu, Jin1 aGibbs, Richard, A1 aKeinan, Alon1 aClark, Andrew, G1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/681401770nas a2200265 4500008004100000022001400041245011300055210006900168260001700237300002100254490000600275520097000281100001701251700001901268700001801287700001801305700002301323700002201346700002101368700002001389700001901409700002301428700001701451856003601468 2015 eng d a2333-721400aPredicting Future Years of Life, Health, and Functional Ability: A Healthy Life Calculator for Older Adults.0 aPredicting Future Years of Life Health and Functional Ability A c2015 Jan-Dec a23337214156059890 v13 a
To create personalized estimates of future health and ability status for older adults.Data came from the Cardiovascular Health Study (CHS), a large longitudinal study. Outcomes included years of life, years of healthy life (based on self-rated health), years of able life (based on activities of daily living), and years of healthy and able life. We developed regression estimates using the demographic and health characteristics that best predicted the four outcomes. Internal and external validity were assessed.A prediction equation based on 11 variables accounted for about 40% of the variability for each outcome. Internal validity was excellent, and external validity was satisfactory. The resulting CHS Healthy Life Calculator (CHSHLC) is available at http://healthylifecalculator.org.CHSHLC provides a well-documented estimate of future years of healthy and able life for older adults, who may use it in planning for the future.
1 aDiehr, Paula1 aDiehr, Michael1 aArnold, Alice1 aYee, Laura, M1 aOdden, Michelle, C1 aHirsch, Calvin, H1 aThielke, Stephen1 aPsaty, Bruce, M1 aJohnson, Craig1 aMd, Jorge, R Kizer1 aNewman, Anne uhttps://chs-nhlbi.org/node/764803186nas a2200481 4500008004100000022001400041245017800055210006900233260001300302300001200315490000700327520177800334653000902112653002002121653001502141653002802156653001102184653001802195653001102213653002302224653002302247653002502270653000902295653001602304653002602320653001402346653002002360653001702380653001602397653001502413100002002428700002402448700002002472700001702492700002402509700001702533700001802550700002402568700002102592700002502613700003002638856003602668 2015 eng d a1530-856100aPrognostic Significance of High-Sensitivity Cardiac Troponin T Concentrations between the Limit of Blank and Limit of Detection in Community-Dwelling Adults: A Metaanalysis.0 aPrognostic Significance of HighSensitivity Cardiac Troponin T Co c2015 Dec a1524-310 v613 aBACKGROUND: There is controversy regarding whether to report concentrations of high-sensitivity cardiac troponin T (hs-cTnT) to the limit of blank (LOB) (3 ng/L) or the limit of detection (LOD) (5 ng/L) of the assay in community-based cohorts. We hypothesized that hs-cTnT concentrations between the LOB and LOD would be associated with poorer cardiovascular outcomes compared to concentrations below the LOB.
METHODS: hs-cTnT was analyzed in a total of 10 723 participants from the Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, and Dallas Heart Study (DHS). Participants were divided into 2 groups, those with hs-cTnT concentrations below the limit of blank (LOB) (<3 ng/L) and those with hs-cTnT between the LOB and limit of detection (LOD) (3-4.99 ng/L). Cross-sectional associations with traditional cardiovascular risk factors and cardiac structural measurements, and longitudinal associations with long-term cardiovascular outcomes of incident heart failure and cardiovascular death, were determined.
RESULTS: Participants with hs-cTnT between the LOB and LOD for all 3 cohorts were older, more likely to be male, and have a higher burden of cardiovascular risk factors and structural pathology. A metaanalysis of the 3 cohorts showed participants with hs-cTnT between the LOB and LOD were at increased risk of new-onset heart failure (hazard ratio, 1.18; 95% CI, 1.02-1.38) and cardiovascular mortality (hazard ratio, 1.29; 95% CI, 1.06-1.57).
CONCLUSIONS: hs-cTnT concentrations between the LOB and LOD (3-4.99 ng/L) are associated with a higher prevalence of traditional risk factors, more cardiac pathology, and worse outcomes than concentrations below the LOB (<3 ng/L).
10aAged10aAtherosclerosis10aBiomarkers10aCross-Sectional Studies10aFemale10aHeart Failure10aHumans10aIndependent Living10aLimit of Detection10aLongitudinal Studies10aMale10aMiddle Aged10aMyocardial Infarction10aPrognosis10aRisk Assessment10aRisk Factors10aSex Factors10aTroponin T1 aParikh, Ravi, H1 aSeliger, Stephen, L1 ade Lemos, James1 aNambi, Vijay1 aChristenson, Robert1 aAyers, Colby1 aSun, Wensheng1 aGottdiener, John, S1 aKuller, Lewis, H1 aBallantyne, Christie1 adeFilippi, Christopher, R uhttps://chs-nhlbi.org/node/687802704nas a2200421 4500008004100000022001400041245015100055210006900206260001300275300001200288490000700300520145600307653002201763653000901785653001201794653004001806653001401846653001101860653002001871653001101891653001401902653002501916653000901941653001601950653003601966653003202002653002402034653001702058653001802075653002702093100002102120700001802141700002502159700002302184700001802207700002102225856003602246 2015 eng d a1096-865200aProspective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).0 aProspective study of circulating factor XI and incident venous t c2015 Nov a1047-510 v903 aElevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African-Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (P < 0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African-Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15-fold greater incidence of VTE per risk allele). In African-Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow-up, not only in whites but also in African-Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African-Americans.
10aAfrican Americans10aAged10aAlleles10aEuropean Continental Ancestry Group10aFactor XI10aFemale10aGene Expression10aHumans10aIncidence10aLongitudinal Studies10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aProspective Studies10aRisk Factors10aUnited States10aVenous Thromboembolism1 aFolsom, Aaron, R1 aTang, Weihong1 aRoetker, Nicholas, S1 aHeckbert, Susan, R1 aCushman, Mary1 aPankow, James, S uhttps://chs-nhlbi.org/node/693004529nas a2200901 4500008004100000022001400041245012300055210006900178260000900247300001300256490000700269520197100276653001002247653002102257653000902278653002802287653003502315653002102350653002102371653001602392653003402408653002202442653001802464653001802482653001102500653002202511653001802533653001102551653001702562653001402579653001802593653000902611653001602620653002602636653001502662653003202677653001702709653001202726653001102738100002602749700002802775700001902803700002802822700002702850700002202877700002202899700002602921700002202947700001902969700002502988700002603013700001603039700002203055700001403077700002003091700002203111700003003133700001703163700002403180700002603204700001803230700002003248700002303268700002303291700002303314700002103337700002503358700002503383700002803408700001903436700002003455700002203475700002103497700002503518700002103543700002703564856003603591 2015 eng d a1932-620300aRace/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.0 aRaceEthnic Differences in the Associations of the Framingham Ris c2015 ae01323210 v103 aBACKGROUND: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
METHODS: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.
RESULTS: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.
CONCLUSION: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.
10aAdult10aAge Distribution10aAged10aCarotid Artery Diseases10aCarotid Intima-Media Thickness10aCholesterol, HDL10aCholesterol, LDL10aComorbidity10aContinental Population Groups10aDiabetes Mellitus10aDyslipidemias10aEthnic Groups10aFemale10aFollow-Up Studies10aGlobal Health10aHumans10aHypertension10aIncidence10aLinear Models10aMale10aMiddle Aged10aMyocardial Infarction10aPrevalence10aProportional Hazards Models10aRisk Factors10aSmoking10aStroke1 aGijsberts, Crystel, M1 aGroenewegen, Karlijn, A1 aHoefer, Imo, E1 aEijkemans, Marinus, J C1 aAsselbergs, Folkert, W1 aAnderson, Todd, J1 aBritton, Annie, R1 aDekker, Jacqueline, M1 aEngström, Gunnar1 aEvans, Greg, W1 ade Graaf, Jacqueline1 aGrobbee, Diederick, E1 aHedblad, Bo1 aHolewijn, Suzanne1 aIkeda, Ai1 aKitagawa, Kazuo1 aKitamura, Akihiko1 ade Kleijn, Dominique, P V1 aLonn, Eva, M1 aLorenz, Matthias, W1 aMathiesen, Ellisiv, B1 aNijpels, Giel1 aOkazaki, Shuhei1 aO'Leary, Daniel, H1 aPasterkamp, Gerard1 aPeters, Sanne, A E1 aPolak, Joseph, F1 aPrice, Jacqueline, F1 aRobertson, Christine1 aRembold, Christopher, M1 aRosvall, Maria1 aRundek, Tatjana1 aSalonen, Jukka, T1 aSitzer, Matthias1 aStehouwer, Coen, D A1 aBots, Michiel, L1 aRuijter, Hester, M den uhttps://chs-nhlbi.org/node/687604841nas a2200685 4500008004100000022001400041245011900055210006900174260001300243300001000256490000700266520281800273653000903091653001903100653001003119653001103129653003803140653002203178653003403200653001103234653000903245653001603254653002003270653005303290653002103343653002403364653002803388653001103416653001803427100001803445700001603463700002203479700002503501700002003526700002003546700002403566700002403590700002803614700001903642700001803661700002503679700002403704700002003728700001603748700001203764700002403776700002003800700001903820700002903839700002103868700002103889700002203910700002503932700002503957700002603982700001904008700002104027710007104048856003604119 2015 eng d a2168-615700aRare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.0 aRare and Coding Region Genetic Variants Associated With Risk of c2015 Jul a781-80 v723 aIMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.
OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.
DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.
MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).
RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).
CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.
10aAged10aBrain Ischemia10aExome10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMuscle Proteins10aNational Heart, Lung, and Blood Institute (U.S.)10aNuclear Proteins10aOpen Reading Frames10aPalmitoyl-CoA Hydrolase10aStroke10aUnited States1 aAuer, Paul, L1 aNalls, Mike1 aMeschia, James, F1 aWorrall, Bradford, B1 aLongstreth, W T1 aSeshadri, Sudha1 aKooperberg, Charles1 aBurger, Kathleen, M1 aCarlson, Christopher, S1 aCarty, Cara, L1 aChen, Wei-Min1 aCupples, Adrienne, L1 aDeStefano, Anita, L1 aFornage, Myriam1 aHardy, John1 aHsu, Li1 aJackson, Rebecca, D1 aJarvik, Gail, P1 aKim, Daniel, S1 aLakshminarayan, Kamakshi1 aLange, Leslie, A1 aManichaikul, Ani1 aQuinlan, Aaron, R1 aSingleton, Andrew, B1 aThornton, Timothy, A1 aNickerson, Deborah, A1 aPeters, Ulrike1 aRich, Stephen, S1 aNational Heart, Lung, and Blood Institute Exome Sequencing Project uhttps://chs-nhlbi.org/node/684904476nas a2201081 4500008004100000022001400041245011400055210006900169260001600238300001100254490000800265520141200273653001901685653001501704653001601719653001501735653001901750653003201769653002201801653001101823653002601834653003601860653002301896653002601919100002501945700002201970700002401992700002502016700002002041700001802061700002302079700002302102700002002125700001702145700001502162700002502177700003002202700001902232700002102251700002002272700002502292700001802317700002202335700001502357700002002372700002102392700001902413700001802432700002602450700001902476700001502495700002002510700002202530700002802552700002202580700001302602700001802615700001702633700002602650700002102676700002102697700002302718700002402741700001902765700002402784700002402808700002102832700001902853700002402872700002502896700002002921700002202941700002102963700001602984700002303000700002003023700002003043700002403063700001703087700001803104700002003122700002003142700001803162700002103180700002103201700002203222700002203244700001903266700002003285700003003305700002303335856003603358 2015 eng d a1528-002000aRare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.0 aRare and lowfrequency variants and their association with plasma c2015 Sep 10 ae19-290 v1263 aFibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.
10aCohort Studies10aFactor VII10aFactor VIII10aFibrinogen10aGene Frequency10aGenetic Association Studies10aGenetic Variation10aHumans10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels10avon Willebrand Factor1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMorrison, Alanna, C1 aSabater-Lleal, Maria1 aKacprowski, Tim1 aAuer, Paul, L1 aBrody, Jennifer, A1 aChasman, Daniel, I1 aChen, Ming-Huei1 aGuo, Xiuqing1 aLin, Li-An1 aMarioni, Riccardo, E1 aMüller-Nurasyid, Martina1 aYanek, Lisa, R1 aPankratz, Nathan1 aGrove, Megan, L1 ade Maat, Moniek, P M1 aCushman, Mary1 aWiggins, Kerri, L1 aQi, Lihong1 aSennblad, Bengt1 aHarris, Sarah, E1 aPolasek, Ozren1 aRiess, Helene1 aRivadeneira, Fernando1 aRose, Lynda, M1 aGoel, Anuj1 aTaylor, Kent, D1 aTeumer, Alexander1 aUitterlinden, André, G1 aVaidya, Dhananjay1 aYao, Jie1 aTang, Weihong1 aLevy, Daniel1 aWaldenberger, Melanie1 aBecker, Diane, M1 aFolsom, Aaron, R1 aGiulianini, Franco1 aGreinacher, Andreas1 aHofman, Albert1 aHuang, Chiang-Ching1 aKooperberg, Charles1 aSilveira, Angela1 aStarr, John, M1 aStrauch, Konstantin1 aStrawbridge, Rona, J1 aWright, Alan, F1 aMcKnight, Barbara1 aFranco, Oscar, H1 aZakai, Neil1 aMathias, Rasika, A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aTofler, Geoffrey, H1 aVölker, Uwe1 aWatkins, Hugh1 aFornage, Myriam1 aHamsten, Anders1 aDeary, Ian, J1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aRotter, Jerome, I1 aHayward, Caroline1 aDehghan, Abbas1 aReiner, Alex, P1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/678804070nas a2200865 4500008004100000022001400041245010200055210006900157260001600226300001200242490000700254520151500261653001901776653003401795653001101829653002301840653002601863653001101889100001801900700002301918700002401941700002101965700002601986700002102012700002102033700002702054700002402081700002002105700001902125700002302144700002302167700002502190700001902215700001902234700002302253700002002276700002202296700002202318700001902340700001902359700002302378700002502401700001802426700001902444700002002463700002302483700001802506700002002524700002002544700002002564700002302584700002302607700001902630700002002649700001702669700001802686700002102704700002102725700002102746700002802767700002502795700002302820700002102843700002502864700002002889700002002909700003602929700002002965700001902985700001903004700002103023710004703044710007703091856003603168 2015 eng d a1526-632X00aShared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.0 aShared genetic basis for migraine and ischemic stroke A genomewi c2015 May 26 a2132-450 v843 aOBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.
METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.
RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).
CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.
10aBrain Ischemia10aGenome-Wide Association Study10aHumans10aMigraine with Aura10aMigraine without Aura10aStroke1 aMalik, Rainer1 aFreilinger, Tobias1 aWinsvold, Bendik, S1 aAnttila, Verneri1 aHeiden, Jason, Vander1 aTraylor, Matthew1 ade Vries, Boukje1 aHolliday, Elizabeth, G1 aTerwindt, Gisela, M1 aSturm, Jonathan1 aBis, Joshua, C1 aHopewell, Jemma, C1 aFerrari, Michel, D1 aRannikmae, Kristiina1 aWessman, Maija1 aKallela, Mikko1 aKubisch, Christian1 aFornage, Myriam1 aMeschia, James, F1 aLehtimäki, Terho1 aSudlow, Cathie1 aClarke, Robert1 aChasman, Daniel, I1 aMitchell, Braxton, D1 aMaguire, Jane1 aKaprio, Jaakko1 aFarrall, Martin1 aRaitakari, Olli, T1 aKurth, Tobias1 aIkram, Arfan, M1 aReiner, Alex, P1 aLongstreth, W T1 aRothwell, Peter, M1 aStrachan, David, P1 aSharma, Pankaj1 aSeshadri, Sudha1 aQuaye, Lydia1 aCherkas, Lynn1 aSchürks, Markus1 aRosand, Jonathan1 aLigthart, Lannie1 aBoncoraglio, Giorgio, B1 aSmith, George, Davey1 aDuijn, Cornelia, M1 aStefansson, Kari1 aWorrall, Bradford, B1 aNyholt, Dale, R1 aMarkus, Hugh, S1 avan den Maagdenberg, Arn, M J M1 aCotsapas, Chris1 aZwart, John, A1 aPalotie, Aarno1 aDichgans, Martin1 aInternational Headache Genetics Consortium1 aMETASTROKE Collaboration of the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/681303610nas a2200493 4500008004100000022001400041245009600055210006900151260001300220300001100233490000700244520223400251653001002485653000902495653001802504653002602522653002802548653003002576653001202606653001102618653002702629653001102656653001402667653001202681653002302693653000902716653001602725653002602741653004702767653001202814653001802826100002402844700002402868700002102892700001802913700002202931700002402953700002102977700001902998700002103017700001803038700002403056856003603080 2015 eng d a1935-554800aSleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study.0 aSleep Disturbances and Glucose Metabolism in Older Adults The Ca c2015 Nov a2050-80 v383 aOBJECTIVE: We examined the associations of symptoms of sleep-disordered breathing (SDB), which was defined as loud snoring, stopping breathing for a while during sleep, and daytime sleepiness, and insomnia with glucose metabolism and incident type 2 diabetes in older adults.
RESEARCH DESIGN AND METHODS: Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 participants ≥65 years of age from four U.S. communities. Participants reported SDB and insomnia symptoms yearly through 1989-1994. In 1989-1990, participants underwent an oral glucose tolerance test, from which insulin secretion and insulin sensitivity were estimated. Fasting glucose levels were measured in 1989-1990 and again in 1992-1993, 1994-1995, 1996-1997, and 1998-1999, and medication use was ascertained yearly. We determined the cross-sectional associations of sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, and insulin secretion using generalized estimated equations and linear regression models. We determined the associations of updated and averaged sleep symptoms with incident diabetes in Cox proportional hazards models. We adjusted for sociodemographics, lifestyle factors, and medical history.
RESULTS: Observed apnea, snoring, and daytime sleepiness were associated with higher fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and higher insulin secretion. The risk of the development of type 2 diabetes was positively associated with observed apnea (hazard ratio [HR] 1.84 [95% CI 1.19-2.86]), snoring (HR 1.27 [95% CI 0.95-1.71]), and daytime sleepiness (HR 1.54 [95% CI 1.13-2.12]). In contrast, we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes.
CONCLUSIONS: Easily collected symptoms of SDB are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults. Monitoring glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy. Further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults.
10aAdult10aAged10aBlood Glucose10aCardiovascular System10aCross-Sectional Studies10aDiabetes Mellitus, Type 210aFasting10aFemale10aGlucose Tolerance Test10aHumans10aIncidence10aInsulin10aInsulin Resistance10aMale10aMiddle Aged10aSleep Apnea Syndromes10aSleep Initiation and Maintenance Disorders10aSnoring10aUnited States1 aStrand, Linn, Beate1 aCarnethon, Mercedes1 aBiggs, Mary, Lou1 aDjoussé, Luc1 aKaplan, Robert, C1 aSiscovick, David, S1 aRobbins, John, A1 aRedline, Susan1 aPatel, Sanjay, R1 aJanszky, Imre1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/685403870nas a2200721 4500008004100000022001400041245012000055210006900175260001300244300001200257490000800269520185000277653001002127653002602137653001102163653001102174653001902185653001402204653000902218653001702227653001102244653001602255100001802271700002702289700002602316700002002342700002002362700002102382700002502403700001902428700002602447700002102473700001902494700002902513700001802542700002102560700002002581700001402601700002302615700002202638700002002660700002002680700002302700700002102723700002302744700002102767700002402788700001902812700001902831700002302850700002202873700001902895700001802914700001802932700002102950700001902971700002102990700002403011700002103035700002203056710003403078856003603112 2015 eng d a1945-719700aSubclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis.0 aSubclinical Hypothyroidism and the Risk of Stroke Events and Fat c2015 Jun a2181-910 v1003 aOBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism.
DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels.
DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations.
CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.
10aAdult10aAsymptomatic Diseases10aFemale10aHumans10aHypothyroidism10aIncidence10aMale10aRisk Factors10aStroke10aThyrotropin1 aChaker, Layal1 aBaumgartner, Christine1 aElzen, Wendy, P J den1 aIkram, Arfan, M1 aBlum, Manuel, R1 aCollet, Tinh-Hai1 aBakker, Stephan, J L1 aDehghan, Abbas1 aDrechsler, Christiane1 aLuben, Robert, N1 aHofman, Albert1 aPortegies, Marileen, L P1 aMedici, Marco1 aIervasi, Giorgio1 aStott, David, J1 aFord, Ian1 aBremner, Alexandra1 aWanner, Christoph1 aFerrucci, Luigi1 aNewman, Anne, B1 aDullaart, Robin, P1 aSgarbi, José, A1 aCeresini, Graziano1 aMaciel, Rui, M B1 aWestendorp, Rudi, G1 aJukema, Wouter1 aImaizumi, Misa1 aFranklyn, Jayne, A1 aBauer, Douglas, C1 aWalsh, John, P1 aRazvi, Salman1 aKhaw, Kay-Tee1 aCappola, Anne, R1 aVölzke, Henry1 aFranco, Oscar, H1 aGussekloo, Jacobijn1 aRodondi, Nicolas1 aPeeters, Robin, P1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/680005194nas a2200733 4500008004100000022001400041245007200055210006900127260001600196300001200212490000800224520318200232653001503414653001003429653000903439653002203448653001103470653002003481653001803501653001103519653002003530653001903550653000903569653001603578653001703594653002103611653001603632653001603648100002003664700002203684700002103706700002003727700002103747700002303768700002403791700002203815700002203837700002603859700002103885700001903906700002603925700002303951700002103974700002503995700002404020700002104044700001504065700002304080700002604103700002804129700002004157700002604177700001804203700002204221700002004243700002404263700002404287700001904311700001704330700002204347700002104369710003404390856003604424 2015 eng d a1538-359800aSubclinical thyroid dysfunction and fracture risk: a meta-analysis.0 aSubclinical thyroid dysfunction and fracture risk a metaanalysis c2015 May 26 a2055-650 v3133 aIMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking.
OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures.
DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures.
DATA EXTRACTION: Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations.
MAIN OUTCOME AND MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes.
RESULTS: Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk.
CONCLUSIONS AND RELEVANCE: Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aFemale10aFractures, Bone10aHip Fractures10aHumans10aHyperthyroidism10aHypothyroidism10aMale10aMiddle Aged10aRisk Factors10aSpinal Fractures10aThyrotropin10aYoung Adult1 aBlum, Manuel, R1 aBauer, Douglas, C1 aCollet, Tinh-Hai1 aFink, Howard, A1 aCappola, Anne, R1 ada Costa, Bruno, R1 aWirth, Christina, D1 aPeeters, Robin, P1 aAsvold, Bjørn, O1 aElzen, Wendy, P J den1 aLuben, Robert, N1 aImaizumi, Misa1 aBremner, Alexandra, P1 aGogakos, Apostolos1 aEastell, Richard1 aKearney, Patricia, M1 aStrotmeyer, Elsa, S1 aWallace, Erin, R1 aHoff, Mari1 aCeresini, Graziano1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aStott, David, J1 aWestendorp, Rudi, G J1 aKhaw, Kay-Tee1 aLanghammer, Arnuf1 aFerrucci, Luigi1 aGussekloo, Jacobijn1 aWilliams, Graham, R1 aWalsh, John, P1 aJüni, Peter1 aAujesky, Drahomir1 aRodondi, Nicolas1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/679502991nas a2200421 4500008004100000022001400041245008200055210006900137260001300206300001200219490000800231520187100239653000902110653002202119653001002141653002402151653001902175653002102194653001302215653001102228653001802239653001802257653001102275653001402286653000902300653001402309653002102323653002202344653002702366653001802393100002102411700002102432700002002453700002202473700001802495700002002513856003602533 2015 eng d a1945-719700aThyroid function in the euthyroid range and adverse outcomes in older adults.0 aThyroid function in the euthyroid range and adverse outcomes in c2015 Mar a1088-960 v1003 aCONTEXT: The appropriateness of current reference ranges for thyroid function testing in older adults has been questioned.
OBJECTIVE: This study aimed to determine the relationship between thyroid function tests within the euthyroid range and adverse outcomes in older adults not taking thyroid medication.
DESIGN, SETTING, AND PARTICIPANTS: US community-dwelling adults years of older (n = 2843) enrolled onto the Cardiovascular Health Study with TSH, free T4 (FT4), and total T3 concentrations in the euthyroid range.
MAIN OUTCOME MEASURES: Incidence of atrial fibrillation, coronary heart disease, heart failure, hip fracture, dementia, and all-cause death were measured.
RESULTS: No departures from linearity were detected. Higher TSH was negatively associated (P = .03) and higher FT4 was positively associated (P = .007) with mortality. Higher FT4 was associated with atrial fibrillation (P < .001) and heart failure (P = .004). Compared with the first quartile, individuals with TSH in the fourth quartile had a 9.6 per 1000 person-year lower incidence of dementia (P < .05) and those with FT4 in the fourth quartile had higher incidences of atrial fibrillation, coronary heart disease, heart failure, and mortality (11.0, 8.0, 7.8, and 14.3 per 1000 person-years, respectively, all P < .05). Total T3 was not associated with any outcome.
CONCLUSIONS: Higher TSH and lower FT4 concentrations within the euthyroid range are associated with lower risk of multiple adverse events in older people, including mortality. This suggests tolerance for lower thyroid hormone levels in this age group. Clinical trials are needed to evaluate the risk-benefit profile of new thresholds for initiating treatment and optimal target concentrations for thyroid hormone replacement in older people.
10aAged10aAged, 80 and over10aAging10aAtrial Fibrillation10aCause of Death10aCoronary Disease10aDementia10aFemale10aHeart Failure10aHip Fractures10aHumans10aIncidence10aMale10aPrognosis10aReference Values10aSurvival Analysis10aThyroid Function Tests10aThyroid Gland1 aCappola, Anne, R1 aArnold, Alice, M1 aWulczyn, Kendra1 aCarlson, Michelle1 aRobbins, John1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/655104076nas a2200553 4500008004100000022001400041245013600055210006900191260001300260300001200273490000800285520245400293653001902747653002102766653001102787653001902798653001602817100002202833700002002855700001802875700002202893700002302915700002102938700002302959700002602982700002003008700002103028700002303049700002403072700002103096700001903117700002503136700001803161700002103179700002003200700002203220700002003242700001803262700002103280700002003301700002003321700002603341700001903367700001903386700002603405700002103431710003403452856003603486 2015 eng d a2168-611400aThyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts.0 aThyroid function within the normal range and risk of coronary he c2015 Jun a1037-470 v1753 aIMPORTANCE: Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD).
OBJECTIVE: To assess the association between differences in thyroid function within the reference range and CHD risk.
DESIGN, SETTING, AND PARTICIPANTS: Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline.
EXPOSURES: Thyroid function as expressed by serum thyrotropin levels at baseline.
MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status.
RESULTS: Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results.
CONCLUSIONS AND RELEVANCE: Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.
10aCohort Studies10aCoronary Disease10aHumans10aHypothyroidism10aThyrotropin1 aAsvold, Bjørn, O1 aVatten, Lars, J1 aBjøro, Trine1 aBauer, Douglas, C1 aBremner, Alexandra1 aCappola, Anne, R1 aCeresini, Graziano1 aElzen, Wendy, P J den1 aFerrucci, Luigi1 aFranco, Oscar, H1 aFranklyn, Jayne, A1 aGussekloo, Jacobijn1 aIervasi, Giorgio1 aImaizumi, Misa1 aKearney, Patricia, M1 aKhaw, Kay-Tee1 aMaciel, Rui, M B1 aNewman, Anne, B1 aPeeters, Robin, P1 aPsaty, Bruce, M1 aRazvi, Salman1 aSgarbi, José, A1 aStott, David, J1 aTrompet, Stella1 aVanderpump, Mark, P J1 aVölzke, Henry1 aWalsh, John, P1 aWestendorp, Rudi, G J1 aRodondi, Nicolas1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/679803153nas a2200529 4500008004100000022001400041245012000055210006900175260001300244300001000257490000800267520166400275653000901939653002201948653001901970653002401989653001102013653002202024653001502046653001102061653001402072653001802086653000902104653002602113653003702139653001402176653003202190653002402222653000902246653001702255653000902272653001502281100002002296700002402316700002202340700001802362700002402380700002402404700002702428700002402455700002202479700002302501700002202524700002102546700002002567856003602587 2015 eng d a1468-201X00aVariation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults.0 aVariation in resting heart rate over 4 years and the risks of my c2015 Jan a132-80 v1013 aOBJECTIVE: Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults.
METHODS: 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively.
RESULTS: 262 subjects had an incident MI event (13%) and 1326 died (67%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95% CI 1.05 to 1.20) and variation (HR 1.08; 95% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex.
CONCLUSIONS: Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.
10aAged10aAged, 80 and over10aCause of Death10aElectrocardiography10aFemale10aFollow-Up Studies10aHeart Rate10aHumans10aIncidence10aLinear Models10aMale10aMyocardial Infarction10aOutcome Assessment (Health Care)10aPrognosis10aProportional Hazards Models10aProspective Studies10aRest10aRisk Factors10aTime10aWashington1 aFloyd, James, S1 aSitlani, Colleen, M1 aWiggins, Kerri, L1 aWallace, Erin1 aSuchy-Dicey, Astrid1 aAbbasi, Siddique, A1 aCarnethon, Mercedes, R1 aSiscovick, David, S1 aSotoodehnia, Nona1 aHeckbert, Susan, R1 aMcKnight, Barbara1 aRice, Kenneth, M1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/656103175nas a2200409 4500008004100000022001400041245006600055210006500121260001600186300001000202490000700212520203900219653000902258653002202267653002102289653003602310653001102346653001602357653001802373653001102391653000902402653001702411653001802428653003602446100002302482700002302505700002202528700002102550700002302571700002402594700002202618700002002640700002202660700002402682700002302706856003602729 2015 eng d a1558-359700aVentricular Ectopy as a Predictor of Heart Failure and Death.0 aVentricular Ectopy as a Predictor of Heart Failure and Death c2015 Jul 14 a101-90 v663 aBACKGROUND: Studies of patients presenting for catheter ablation suggest that premature ventricular contractions (PVCs) are a modifiable risk factor for congestive heart failure (CHF). The relationship among PVC frequency, incident CHF, and mortality in the general population remains unknown.
OBJECTIVES: The goal of this study was to determine whether PVC frequency ascertained using a 24-h Holter monitor is a predictor of a decrease in the left ventricular ejection fraction (LVEF), incident CHF, and death in a population-based cohort.
METHODS: We studied 1,139 Cardiovascular Health Study (CHS) participants who were randomly assigned to 24-h ambulatory electrocardiography (Holter) monitoring and who had a normal LVEF and no history of CHF. PVC frequency was quantified using Holter studies, and LVEF was measured from baseline and 5-year echocardiograms. Participants were followed for incident CHF and death.
RESULTS: Those in the upper quartile versus the lowest quartile of PVC frequency had a multivariable-adjusted, 3-fold greater odds of a 5-year decrease in LVEF (odds ratio [OR]: 3.10; 95% confidence interval [CI]: 1.42 to 6.77; p = 0.005), a 48% increased risk of incident CHF (HR: 1.48; 95% CI: 1.08 to 2.04; p = 0.02), and a 31% increased risk of death (HR: 1.31; 95% CI: 1.06 to 1.63; p = 0.01) during a median follow-up of >13 years. Similar statistically significant results were observed for PVCs analyzed as a continuous variable. The specificity for the 15-year risk of CHF exceeded 90% when PVCs included at least 0.7% of ventricular beats. The population-level risk for incident CHF attributed to PVCs was 8.1% (95% CI: 1.2% to 14.9%).
CONCLUSIONS: In a population-based sample, a higher frequency of PVCs was associated with a decrease in LVEF, an increase in incident CHF, and increased mortality. Because of the capacity to prevent PVCs through medical or ablation therapy, PVCs may represent a modifiable risk factor for CHF and death.
10aAged10aCatheter Ablation10aEchocardiography10aElectrocardiography, Ambulatory10aFemale10aForecasting10aHeart Failure10aHumans10aMale10aRisk Factors10aStroke Volume10aVentricular Premature Complexes1 aDukes, Jonathan, W1 aDewland, Thomas, A1 aVittinghoff, Eric1 aMandyam, Mala, C1 aHeckbert, Susan, R1 aSiscovick, David, S1 aStein, Phyllis, K1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/676704741nas a2201021 4500008004100000022001400041245008000055210006900135260001300204300001200217490000700229520186200236653001002098653000902108653001902117653002402136653001102160653003802171653003402209653001102243653002602254653000902280653001602289653002402305653001702329100001702346700002602363700001902389700002102408700002002429700002502449700002302474700002002497700002902517700002102546700001602567700002202583700002202605700001802627700002402645700002302669700002002692700002502712700002002737700002302757700001402780700002402794700002602818700002402844700001902868700001902887700001902906700002102925700002102946700001702967700002102984700001603005700002003021700002603041700001903067700002303086700002103109700002003130700001803150700002003168700002003188700002103208700002403229700002403253700002103277700001503298700002603313700001803339700002303357700002003380700001903400700002303419700002003442700001903462700002203481700002003503700002203523700002003545700002003565700002203585710007603607856003603683 2015 eng d a1524-462800aWhite Matter Lesion Progression: Genome-Wide Search for Genetic Influences.0 aWhite Matter Lesion Progression GenomeWide Search for Genetic In c2015 Nov a3048-570 v463 aBACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.
RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.
CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
10aAdult10aAged10aCohort Studies10aDisease Progression10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLeukoencephalopathies10aMale10aMiddle Aged10aProspective Studies10aWhite Matter1 aHofer, Edith1 aCavalieri, Margherita1 aBis, Joshua, C1 aDeCarli, Charles1 aFornage, Myriam1 aSigurdsson, Sigurdur1 aSrikanth, Velandai1 aTrompet, Stella1 aVerhaaren, Benjamin, F J1 aWolf, Christiane1 aYang, Qiong1 aAdams, Hieab, H H1 aAmouyel, Philippe1 aBeiser, Alexa1 aBuckley, Brendan, M1 aCallisaya, Michele1 aChauhan, Ganesh1 ade Craen, Anton, J M1 aDufouil, Carole1 aDuijn, Cornelia, M1 aFord, Ian1 aFreudenberger, Paul1 aGottesman, Rebecca, F1 aGudnason, Vilmundur1 aHeiss, Gerardo1 aHofman, Albert1 aLumley, Thomas1 aMartinez, Oliver1 aMazoyer, Bernard1 aMoran, Chris1 aNiessen, Wiro, J1 aPhan, Thanh1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aSattar, Naveed1 aSchilling, Sabrina1 aShibata, Dean, K1 aSlagboom, Eline1 aSmith, Albert1 aStott, David, J1 aTaylor, Kent, D1 aThomson, Russell1 aTöglhofer, Anna, M1 aTzourio, Christophe1 avan Buchem, Mark1 aWang, Jing1 aWestendorp, Rudi, G J1 aWindham, Gwen1 aVernooij, Meike, W1 aZijdenbos, Alex1 aBeare, Richard1 aDebette, Stephanie1 aIkram, Arfan, M1 aJukema, Wouter1 aLauner, Lenore, J1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aSchmidt, Helena1 aSchmidt, Reinhold1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium uhttps://chs-nhlbi.org/node/686103031nas a2200709 4500008004100000245011000041210006900151260000800220300001600228490000800244520116300252100002201415700001601437700001901453700001701472700002101489700001701510700001901527700001901546700001501565700002501580700001901605700001601624700001801640700001301658700001501671700001501686700001301701700001501714700001801729700001701747700002501764700001501789700001901804700001101823700001801834700002001852700001801872700001501890700002001905700001801925700001701943700001601960700002101976700001301997700001802010700001702028700001202045700001602057700001902073700002202092700001702114700002002131700002002151700001702171700002002188700002002208700002002228700001702248700002002265856003602285 2016 eng d00a-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies0 a3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disea cAug a1155–11660 v1763 a-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers.\ -3) for incident CHD.\ A global consortium of 19 studies identified by November 2014.\ -3 biomarkers and ascertained CHD.\ -6 levels, and FADS desaturase genes.\ Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI).\ -3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses.\ -3 fatty acids are associated with a modestly lower incidence of fatal CHD.1 aDel Gobbo, L., C.1 aImamura, F.1 aAslibekyan, S.1 aMarklund, M.1 aVirtanen, J., K.1 aWennberg, M.1 aYakoob, M., Y.1 aChiuve, S., E.1 aCruz, Dela1 aFrazier-Wood, A., C.1 aFretts, A., M.1 aGuallar, E.1 aMatsumoto, C.1 aPrem, K.1 aTanaka, T.1 aWu, J., H.1 aZhou, X.1 aHelmer, C.1 aIngelsson, E.1 aYuan, J., M.1 aBarberger-Gateau, P.1 aCampos, H.1 aChaves, P., H.1 aé, L.1 aGiles, G., G.1 amez-Aracena, J.1 aHodge, A., M.1 aHu, F., B.1 aJansson, J., H.1 aJohansson, I.1 aKhaw, K., T.1 aKoh, W., P.1 aLemaitre, R., N.1 aLind, L.1 aLuben, R., N.1 aRimm, E., B.1 arus, U.1 aSamieri, C.1 aFranks, P., W.1 aSiscovick, D., S.1 aStampfer, M.1 aSteffen, L., M.1 aSteffen, B., T.1 aTsai, M., Y.1 avan Dam, R., M.1 aVoutilainen, S.1 aWillett, W., C.1 aWoodward, M.1 aMozaffarian, D. uhttps://chs-nhlbi.org/node/946407420nas a2202053 4500008004100000022001400041245005000055210004800105260001600153300001200169490000700181520170000188100001501888700002401903700001801927700001801945700001701963700002401980700001802004700002402022700002202046700002202068700002202090700002102112700002202133700002802155700001902183700002002202700001902222700001802241700002002259700003002279700002102309700001802330700002202348700002202370700002602392700001802418700001902436700002202455700002502477700002302502700001602525700002502541700002502566700001902591700001802610700001902628700001702647700002402664700002002688700002102708700002602729700001702755700002502772700002502797700002602822700002402848700002002872700001402892700002202906700002202928700001702950700002102967700002302988700002103011700002403032700001903056700002003075700002003095700002103115700002003136700002003156700001803176700002503194700002203219700001703241700002303258700001703281700002203298700001703320700001903337700002503356700001503381700002203396700002103418700002003439700001903459700001603478700001803494700001903512700001903531700002103550700001903571700002403590700002303614700001803637700002003655700002003675700002003695700001803715700002503733700002603758700001903784700002303803700002503826700001703851700002503868700002203893700002303915700002403938700002403962700002203986700002504008700002404033700002204057700002304079700002404102700002404126700002004150700003204170700002104202700002404223700002004247700002304267700001704290700002804307700002804335700002304363700001904386700002204405700002304427700002204450700001704472700002604489700003204515700002104547700002004568700002804588700001504616700002304631700002404654700002004678700002004698700001604718700002104734700002704755700002804782700002304810700002004833700001904853700001804872700002204890700002104912700002504933700001904958700002104977700001904998700001905017700002405036700002205060700002305082700002305105700002905128700002105157700002205178700002005200700001605220700002905236700001805265700002205283700002505305856003605330 2016 eng d a1558-359700a52 Genetic Loci Influencing Myocardial Mass.0 a52 Genetic Loci Influencing Myocardial Mass c2016 Sep 27 a1435-480 v683 aBACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.
OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.
METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.
RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.
CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
1 aHarst, Pim1 avan Setten, Jessica1 aVerweij, Niek1 aVogler, Georg1 aFranke, Lude1 aMaurano, Matthew, T1 aWang, Xinchen1 aLeach, Irene, Mateo1 aEijgelsheim, Mark1 aSotoodehnia, Nona1 aHayward, Caroline1 aSorice, Rossella1 aMeirelles, Osorio1 aLyytikäinen, Leo-Pekka1 aPolasek, Ozren1 aTanaka, Toshiko1 aArking, Dan, E1 aUlivi, Sheila1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aSmith, Albert, V1 aDörr, Marcus1 aKerr, Kathleen, F1 aMagnani, Jared, W1 aM, Fabiola, del Greco1 aZhang, Weihua1 aNolte, Ilja, M1 aSilva, Claudia, T1 aPadmanabhan, Sandosh1 aTragante, Vinicius1 aEsko, Tõnu1 aAbecasis, Goncalo, R1 aAdriaens, Michiel, E1 aAndersen, Karl1 aBarnett, Phil1 aBis, Joshua, C1 aBodmer, Rolf1 aBuckley, Brendan, M1 aCampbell, Harry1 aCannon, Megan, V1 aChakravarti, Aravinda1 aChen, Lin, Y1 aDelitala, Alessandro1 aDevereux, Richard, B1 aDoevendans, Pieter, A1 aDominiczak, Anna, F1 aFerrucci, Luigi1 aFord, Ian1 aGieger, Christian1 aHarris, Tamara, B1 aHaugen, Eric1 aHeinig, Matthias1 aHernandez, Dena, G1 aHillege, Hans, L1 aHirschhorn, Joel, N1 aHofman, Albert1 aHubner, Norbert1 aHwang, Shih-Jen1 aIorio, Annamaria1 aKähönen, Mika1 aKellis, Manolis1 aKolcic, Ivana1 aKooner, Ishminder, K1 aKooner, Jaspal, S1 aKors, Jan, A1 aLakatta, Edward, G1 aLage, Kasper1 aLauner, Lenore, J1 aLevy, Daniel1 aLundby, Alicia1 aMacfarlane, Peter, W1 aMay, Dalit1 aMeitinger, Thomas1 aMetspalu, Andres1 aNappo, Stefania1 aNaitza, Silvia1 aNeph, Shane1 aNord, Alex, S1 aNutile, Teresa1 aOkin, Peter, M1 aOlsen, Jesper, V1 aOostra, Ben, A1 aPenninger, Josef, M1 aPennacchio, Len, A1 aPers, Tune, H1 aPerz, Siegfried1 aPeters, Annette1 aPinto, Yigal, M1 aPfeufer, Arne1 aPilia, Maria, Grazia1 aPramstaller, Peter, P1 aPrins, Bram, P1 aRaitakari, Olli, T1 aRaychaudhuri, Soumya1 aRice, Ken, M1 aRossin, Elizabeth, J1 aRotter, Jerome, I1 aSchafer, Sebastian1 aSchlessinger, David1 aSchmidt, Carsten, O1 aSehmi, Jobanpreet1 aSilljé, Herman, H W1 aSinagra, Gianfranco1 aSinner, Moritz, F1 aSlowikowski, Kamil1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aSpiering, Wilko1 aStamatoyannopoulos, John, A1 aStolk, Ronald, P1 aStrauch, Konstantin1 aTan, Sian-Tsung1 aTarasov, Kirill, V1 aTrinh, Bosco1 aUitterlinden, André, G1 avan den Boogaard, Malou1 aDuijn, Cornelia, M1 aGilst, Wiek, H1 aViikari, Jorma, S1 aVisscher, Peter, M1 aVitart, Veronique1 aVölker, Uwe1 aWaldenberger, Melanie1 aWeichenberger, Christian, X1 aWestra, Harm-Jan1 aWijmenga, Cisca1 aWolffenbuttel, Bruce, H1 aYang, Jian1 aBezzina, Connie, R1 aMunroe, Patricia, B1 aSnieder, Harold1 aWright, Alan, F1 aRudan, Igor1 aBoyer, Laurie, A1 aAsselbergs, Folkert, W1 avan Veldhuisen, Dirk, J1 aStricker, Bruno, H1 aPsaty, Bruce, M1 aCiullo, Marina1 aSanna, Serena1 aLehtimäki, Terho1 aWilson, James, F1 aBandinelli, Stefania1 aAlonso, Alvaro1 aGasparini, Paolo1 aJukema, Wouter1 aKääb, Stefan1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aHeckbert, Susan, R1 ade Boer, Rudolf, A1 aNewton-Cheh, Christopher1 aHicks, Andrew, A1 aChambers, John, C1 aJamshidi, Yalda1 aVisel, Axel1 aChristoffels, Vincent, M1 aIsaacs, Aaron1 aSamani, Nilesh, J1 ade Bakker, Paul, I W uhttps://chs-nhlbi.org/node/726202547nas a2200229 4500008004100000022001400041245016500055210006900220260001300289300000900302490000700311520179200318100002502110700002702135700002102162700001402183700001702197700002002214700002502234700002202259856003602281 2016 eng d a1532-223800aAgreement between circulating IGF-I, IGFBP-1 and IGFBP-3 levels measured by current assays versus unavailable assays previously used in epidemiological studies.0 aAgreement between circulating IGFI IGFBP1 and IGFBP3 levels meas c2016 Feb a11-60 v263 aOBJECTIVE: Levels of insulin-like growth factor (IGF) proteins are associated with the risk of cancer and mortality. IGF assays produced by Diagnostic Systems Laboratories (DSL) were widely used in epidemiological studies, were not calibrated against recommended standards and are no longer commercially available.
DESIGN: In a split sample study among 1471 adults participating in the Cardiovascular Health Study, we compared values obtained using DSL assays with alternative assays for serum IGF-I (Immunodiagnostic Systems, IDS), IGFBP-1 (American Laboratory Products Company, ALPCO) and IGFBP-3 (IDS).
RESULTS: Results were compared using kernel density estimation plots, quartile analysis with weighted kappa statistics and linear regression models to assess the concordance of data from the different assays. Participants had a mean age of 77years. Results between alternative assays were strongly correlated (IGF-I, r=0.93 for DSL versus IDS; log-IGFBP-1, r=0.90 for DSL versus ALPCO; IGFBP-3, r=0.92 for DSL versus IDS). Cross tabulations showed that participants were usually in the same quartile categories regardless of the assay used (overall agreement, 74% for IGF-I, 64% for IGFBP-1, 71% for IGFBP-3). Weighted kappa also showed substantial agreement between assays (kw, 0.78 for IGF-I, 0.69 for IGFBP-1, 0.76 for IGFBP-3). Regressions of levels obtained with DSL assays (denoted X) to alternative assays were, IGF-I: 0.52X+15.2ng/ml, log-IGFBP-1: 1.01X-1.73ng/ml IGFBP-3: 0.87X+791.1ng/ml. Serum values of IGF-I, IGFBP-1 and IGFBP-3 measured using alternative assays are moderately correlated.
CONCLUSIONS: Care is needed in the interpretation of data sets involving IGF analytes if assay methodologies are not uniform.
1 aAneke-Nash, Chino, S1 aDominguez-Islas, Clara1 aBůzková, Petra1 aQi, Qibin1 aXue, XiaoNan1 aPollak, Michael1 aStrickler, Howard, D1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/695203481nas a2200565 4500008004100000022001400041245008200055210006900137260001300206300001200219490000700231520189800238653002202136653001602158653000902174653001602183653002002199653002002219653002802239653001902267653004002286653001102326653001902337653003802356653003002394653001702424653001502441653001102456653001402467653002602481653002002507653002202527653000902549653002602558653001402584653003202598653002402630653002002654653001702674653001702691653001802708100002402726700002202750700002302772700001902795700002102814700002202835700002202857856003602879 2016 eng d a1524-463600aAPOL1 Genotype, Kidney and Cardiovascular Disease, and Death in Older Adults.0 aAPOL1 Genotype Kidney and Cardiovascular Disease and Death in Ol c2016 Feb a398-4030 v363 aOBJECTIVE: We sought to evaluate the cardiovascular impact of coding variants in the apolipoprotein L1 gene APOL1 that protect against trypanosome infection but have been associated with kidney disease among African Americans.
APPROACH AND RESULTS: As part of the Cardiovascular Health Study, a population-based cohort of Americans aged ≥65 years, we genotyped APOL1 polymorphisms rs73885319 and rs71785153 and examined kidney function, subclinical atherosclerosis, and incident cardiovascular disease and death over 13 years of follow-up among 91 African Americans with 2 risk alleles, 707 other African Americans, and 4964 white participants. The high-risk genotype with 2 risk alleles was associated with 2-fold higher levels of albuminuria and lower ankle-brachial indices but similar carotid intima-media thickness among African Americans. Median survival among high-risk African Americans was 9.9 years (95% confidence interval [CI], 8.7-11.9), compared with 13.6 years (95% CI, 12.5-14.3) among other African Americans and 13.3 years (95% CI, 13.0-13.6) among whites (P=0.03). The high-risk genotype was also associated with increased risk for incident myocardial infarction (adjusted hazard ratio 1.8; 95% CI, 1.1-3.0) and mortality (adjusted hazard ratio 1.3; 95% CI 1.0-1.7). Albuminuria and risk for myocardial infarction and mortality were nearly identical between African Americans with 0 to 1 risk alleles and whites.
CONCLUSIONS: APOL1 genotype is associated with albuminuria, subclinical atherosclerosis, incident myocardial infarction, and mortality in older African Americans. African Americans without 2 risk alleles do not differ significantly in risk of myocardial infarction or mortality from whites. APOL1 trypanolytic variants may account for a substantial proportion of the excess risk of chronic disease in African Americans.
10aAfrican Americans10aAge Factors10aAged10aAlbuminuria10aApolipoproteins10aAtherosclerosis10aCardiovascular Diseases10aCause of Death10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aHealth Status Disparities10aHeterozygote10aHomozygote10aHumans10aIncidence10aKaplan-Meier Estimate10aKidney Diseases10aLipoproteins, HDL10aMale10aMyocardial Infarction10aPhenotype10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aTime Factors10aUnited States1 aMukamal, Kenneth, J1 aTremaglio, Joseph1 aFriedman, David, J1 aIx, Joachim, H1 aKuller, Lewis, H1 aTracy, Russell, P1 aPollak, Martin, R uhttps://chs-nhlbi.org/node/693102482nas a2200397 4500008004100000022001400041245006200055210006100117260001300178300001200191490000700203520137600210100002101586700002301607700002301630700002401653700002201677700001801699700001701717700001801734700002001752700002201772700001701794700002101811700002001832700002101852700002201873700002401895700002701919700002201946700001801968700001901986700002302005700002002028856003602048 2016 eng d a1476-543800aAssociation of the IGF1 gene with fasting insulin levels.0 aAssociation of the IGF1 gene with fasting insulin levels c2016 Aug a1337-430 v243 aInsulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (PSKAT=5.7 × 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (Pconditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology.
1 aWillems, Sara, M1 aCornes, Belinda, K1 aBrody, Jennifer, A1 aMorrison, Alanna, C1 aLipovich, Leonard1 aDauriz, Marco1 aChen, Yuning1 aLiu, Ching-Ti1 aRybin, Denis, V1 aGibbs, Richard, A1 aMuzny, Donna1 aPankow, James, S1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aSiscovick, David, S1 aVasan, Ramachandran, S1 aKaplan, Robert, C1 aIsaacs, Aaron1 aDupuis, Josée1 aDuijn, Cornelia, M1 aMeigs, James, B uhttps://chs-nhlbi.org/node/700503076nas a2200481 4500008004100000022001400041245013900055210006900194260001300263300001200276490000800288520173100296653000902027653002202036653001902058653000902077653001702086653002102103653001602124653001102140653001102151653000902162653001402171653001802185653001802203653002402221653001702245653001802262100002202280700002502302700002402327700001902351700002202370700002002392700001802412700002102430700002002451700001902471700002202490700002202512700002402534856003602558 2016 eng d a1541-610000aAssociations of Plasma Phospholipid SFAs with Total and Cause-Specific Mortality in Older Adults Differ According to SFA Chain Length.0 aAssociations of Plasma Phospholipid SFAs with Total and CauseSpe c2016 Feb a298-3050 v1463 aBACKGROUND: Not much is known about the relations of circulating saturated fatty acids (SFAs), which are influenced by both metabolic and dietary determinants, with total and cause-specific mortality.
OBJECTIVE: We examined the associations of plasma phospholipid SFAs with total and cause-specific mortality among 3941 older adults from the Cardiovascular Health Study, a population-based prospective study of adults aged ≥65 y who were followed from 1992 through 2011.
METHODS: The relations of total and cause-specific mortality with plasma phospholipid palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) were assessed using Cox proportional hazards models.
RESULTS: During 45,450 person-years of follow-up, 3134 deaths occurred. Higher concentrations of the plasma phospholipid SFAs 18:0, 22:0, and 24:0 were associated with a lower risk of total mortality [multivariable-adjusted HRs (95% CIs)] for the top compared with the bottom quintile: 0.85 (0.75, 0.95) for 18:0; 0.85 (0.75, 0.95) for 22:0; and 0.80 (0.71, 0.90) for 24:0. In contrast, plasma 16:0 concentrations in the highest quintile were associated with a higher risk of total mortality compared with concentrations in the lowest quintile [1.25 (1.11, 1.41)]. We also found no association of plasma phospholipid 20:0 with total mortality.
CONCLUSIONS: These findings suggest that the associations of plasma phospholipid SFAs with the risk of death differ according to SFA chain length and support future studies to better characterize the determinants of circulating SFAs and to explore the mechanisms underlying these relations.
10aAged10aAged, 80 and over10aCause of Death10aDiet10aDietary Fats10aEicosanoic Acids10aFatty Acids10aFemale10aHumans10aMale10aMortality10aPalmitic Acid10aPhospholipids10aProspective Studies10aRisk Factors10aStearic Acids1 aFretts, Amanda, M1 aMozaffarian, Dariush1 aSiscovick, David, S1 aKing, Irena, B1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aRimm, Eric, B1 aSitlani, Colleen1 aSacks, Frank, M1 aSong, Xiaoling1 aSotoodehnia, Nona1 aSpiegelman, Donna1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/692902836nas a2200277 4500008004100000022001400041245007000055210006900125260001600194520207400210100001102284700001602295700001602311700002002327700001802347700001702365700001802382700001502400700002002415700001602435700001802451700001502469700002002484700001802504856003602522 2016 eng d a1464-549100aBrain natriuretic peptide and insulin resistance in older adults.0 aBrain natriuretic peptide and insulin resistance in older adults c2016 Apr 213 aAIMS: Higher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established.
METHODS: N-Terminal (NT)-proBNP was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance.
RESULTS: Lower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P < 0.001 for all four indices). Although the genetic score was strongly related to measured NT-proBNP levels amongst European Americans (F statistic = 71.08), we observed no association of genetically determined NT-proBNP with insulin resistance (P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-proBNP).
CONCLUSIONS: In older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study. This article is protected by copyright. All rights reserved.
1 aKim, F1 aBiggs, M, L1 aKizer, J, R1 aBrutsaert, E, F1 ade Fillipi, C1 aNewman, A, B1 aKronmal, R, A1 aTracy, R P1 aGottdiener, J S1 aDjoussé, L1 ade Boer, I, H1 aPsaty, B M1 aSiscovick, D, S1 aMukamal, K, J uhttps://chs-nhlbi.org/node/712402578nas a2200229 4500008004100000022001400041245010100055210006900156260001600225520185100241100001902092700002402111700003102135700001702166700002002183700002302203700002802226700001902254700002002273700001902293856003602312 2016 eng d a1524-462800aChanges in Depressive Symptoms and Subsequent Risk of Stroke in the Cardiovascular Health Study.0 aChanges in Depressive Symptoms and Subsequent Risk of Stroke in c2016 Dec 063 aBACKGROUND AND PURPOSE: Depression is associated with stroke, but the effects of changes in depressive symptoms on stroke risk are not well understood. This study examined whether depressive symptom changes across 2 successive annual assessments were associated with incident stroke the following year.
METHODS: We used visit data from 4319 participants of the Cardiovascular Health Study who were stroke free at baseline to examine whether changes in depressive symptoms classified across 2 consecutive annual assessments predicted incident first stroke during the subsequent year. Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression scale (high versus low at ≥10). Survival models were inverse probability weighted to adjust for demographics, health behaviors, medical conditions, past depressive symptoms, censoring, and survival.
RESULTS: During follow-up, 334 strokes occurred. Relative to stable low scores of depressive symptoms, improved depression symptoms were associated with almost no excess risk of stroke (adjusted hazards ratio, 1.02; 95% confidence interval, 0.66-1.58). New-onset symptoms were nonsignificantly associated with elevated stroke risk (adjusted hazards ratio, 1.44; 95% confidence interval, 0.97-2.14), whereas persistently high depressive symptoms were associated with elevated adjusted hazard of all-cause stroke (adjusted hazards ratio, 1.65; 95% confidence interval, 1.06-2.56). No evidence for effect modification by race, age, or sex was found.
CONCLUSIONS: Persistently high symptoms of depression predicted elevated hazard of stroke. Participants with improved depressive symptoms had no elevation in stroke risk. Such findings suggest that strategies to reduce depressive symptoms may ameliorate stroke risk.
1 aGilsanz, Paola1 aKubzansky, Laura, D1 aTchetgen, Eric, J Tchetgen1 aWang, Qianyi1 aKawachi, Ichiro1 aPatton, Kristen, K1 aFitzpatrick, Annette, L1 aKop, Willem, J1 aLongstreth, W T1 aGlymour, Maria uhttps://chs-nhlbi.org/node/724503096nas a2200541 4500008004100000022001400041245008500055210006900140260001500209300001100224490000700235520160100242653001901843653001801862653001101880653003601891653002001927653002701947653001001974653001701984100001902001700002402020700002502044700002202069700002102091700002202112700002402134700002102158700001702179700002002196700001902216700001402235700002002249700001902269700001902288700002302307700001502330700002002345700002302365700001402388700002002402700002002422700002102442700001802463700001902481700001802500856003602518 2016 eng d a1460-208300aCommon variants in DRD2 are associated with sleep duration: the CARe consortium.0 aCommon variants in DRD2 are associated with sleep duration the C c2016 Jan 1 a167-790 v253 aSleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.
10aCohort Studies10aEthnic Groups10aHumans10aPolymorphism, Single Nucleotide10aPolysomnography10aReceptors, Dopamine D210aSleep10aTime Factors1 aCade, Brian, E1 aGottlieb, Daniel, J1 aLauderdale, Diane, S1 aBennett, David, A1 aBuchman, Aron, S1 aBuxbaum, Sarah, G1 aDe Jager, Philip, L1 aEvans, Daniel, S1 aFulop, Tibor1 aGharib, Sina, A1 aJohnson, Craig1 aKim, Hyun1 aLarkin, Emma, K1 aLee, Seung, Ku1 aLim, Andrew, S1 aPunjabi, Naresh, M1 aShin, Chol1 aStone, Katie, L1 aTranah, Gregory, J1 aWeng, Jia1 aYaffe, Kristine1 aZee, Phyllis, C1 aPatel, Sanjay, R1 aZhu, Xiaofeng1 aRedline, Susan1 aSaxena, Richa uhttps://chs-nhlbi.org/node/712103463nas a2200325 4500008004100000022001400041245010200055210006900157260001600226300001100242490000800253520250800261100001502769700001902784700001602803700002202819700001902841700003002860700002202890700001702912700002302929700002102952700002402973700001702997700002303014700002103037700002403058700001903082856003603101 2016 eng d a1524-453900aDevelopment and Validation of a Sudden Cardiac Death Prediction Model for the General Population.0 aDevelopment and Validation of a Sudden Cardiac Death Prediction c2016 Sep 13 a806-160 v1343 aBACKGROUND: Most sudden cardiac death (SCD) events occur in the general population among persons who do not have any prior history of clinical heart disease. We sought to develop a predictive model of SCD among US adults.
METHODS: We evaluated a series of demographic, clinical, laboratory, electrocardiographic, and echocardiographic measures in participants in the ARIC study (Atherosclerosis Risk in Communities) (n=13 677) and the CHS (Cardiovascular Health Study) (n=4207) who were free of baseline cardiovascular disease. Our initial objective was to derive a SCD prediction model using the ARIC cohort and validate it in CHS. Independent risk factors for SCD were first identified in the ARIC cohort to derive a 10-year risk model of SCD. We compared the prediction of SCD with non-SCD and all-cause mortality in both the derivation and validation cohorts. Furthermore, we evaluated whether the SCD prediction equation was better at predicting SCD than the 2013 American College of Cardiology/American Heart Association Cardiovascular Disease Pooled Cohort risk equation.
RESULTS: There were a total of 345 adjudicated SCD events in our analyses, and the 12 independent risk factors in the ARIC study included age, male sex, black race, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, serum potassium, serum albumin, high-density lipoprotein, estimated glomerular filtration rate, and QTc interval. During a 10-year follow-up period, a model combining these risk factors showed good to excellent discrimination for SCD risk (c-statistic 0.820 in ARIC and 0.745 in CHS). The SCD prediction model was slightly better in predicting SCD than the 2013 American College of Cardiology/American Heart Association Pooled Cohort risk equations (c-statistic 0.808 in ARIC and 0.743 in CHS). Only the SCD prediction model, however, demonstrated similar and accurate prediction for SCD using both the original, uncalibrated score and the recalibrated equation. Finally, in the echocardiographic subcohort, a left ventricular ejection fraction <50% was present in only 1.1% of participants and did not enhance SCD prediction.
CONCLUSIONS: Our study is the first to derive and validate a generalizable risk score that provides well-calibrated, absolute risk estimates across different risk strata in an adult population of white and black participants without a clinical diagnosis of cardiovascular disease.
1 aDeo, Rajat1 aNorby, Faye, L1 aKatz, Ronit1 aSotoodehnia, Nona1 aAdabag, Selcuk1 adeFilippi, Christopher, R1 aKestenbaum, Bryan1 aChen, Lin, Y1 aHeckbert, Susan, R1 aFolsom, Aaron, R1 aKronmal, Richard, A1 aKonety, Suma1 aPatton, Kristen, K1 aSiscovick, David1 aShlipak, Michael, G1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/724303793nas a2200553 4500008004100000022001400041245013800055210006900193260001500262300001200277490000700289520217800296100001902474700001802493700002002511700001902531700002002550700001502570700003002585700002302615700002102638700002302659700002402682700002302706700001902729700002002748700002202768700001802790700001902808700002302827700002502850700001702875700002102892700001702913700002402930700002002954700002002974700001802994700001703012700002103029700001903050700002103069700002903090700002103119700002103140700002003161700002203181856003603203 2016 eng d a1558-359700aDiagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.0 aDiagnostic Yield and Clinical Utility of Sequencing Familial Hyp c2016 Jun 7 a2578-890 v673 aBACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement.
OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.
METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.
RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.
CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.
1 aKhera, Amit, V1 aWon, Hong-Hee1 aPeloso, Gina, M1 aLawson, Kim, S1 aBartz, Traci, M1 aDeng, Xuan1 avan Leeuwen, Elisabeth, M1 aNatarajan, Pradeep1 aEmdin, Connor, A1 aBick, Alexander, G1 aMorrison, Alanna, C1 aBrody, Jennifer, A1 aGupta, Namrata1 aNomura, Akihiro1 aKessler, Thorsten1 aDuga, Stefano1 aBis, Joshua, C1 aDuijn, Cornelia, M1 aCupples, Adrienne, L1 aPsaty, Bruce1 aRader, Daniel, J1 aDanesh, John1 aSchunkert, Heribert1 aMcPherson, Ruth1 aFarrall, Martin1 aWatkins, Hugh1 aLander, Eric1 aWilson, James, G1 aCorrea, Adolfo1 aBoerwinkle, Eric1 aMerlini, Piera, Angelica1 aArdissino, Diego1 aSaleheen, Danish1 aGabriel, Stacey1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/701002552nas a2200205 4500008004100000022001400041245013000055210006900185260001300254300001100267490000700278520189100285100002102176700002102197700002002218700002002238700002702258700002502285856003602310 2016 eng d a1468-283400aDigit Symbol Substitution test and future clinical and subclinical disorders of cognition, mobility and mood in older adults.0 aDigit Symbol Substitution test and future clinical and subclinic c2016 Sep a688-950 v453 aOBJECTIVE: to examine whether psychomotor speed predicts individual and combined disorders in cognition, mobility and mood and if white matter hyperintensities explain these associations.
DESIGN AND SETTING: longitudinal; Cardiovascular Health Study.
SUBJECTS: 5,888 participants (57.6% women, 15.7% black, 75.1 (5.5), mean years (SD)).
METHODS: psychomotor speed (Digit Symbol Substitution Test (DSST)) and small vessel disease (white matter hyperintensities (WMH)) were measured in 1992-94. Global cognition (Modified Mini-Mental State (3MS) examination), mobility (gait speed (GS)) and mood (Center for Epidemiologic Studies Depression (CES-D) scale) were measured annually over 5 years and classified as clinical, subclinical or no disorders based on established values (3MS: 80 and 85 points; GS: 0.6 and 1.0 m/s; CES-D: 10 and 5 points). Analyses were adjusted for demographics, baseline status, education, diabetes, hypertension, ankle-arm index.
RESULTS: among those with no disorder in cognition, mobility and mood (N = 619) in 1992-94, being in the lowest DSST quartile compared to the highest was associated with nearly twice the odds of developing 1+ clinical or subclinical disorders (N = 413) during follow-up. Associations were stronger for incident clinical disorders in cognition (OR: 8.44, p < 0.01) or mobility (OR: 9.09, p < 0.05) than for mood (OR: 1.88, p < 0.10). Results were similar after adjustment for WMH.
CONCLUSIONS: slower psychomotor speed may serve as a biomarker of risk of clinical disorders of cognition, mobility and mood. While in part attributable to vascular brain disease, other potentially modifiable contributors may be present. Further studying the causes of psychomotor slowing with ageing might provide novel insights into age-related brain disorders.
1 aRosano, Caterina1 aPerera, Subashan1 aInzitari, Marco1 aNewman, Anne, B1 aLongstreth, William, T1 aStudenski, Stephanie uhttps://chs-nhlbi.org/node/713103786nas a2200841 4500008004100000022001400041245009800055210006900153260001300222300001300235490000700248520140700255100001801662700002101680700002401701700002801725700002001753700001901773700001801792700001801810700002001828700002301848700001901871700002001890700001801910700001901928700001801947700002201965700001701987700002502004700002002029700001902049700002102068700002102089700002302110700002402133700002002157700001402177700001402191700001602205700002202221700001502243700002602258700002802284700001702312700002102329700001902350700002602369700002802395700002002423700002402443700002602467700001902493700001702512700001702529700002002546700002502566700001902591700001802610700002102628700002102649700002102670700002902691700001802720700002702738700002302765700002302788710002602811710002302837710002202860710002602882856003602908 2016 eng d a1553-740400aDiscovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.0 aDiscovery of Genetic Variation on Chromosome 5q22 Associated wit c2016 May ae10060340 v123 aFailure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
1 aSmith, Gustav1 aFelix, Janine, F1 aMorrison, Alanna, C1 aKalogeropoulos, Andreas1 aTrompet, Stella1 aWilk, Jemma, B1 aGidlöf, Olof1 aWang, Xinchen1 aMorley, Michael1 aMendelson, Michael1 aJoehanes, Roby1 aLigthart, Symen1 aShan, Xiaoyin1 aBis, Joshua, C1 aWang, Ying, A1 aSjögren, Marketa1 aNgwa, Julius1 aBrandimarto, Jeffrey1 aStott, David, J1 aAguilar, David1 aRice, Kenneth, M1 aSesso, Howard, D1 aDemissie, Serkalem1 aBuckley, Brendan, M1 aTaylor, Kent, D1 aFord, Ian1 aYao, Chen1 aLiu, Chunyu1 aSotoodehnia, Nona1 aHarst, Pim1 aStricker, Bruno, H Ch1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aGaziano, Michael1 aHofman, Albert1 aMoravec, Christine, S1 aUitterlinden, André, G1 aKellis, Manolis1 avan Meurs, Joyce, B1 aMargulies, Kenneth, B1 aDehghan, Abbas1 aLevy, Daniel1 aOlde, Björn1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aJukema, Wouter1 aDjoussé, Luc1 aFranco, Oscar, H1 aBoerwinkle, Eric1 aBoyer, Laurie, A1 aNewton-Cheh, Christopher1 aButler, Javed1 aVasan, Ramachandran, S1 aCappola, Thomas, P1 aSmith, Nicholas, L1 aCHARGE-SCD consortium1 aEchoGen consortium1 aQT-IGC consortium1 aCHARGE-QRS consortium uhttps://chs-nhlbi.org/node/714404289nas a2200985 4500008004100000022001400041245005600055210005300111260001600164520193800180100001102118700001802129700001802147700001602165700001402181700001902195700001502214700001202229700001502241700001402256700001502270700001802285700001602303700001502319700001402334700001602348700001102364700001202375700001202387700001102399700002002410700001602430700001302446700001402459700001202473700001202485700001602497700001802513700001602531700001502547700001402562700001902576700001502595700001102610700001802621700001602639700001702655700001802672700001602690700001702706700001702723700001602740700001802756700001402774700001202788700001502800700001802815700001902833700001302852700002202865700001102887700002902898700001702927700001902944700001502963700001202978700001002990700001503000700001603015700001703031700001903048700001403067700002203081700001903103700002103122700001603143700001503159700001603174700001103190700002003201700001703221700001703238700001203255856003603267 2016 eng d a1476-557800aA DNA methylation biomarker of alcohol consumption.0 aDNA methylation biomarker of alcohol consumption c2016 Nov 153 aThe lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.Molecular Psychiatry advance online publication, 15 November 2016; doi:10.1038/mp.2016.192.
1 aLiu, C1 aMarioni, R, E1 aHedman, Å, K1 aPfeiffer, L1 aTsai, P-C1 aReynolds, L, M1 aJust, A, C1 aDuan, Q1 aBoer, C, G1 aTanaka, T1 aElks, C, E1 aAslibekyan, S1 aBrody, J, A1 aKühnel, B1 aHerder, C1 aAlmli, L, M1 aZhi, D1 aWang, Y1 aHuan, T1 aYao, C1 aMendelson, M, M1 aJoehanes, R1 aLiang, L1 aLove, S-A1 aGuan, W1 aShah, S1 aMcRae, A, F1 aKretschmer, A1 aProkisch, H1 aStrauch, K1 aPeters, A1 aVisscher, P, M1 aWray, N, R1 aGuo, X1 aWiggins, K, L1 aSmith, A, K1 aBinder, E, B1 aRessler, K, J1 aIrvin, M, R1 aAbsher, D, M1 aHernandez, D1 aFerrucci, L1 aBandinelli, S1 aLohman, K1 aDing, J1 aTrevisi, L1 aGustafsson, S1 aSandling, J, H1 aStolk, L1 aUitterlinden, A G1 aYet, I1 aCastillo-Fernandez, J, E1 aSpector, T D1 aSchwartz, J, D1 aVokonas, P1 aLind, L1 aLi, Y1 aFornage, M1 aArnett, D K1 aWareham, N J1 aSotoodehnia, N1 aOng, K, K1 avan Meurs, J, B J1 aConneely, K, N1 aBaccarelli, A, A1 aDeary, I, J1 aBell, J, T1 aNorth, K, E1 aLiu, Y1 aWaldenberger, M1 aLondon, S, J1 aIngelsson, E1 aLevy, D uhttps://chs-nhlbi.org/node/737505220nas a2201201 4500008004100000022001400041245010300055210006900158260001600227300000800243490000700251520181700258100002002075700001802095700002302113700002602136700002302162700002002185700002002205700002202225700001902247700001702266700002302283700001602306700002202322700001702344700001802361700001802379700002802397700001902425700001902444700002002463700002202483700002202505700001702527700002302544700001302567700002302580700001902603700002302622700002202645700002102667700002102688700001802709700001602727700001402743700002402757700002902781700002102810700002502831700001802856700002002874700002002894700002102914700001902935700001902954700002202973700002102995700001403016700001603030700002003046700001903066700001903085700002003104700001903124700002503143700002203168700002403190700001903214700002303233700002403256700002403280700002103304700002503325700002503350700002503375700002003400700002603420700002203446700002203468700002303490700002803513700002603541700002103567700002203588700001703610700002303627700001803650700002203668700001903690700002003709700001603729700002903745700002103774700002103795700002103816700002603837700002403863700001903887710002703906710004903933856003603982 2016 eng d a1474-760X00aDNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.0 aDNA methylation signatures of chronic lowgrade inflammation are c2016 Dec 12 a2550 v173 aBACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
1 aLigthart, Symen1 aMarzi, Carola1 aAslibekyan, Stella1 aMendelson, Michael, M1 aConneely, Karen, N1 aTanaka, Toshiko1 aColicino, Elena1 aWaite, Lindsay, L1 aJoehanes, Roby1 aGuan, Weihua1 aBrody, Jennifer, A1 aElks, Cathy1 aMarioni, Riccardo1 aJhun, Min, A1 aAgha, Golareh1 aBressler, Jan1 aWard-Caviness, Cavin, K1 aChen, Brian, H1 aHuan, Tianxiao1 aBakulski, Kelly1 aSalfati, Elias, L1 aFiorito, Giovanni1 aWahl, Simone1 aSchramm, Katharina1 aSha, Jin1 aHernandez, Dena, G1 aJust, Allan, C1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aPilling, Luke, C1 aPankow, James, S1 aTsao, Phil, S1 aLiu, Chunyu1 aZhao, Wei1 aGuarrera, Simonetta1 aMichopoulos, Vasiliki, J1 aSmith, Alicia, K1 aPeters, Marjolein, J1 aMelzer, David1 aVokonas, Pantel1 aFornage, Myriam1 aProkisch, Holger1 aBis, Joshua, C1 aChu, Audrey, Y1 aHerder, Christian1 aGrallert, Harald1 aYao, Chen1 aShah, Sonia1 aMcRae, Allan, F1 aLin, Honghuang1 aHorvath, Steve1 aFallin, Daniele1 aHofman, Albert1 aWareham, Nicholas, J1 aWiggins, Kerri, L1 aFeinberg, Andrew, P1 aStarr, John, M1 aVisscher, Peter, M1 aMurabito, Joanne, M1 aKardia, Sharon, L R1 aAbsher, Devin, M1 aBinder, Elisabeth, B1 aSingleton, Andrew, B1 aBandinelli, Stefania1 aPeters, Annette1 aWaldenberger, Melanie1 aMatullo, Giuseppe1 aSchwartz, Joel, D1 aDemerath, Ellen, W1 aUitterlinden, André, G1 avan Meurs, Joyce, B J1 aFranco, Oscar, H1 aChen, Yii-Der Ida1 aLevy, Daniel1 aTurner, Stephen, T1 aDeary, Ian, J1 aRessler, Kerry, J1 aDupuis, Josée1 aFerrucci, Luigi1 aOng, Ken, K1 aAssimes, Themistocles, L1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aArnett, Donna, K1 aBaccarelli, Andrea, A1 aBenjamin, Emelia, J1 aDehghan, Abbas1 aWHI-EMPC Investigators1 aCHARGE epigenetics of Coronary Heart Disease uhttps://chs-nhlbi.org/node/734904238nas a2200829 4500008004100000022001400041245019000055210006900245260001300314300001100327490000700338520184100345100001802186700002302204700002202227700002002249700002402269700002202293700002102315700002102336700002202357700002402379700002002403700001502423700002102438700002002459700002002479700002202499700001902521700002102540700001602561700002102577700001902598700002502617700001502642700002402657700001702681700002402698700002002722700002502742700002502767700002002792700002002812700001702832700001702849700002102866700002002887700001902907700001802926700002102944700001702965700001902982700002203001700001903023700002403042700002003066700001603086700002103102700002303123700002003146700002303166700002003189700001903209700001903228700001803247700001803265700002303283700002003306700002103326700002503347856003603372 2016 eng d a1098-227200aAn Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group.0 aEmpirical Comparison of Joint and Stratified Frameworks for Stud c2016 Jul a404-150 v403 aStudying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.
1 aSung, Yun, Ju1 aWinkler, Thomas, W1 aManning, Alisa, K1 aAschard, Hugues1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aSmith, Albert, V1 aBoerwinkle, Eric1 aBrown, Michael, R1 aMorrison, Alanna, C1 aFornage, Myriam1 aLin, Li-An1 aRichard, Melissa1 aBartz, Traci, M1 aPsaty, Bruce, M1 aHayward, Caroline1 aPolasek, Ozren1 aMarten, Jonathan1 aRudan, Igor1 aFeitosa, Mary, F1 aKraja, Aldi, T1 aProvince, Michael, A1 aDeng, Xuan1 aFisher, Virginia, A1 aZhou, Yanhua1 aBielak, Lawrence, F1 aSmith, Jennifer1 aHuffman, Jennifer, E1 aPadmanabhan, Sandosh1 aSmith, Blair, H1 aDing, Jingzhong1 aLiu, Yongmei1 aLohman, Kurt1 aBouchard, Claude1 aRankinen, Tuomo1 aRice, Treva, K1 aArnett, Donna1 aSchwander, Karen1 aGuo, Xiuqing1 aPalmas, Walter1 aRotter, Jerome, I1 aAlfred, Tamuno1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aAmin, Najaf1 aFranco, Oscar, H1 aDuijn, Cornelia, M1 aVojinovic, Dina1 aChasman, Daniel, I1 aRidker, Paul, M1 aRose, Lynda, M1 aKardia, Sharon1 aZhu, Xiaofeng1 aRice, Kenneth1 aBorecki, Ingrid, B1 aRao, Dabeeru, C1 aGauderman, James1 aCupples, Adrienne, L uhttps://chs-nhlbi.org/node/714505010nas a2201129 4500008004100000022001400041245004800055210004700103260001300150300001200163490000600175520193900181100001902120700001902139700002502158700002102183700002502204700002402229700001702253700001202270700001902282700002302301700002902324700002302353700002302376700002102399700001802420700002102438700001702459700001902476700002002495700001702515700001302532700002102545700002002566700001402586700002302600700001802623700002002641700001902661700001602680700002602696700001402722700002102736700002002757700002202777700002302799700001902822700001902841700002002860700002502880700002502905700002502930700001502955700002002970700001802990700002403008700002803032700001903060700001903079700002003098700001603118700002303134700002303157700002503180700002503205700002303230700001803253700002103271700002103292700002503313700002003338700002003358700002003378700002403398700001803422700001903440700002403459700001903483700002203502700002303524700002203547700002403569700001803593700002603611700002603637700002103663700002103684700001603705700001703721700002603738700001803764700002003782700001703802700002503819856003603844 2016 eng d a1942-326800aEpigenetic Signatures of Cigarette Smoking.0 aEpigenetic Signatures of Cigarette Smoking c2016 Oct a436-4470 v93 aBACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.
METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.
CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
1 aJoehanes, Roby1 aJust, Allan, C1 aMarioni, Riccardo, E1 aPilling, Luke, C1 aReynolds, Lindsay, M1 aMandaviya, Pooja, R1 aGuan, Weihua1 aXu, Tao1 aElks, Cathy, E1 aAslibekyan, Stella1 aMoreno-Macias, Hortensia1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aDhingra, Radhika1 aYousefi, Paul1 aPankow, James, S1 aKunze, Sonja1 aShah, Sonia, H1 aMcRae, Allan, F1 aLohman, Kurt1 aSha, Jin1 aAbsher, Devin, M1 aFerrucci, Luigi1 aZhao, Wei1 aDemerath, Ellen, W1 aBressler, Jan1 aGrove, Megan, L1 aHuan, Tianxiao1 aLiu, Chunyu1 aMendelson, Michael, M1 aYao, Chen1 aKiel, Douglas, P1 aPeters, Annette1 aWang-Sattler, Rui1 aVisscher, Peter, M1 aWray, Naomi, R1 aStarr, John, M1 aDing, Jingzhong1 aRodriguez, Carlos, J1 aWareham, Nicholas, J1 aIrvin, Marguerite, R1 aZhi, Degui1 aBarrdahl, Myrto1 aVineis, Paolo1 aAmbatipudi, Srikant1 aUitterlinden, André, G1 aHofman, Albert1 aSchwartz, Joel1 aColicino, Elena1 aHou, Lifang1 aVokonas, Pantel, S1 aHernandez, Dena, G1 aSingleton, Andrew, B1 aBandinelli, Stefania1 aTurner, Stephen, T1 aWare, Erin, B1 aSmith, Alicia, K1 aKlengel, Torsten1 aBinder, Elisabeth, B1 aPsaty, Bruce, M1 aTaylor, Kent, D1 aGharib, Sina, A1 aSwenson, Brenton, R1 aLiang, Liming1 aDeMeo, Dawn, L1 aO'Connor, George, T1 aHerceg, Zdenko1 aRessler, Kerry, J1 aConneely, Karen, N1 aSotoodehnia, Nona1 aKardia, Sharon, L R1 aMelzer, David1 aBaccarelli, Andrea, A1 avan Meurs, Joyce, B J1 aRomieu, Isabelle1 aArnett, Donna, K1 aOng, Ken, K1 aLiu, Yongmei1 aWaldenberger, Melanie1 aDeary, Ian, J1 aFornage, Myriam1 aLevy, Daniel1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/726106025nas a2201489 4500008004100000022001400041245009200055210006900147260001500216300000900231490000700240520184700247100002002094700002002114700002202134700002002156700002502176700002402201700002602225700002002251700002202271700002002293700001602313700002002329700002302349700002302372700002102395700001902416700002102435700001702456700002102473700001602494700002302510700001602533700002002549700002102569700002102590700002102611700002302632700002402655700002802679700002302707700002002730700002402750700001802774700002202792700002202814700002002836700002002856700001202876700002402888700002402912700001902936700002202955700002202977700002302999700002503022700002403047700001903071700002503090700002003115700001703135700002203152700002203174700001203196700002403208700002103232700001703253700001803270700002803288700001803316700002303334700001903357700002103376700001803397700001903415700002603434700001703460700002403477700002503501700001903526700002303545700001803568700002003586700002303606700002103629700002103650700002103671700002603692700002203718700001903740700002603759700001903785700002003804700002203824700002303846700002403869700002203893700002103915700001903936700002703955700002303982700002604005700001804031700001804049700002804067700002604095700002004121700002404141700002104165700002104186700002304207700002204230700001804252700001604270700002004286700002104306700002004327700002104347700002104368700002204389700001804411700002304429700002504452700002204477856003604499 2016 eng d a1537-660500aExome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.0 aExome Genotyping Identifies Pleiotropic Variants Associated with c2016 Jul 7 a8-210 v993 aRed blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
1 aChami, Nathalie1 aChen, Ming-Huei1 aSlater, Andrew, J1 aEicher, John, D1 aEvangelou, Evangelos1 aTajuddin, Salman, M1 aLove-Gregory, Latisha1 aKacprowski, Tim1 aSchick, Ursula, M1 aNomura, Akihiro1 aGiri, Ayush1 aLessard, Samuel1 aBrody, Jennifer, A1 aSchurmann, Claudia1 aPankratz, Nathan1 aYanek, Lisa, R1 aManichaikul, Ani1 aPazoki, Raha1 aMihailov, Evelin1 aHill, David1 aRaffield, Laura, M1 aBurt, Amber1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aO'Donoghue, Michelle, L1 aCrosslin, David, R1 ade Denus, Simon1 aDubé, Marie-Pierre1 aElliott, Paul1 aEngström, Gunnar1 aEvans, Michele, K1 aFloyd, James, S1 aFornage, Myriam1 aGao, He1 aGreinacher, Andreas1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHernesniemi, Jussi1 aHighland, Heather, M1 aHirschhorn, Joel, N1 aHofman, Albert1 aIrvin, Marguerite, R1 aKähönen, Mika1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLi, Jin1 aLiewald, David, C M1 aLinneberg, Allan1 aLiu, Yongmei1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMathias, Rasika, A1 aMelander, Olle1 aMetspalu, Andres1 aMononen, Nina1 aNalls, Mike, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aO'Donnell, Chris, J1 aOrho-Melander, Marju1 aPedersen, Oluf1 aPetersmann, Astrid1 aPolfus, Linda1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRaitoharju, Emma1 aRichard, Melissa1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchmidt, Frank1 aSmith, Albert, Vernon1 aStarr, John, M1 aTaylor, Kent, D1 aTeumer, Alexander1 aThuesen, Betina, H1 aTorstenson, Eric, S1 aTracy, Russell, P1 aTzoulaki, Ioanna1 aZakai, Neil, A1 aVacchi-Suzzi, Caterina1 aDuijn, Cornelia, M1 avan Rooij, Frank, J A1 aCushman, Mary1 aDeary, Ian, J1 aEdwards, Digna, R Velez1 aVergnaud, Anne-Claire1 aWallentin, Lars1 aWaterworth, Dawn, M1 aWhite, Harvey, D1 aWilson, James, G1 aZonderman, Alan, B1 aKathiresan, Sekar1 aGrarup, Niels1 aEsko, Tõnu1 aLoos, Ruth, J F1 aLange, Leslie, A1 aFaraday, Nauder1 aAbumrad, Nada, A1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aAuer, Paul, L1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aLettre, Guillaume uhttps://chs-nhlbi.org/node/713804382nas a2200853 4500008004100000022001400041245015400055210006900209260001600278520191500294100002102209700002202230700001902252700001202271700001802283700001902301700002002320700002002340700002202360700001902382700001902401700002402420700001902444700001902463700001902482700001402501700001902515700002402534700001502558700002202573700001802595700002302613700001902636700002302655700001902678700001802697700002002715700002202735700001502757700001702772700002002789700002202809700002102831700001702852700001702869700002302886700002902909700001902938700002002957700001902977700002202996700002403018700002403042700002103066700002503087700002303112700002403135700002803159700002203187700002603209700002103235700001803256700002003274700002303294700002203317700002003339700002103359700002303380700002103403700002003424700002203444710002603466856003603492 2016 eng d a1460-208300aFine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.0 aFinemapping novel loci identification and SNP association transf c2016 Aug 293 aThe electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.
1 aEvans, Daniel, S1 aAvery, Christy, L1 aNalls, Mike, A1 aLi, Guo1 aBarnard, John1 aSmith, Erin, N1 aTanaka, Toshiko1 aButler, Anne, M1 aBuxbaum, Sarah, G1 aAlonso, Alvaro1 aArking, Dan, E1 aBerenson, Gerald, S1 aBis, Joshua, C1 aBuyske, Steven1 aCarty, Cara, L1 aChen, Wei1 aChung, Mina, K1 aCummings, Steven, R1 aDeo, Rajat1 aEaton, Charles, B1 aFox, Ervin, R1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHindorff, Lucia, A1 aHsueh, Wen-Chi1 aIsaacs, Aaron1 aJamshidi, Yalda1 aKerr, Kathleen, F1 aLiu, Felix1 aLiu, Yongmei1 aLohman, Kurt, K1 aMagnani, Jared, W1 aMaher, Joseph, F1 aMehra, Reena1 aMeng, Yan, A1 aMusani, Solomon, K1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPsaty, Bruce, M1 aRedline, Susan1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aShohet, Ralph, V1 aSingleton, Andrew, B1 aSmith, Jonathan, D1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aTaylor, Herman, A1 aVan Wagoner, David, R1 aWilson, James, G1 aYoung, Taylor1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aEvans, Michele, K1 aFerrucci, Luigi1 aMurray, Sarah, S1 aTranah, Gregory, J1 aWhitsel, Eric, A1 aReiner, Alex, P1 aSotoodehnia, Nona1 aCHARGE QRS Consortium uhttps://chs-nhlbi.org/node/725903368nas a2200577 4500008004100000022001400041245006400055210006200119260001300181300001000194490000700204520180900211653003102020653000902051653002202060653001002082653001902092653002602111653002102137653001102158653000902169653002502178653001102203653002302214653000902237653002402246653003002270653001402300653002802314653002002342653001702362653001402379653002202393653001802415100002102433700002202454700002102476700002002497700002502517700001902542700002102561700001702582700002202599700002302621700002002644700002002664700002202684700002002706700002802726856003602754 2016 ENG d a1758-535X00aGait Speed Predicts Incident Disability: A Pooled Analysis.0 aGait Speed Predicts Incident Disability A Pooled Analysis c2016 Jan a63-710 v713 aBACKGROUND: Functional independence with aging is an important goal for individuals and society. Simple prognostic indicators can inform health promotion and care planning, but evidence is limited by heterogeneity in measures of function.
METHODS: We performed a pooled analysis of data from seven studies of 27,220 community-dwelling older adults aged 65 or older with baseline gait speed, followed for disability and mortality. Outcomes were incident inability or dependence on another person in bathing or dressing; and difficulty walking ¼ - ½ mile or climbing 10 steps within 3 years.
RESULTS: Participants with faster baseline gait had lower rates of incident disability. In subgroups (defined by 0.2 m/s-wide intervals from <0.4 to ≥ 1.4 m/s) with increasingly greater gait speed, 3-year rates of bathing or dressing dependence trended from 10% to 1% in men, and from 15% to 1% in women, while mobility difficulty trended from 47% to 4% in men and 40% to 6% in women. The age-adjusted relative risk ratio per 0.1 m/s greater speed for bathing or dressing dependence in men was 0.68 (0.57-0.81) and in women: 0.74 (0.66-0.82); for mobility difficulty, men: 0.75 (0.68-0.82), women: 0.73 (0.67-0.80). Results were similar for combined disability and mortality. Effects were largely consistent across subgroups based on age, gender, race, body mass index, prior hospitalization, and selected chronic conditions. In the presence of multiple other risk factors for disability, gait speed significantly increased the area under the receiver operator characteristic curve.
CONCLUSION: In older adults, gait speed predicts 3 year incidence of bathing or dressing dependence, mobility difficulty, and a composite outcome of disability and mortality.
10aActivities of Daily Living10aAged10aAged, 80 and over10aAging10aCohort Studies10aDisability Evaluation10aDisabled Persons10aFemale10aGait10aGeriatric Assessment10aHumans10aIndependent Living10aMale10aMobility Limitation10aPredictive Value of Tests10aPrognosis10aPsychomotor Performance10aRisk Assessment10aRisk Factors10aROC Curve10aSurvival Analysis10aUnited States1 aPerera, Subashan1 aPatel, Kushang, V1 aRosano, Caterina1 aRubin, Susan, M1 aSatterfield, Suzanne1 aHarris, Tamara1 aEnsrud, Kristine1 aOrwoll, Eric1 aLee, Christine, G1 aChandler, Julie, M1 aNewman, Anne, B1 aCauley, Jane, A1 aGuralnik, Jack, M1 aFerrucci, Luigi1 aStudenski, Stephanie, A uhttps://chs-nhlbi.org/node/716103027nas a2200829 4500008004100000245006000041210005800101260000700159300001000166490000600176520092500182100001201107700002501119700001801144700001901162700001601181700001801197700002001215700001501235700001901250700001901269700001701288700001601305700002201321700001901343700002001362700001501382700001901397700002101416700001801437700001901455700001901474700002001493700001701513700001801530700002401548700001901572700001801591700001201609700002201621700001301643700002001656700001601676700002201692700002301714700001301737700001501750700002101765700001701786700001901803700001701822700001401839700001501853700001701868700001801885700001901903700001301922700001701935700001501952700001801967700002101985700002102006700001202027700001302039700001702052700001902069700002102088700001302109700001902122700002002141856003602161 2016 eng d00a{Gene-gene Interaction Analyses for Atrial Fibrillation0 aGenegene Interaction Analyses for Atrial Fibrillation c11 a353710 v63 a{Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.651 aLin, H.1 aMueller-Nurasyid, M.1 aSmith, A., V.1 aArking, D., E.1 aBarnard, J.1 aBartz, T., M.1 aLunetta, K., L.1 aLohman, K.1 aKleber, M., E.1 aLubitz, S., A.1 aGeelhoed, B.1 aTrompet, S.1 aNiemeijer, M., N.1 aKacprowski, T.1 aChasman, D., I.1 aKlarin, D.1 aSinner, M., F.1 aWaldenberger, M.1 aMeitinger, T.1 aHarris, T., B.1 aLauner, L., J.1 aSoliman, E., Z.1 aChen, L., Y.1 aSmith, J., D.1 aVan Wagoner, D., R.1 aRotter, J., I.1 aPsaty, B., M.1 aXie, Z.1 aHendricks, A., E.1 aDing, J.1 aDelgado, G., E.1 aVerweij, N.1 avan der Harst, P.1 aMacfarlane, P., W.1 aFord, I.1 aHofman, A.1 aUitterlinden, A.1 aHeeringa, J.1 aFranco, O., H.1 aKors, J., A.1 aWeiss, S.1 aV?lzke, H.1 aRose, L., M.1 aNatarajan, P.1 aKathiresan, S.1 aK??b, S.1 aGudnason, V.1 aAlonso, A.1 aChung, M., K.1 aHeckbert, S., R.1 aBenjamin, E., J.1 aLiu, Y.1 aM?rz, W.1 aRienstra, M.1 aJukema, J., W.1 aStricker, B., H.1 aD?rr, M.1 aAlbert, C., M.1 aEllinor, P., T. uhttps://chs-nhlbi.org/node/856602913nas a2200397 4500008004100000022001400041245007200055210006900127260001300196300001100209490000700220520179900227100001602026700001902042700001302061700001702074700002302091700002102114700002502135700002102160700001902181700002102200700002102221700002102242700001302263700002502276700002502301700002302326700002502349700002202374700002202396700002202418700002002440700001902460856003602479 2016 eng d a1098-227200aGeneral Framework for Meta-Analysis of Haplotype Association Tests.0 aGeneral Framework for MetaAnalysis of Haplotype Association Test c2016 Apr a244-520 v403 aFor complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.
1 aWang, Shuai1 aZhao, Jing Hua1 aAn, Ping1 aGuo, Xiuqing1 aJensen, Richard, A1 aMarten, Jonathan1 aHuffman, Jennifer, E1 aMeidtner, Karina1 aBoeing, Heiner1 aCampbell, Archie1 aRice, Kenneth, M1 aScott, Robert, A1 aYao, Jie1 aSchulze, Matthias, B1 aWareham, Nicholas, J1 aBorecki, Ingrid, B1 aProvince, Michael, A1 aRotter, Jerome, I1 aHayward, Caroline1 aGoodarzi, Mark, O1 aMeigs, James, B1 aDupuis, Josée uhttps://chs-nhlbi.org/node/713621920nas a2208497 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2016 eng d00a{Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function0 aGenetic associations at 53 loci highlight cell types and biologi cJan a100230 v73 aReduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.1 aPattaro, C.1 aTeumer, A.1 aGorski, M.1 aChu, A., Y.1 aLi, M.1 aMijatovic, V.1 aGarnaas, M.1 aTin, A.1 aSorice, R.1 aLi, Y.1 aTaliun, D.1 aOlden, M.1 aFoster, M.1 aYang, Q.1 aChen, M., H.1 aPers, T., H.1 aJohnson, A., D.1 aKo, Y., A.1 aFuchsberger, C.1 aTayo, B.1 aNalls, M.1 aFeitosa, M., F.1 aIsaacs, A.1 aDehghan, A.1 ad'Adamo, P.1 aAdeyemo, A.1 aDieffenbach, A., K.1 aZonderman, A., B.1 aNolte, I., M.1 avan der Most, P., J.1 aWright, A., F.1 aShuldiner, A., R.1 aMorrison, A., C.1 aHofman, A.1 aSmith, A., V.1 aDreisbach, A., W.1 aFranke, A.1 aUitterlinden, A., G.1 aMetspalu, A.1 aTonjes, A.1 aLupo, A.1 aRobino, A.1 aJohansson, ?.1 aDemirkan, A.1 aKollerits, B.1 aFreedman, B., I.1 aPonte, B.1 aOostra, B., A.1 aPaulweber, B.1 aKr?mer, B., K.1 aMitchell, B., D.1 aBuckley, B., M.1 aPeralta, C., A.1 aHayward, C.1 aHelmer, C.1 aRotimi, C., N.1 aShaffer, C., M.1 aM?ller, C.1 aSala, C.1 avan Duijn, C., M.1 aSaint-Pierre, A.1 aAckermann, D.1 aShriner, D.1 aRuggiero, D.1 aToniolo, D.1 aLu, Y.1 aCusi, D.1 aCzamara, D.1 aEllinghaus, D.1 aSiscovick, D., S.1 aRuderfer, D.1 aGieger, C.1 aGrallert, H.1 aRochtchina, E.1 aAtkinson, E., J.1 aHolliday, E., G.1 aBoerwinkle, E.1 aSalvi, E.1 aBottinger, E., P.1 aMurgia, F.1 aRivadeneira, F.1 aErnst, F.1 aKronenberg, F.1 aHu, F., B.1 aNavis, G., J.1 aCurhan, G., C.1 aEhret, G., B.1 aHomuth, G.1 aCoassin, S.1 aThun, G., A.1 aPistis, G.1 aGambaro, G.1 aMalerba, G.1 aMontgomery, G., W.1 aEiriksdottir, G.1 aJacobs, G.1 aLi, G.1 aWichmann, H., E.1 aCampbell, H.1 aSchmidt, H.1 aWallaschofski, H.1 aV?lzke, H.1 aBrenner, H.1 aKroemer, H., K.1 aKramer, H.1 aLin, H.1 aLeach, I., M.1 aFord, I.1 aGuessous, I.1 aRudan, I.1 aProkopenko, I.1 aBorecki, I.1 aHeid, I., M.1 aKolcic, I.1 aPersico, I.1 aJukema, J., W.1 aWilson, J., F.1 aFelix, J., F.1 aDivers, J.1 aLambert, J., C.1 aStafford, J., M.1 aGaspoz, J., M.1 aSmith, J., A.1 aFaul, J., D.1 aWang, J., J.1 aDing, J.1 aHirschhorn, J., N.1 aAttia, J.1 aWhitfield, J., B.1 aChalmers, J.1 aViikari, J.1 aCoresh, J.1 aDenny, J., C.1 aKarjalainen, J.1 aFernandes, J., K.1 aEndlich, K.1 aButterbach, K.1 aKeene, K., L.1 aLohman, K.1 aPortas, L.1 aLauner, L., J.1 aLyytik?inen, L., P.1 aYengo, L.1 aFranke, L.1 aFerrucci, L.1 aRose, L., M.1 aKedenko, L.1 aRao, M.1 aStruchalin, M.1 aKleber, M., E.1 aCavalieri, M.1 aHaun, M.1 aCornelis, M., C.1 aCiullo, M.1 aPirastu, M.1 ade Andrade, M.1 aMcEvoy, M., A.1 aWoodward, M.1 aAdam, M.1 aCocca, M.1 aNauck, M.1 aImboden, M.1 aWaldenberger, M.1 aPruijm, M.1 aMetzger, M.1 aStumvoll, M.1 aEvans, M., K.1 aSale, M., M.1 aK?h?nen, M.1 aBoban, M.1 aBochud, M.1 aRheinberger, M.1 aVerweij, N.1 aBouatia-Naji, N.1 aMartin, N., G.1 aHastie, N.1 aProbst-Hensch, N.1 aSoranzo, N.1 aDevuyst, O.1 aRaitakari, O.1 aGottesman, O.1 aFranco, O., H.1 aPolasek, O.1 aGasparini, P.1 aMunroe, P., B.1 aRidker, P., M.1 aMitchell, P.1 aMuntner, P.1 aMeisinger, C.1 aSmit, J., H.1 aKovacs, P.1 aWild, P., S.1 aFroguel, P.1 aRettig, R.1 aM?gi, R.1 aBiffar, R.1 aSchmidt, R.1 aMiddelberg, R., P.1 aCarroll, R., J.1 aPenninx, B., W.1 aScott, R., J.1 aKatz, R.1 aSedaghat, S.1 aWild, S., H.1 aKardia, S., L.1 aUlivi, S.1 aHwang, S., J.1 aEnroth, S.1 aKloiber, S.1 aTrompet, S.1 aStengel, B.1 aHancock, S., J.1 aTurner, S., T.1 aRosas, S., E.1 aStracke, S.1 aHarris, T., B.1 aZeller, T.1 aZemunik, T.1 aLehtim?ki, T.1 aIllig, T.1 aAspelund, T.1 aNikopensius, T.1 aEsko, T.1 aTanaka, T.1 aGyllensten, U.1 aV?lker, U.1 aEmilsson, V.1 aVitart, V.1 aAalto, V.1 aGudnason, V.1 aChouraki, V.1 aChen, W., M.1 aIgl, W.1 aM?rz, W.1 aKoenig, W.1 aLieb, W.1 aLoos, R., J.1 aLiu, Y.1 aSnieder, H.1 aPramstaller, P., P.1 aParsa, A.1 aO'Connell, J., R.1 aSusztak, K.1 aHamet, P.1 aTremblay, J.1 aDe Boer, I., H.1 aB?ger, C., A.1 aGoessling, W.1 aChasman, D., I.1 aK?ttgen, A.1 aKao, W., H.1 aFox, C., S.1 aAbecasis, G., R.1 aAdair, L., S.1 aAlexander, M.1 aAltshuler, D.1 aAmin, N.1 aArking, D., E.1 aArora, P.1 aAulchenko, Y.1 aBakker, S., J.1 aBandinelli, S.1 aBarroso, I.1 aBeckmann, J., S.1 aBeilby, J., P.1 aBergman, R., N.1 aBergmann, S.1 aBis, J., C.1 aBoehnke, M.1 aBonnycastle, L., L.1 aBornstein, S., R.1 aBots, M., L.1 aBragg-Gresham, J., L.1 aBrand, S., M.1 aBrand, E.1 aBraund, P., S.1 aBrown, M., J.1 aBurton, P., R.1 aCasas, J., P.1 aCaulfield, M., J.1 aChakravarti, A.1 aChambers, J., C.1 aChandak, G., R.1 aChang, Y., P.1 aCharchar, F., J.1 aChaturvedi, N.1 aCho, Shin1 aClarke, R.1 aCollins, F., S.1 aCollins, R.1 aConnell, J., M.1 aCooper, J., A.1 aCooper, M., N.1 aCooper, R., S.1 aCorsi, A., M.1 aD?rr, M.1 aDahgam, S.1 aDanesh, J.1 aSmith, Davey1 aDay, I., N.1 aDeloukas, P.1 aDenniff, M.1 aDominiczak, A., F.1 aDong, Y.1 aDoumatey, A.1 aElliott, P.1 aElosua, R.1 aErdmann, J.1 aEyheramendy, S.1 aFarrall, M.1 aFava, C.1 aForrester, T.1 aFowkes, F., G.1 aFox, E., R.1 aFrayling, T., M.1 aGalan, P.1 aGanesh, S., K.1 aGarcia, M.1 aGaunt, T., R.1 aGlazer, N., L.1 aGo, M., J.1 aGoel, A.1 aGr?ssler, J.1 aGrobbee, D., E.1 aGroop, L.1 aGuarrera, S.1 aGuo, X.1 aHadley, D.1 aHamsten, A.1 aHan, B., G.1 aHardy, R.1 aHartikainen, A., L.1 aHeath, S.1 aHeckbert, S., R.1 aHedblad, B.1 aHercberg, S.1 aHernandez, D.1 aHicks, A., A.1 aHilton, G.1 aHingorani, A., D.1 aBolton, J., A.1 aHopewell, J., C.1 aHoward, P.1 aHumphries, S., E.1 aHunt, S., C.1 aHveem, K.1 aIkram, M., A.1 aIslam, M.1 aIwai, N.1 aJarvelin, M., R.1 aJackson, A., U.1 aJafar, T., H.1 aJanipalli, C., S.1 aJohnson, T.1 aKathiresan, S.1 aKhaw, K., T.1 aKim, H., L.1 aKinra, S.1 aKita, Y.1 aKivimaki, M.1 aKooner, J., S.1 aKumar, M., J.1 aKuh, D.1 aKulkarni, S., R.1 aKumari, M.1 aKuusisto, J.1 aKuznetsova, T.1 aLaakso, M.1 aLaan, M.1 aLaitinen, J.1 aLakatta, E., G.1 aLangefeld, C., D.1 aLarson, M., G.1 aLathrop, M.1 aLawlor, D., A.1 aLawrence, R., W.1 aLee, J., Y.1 aLee, N., R.1 aLevy, D.1 aLi, Y.1 aLongstreth, W., T.1 aLuan, J.1 aLucas, G.1 aLudwig, B.1 aMangino, M.1 aMani, K., R.1 aMarmot, M., G.1 aMattace-Raso, F., U.1 aMatullo, G.1 aMcArdle, W., L.1 aMcKenzie, C., A.1 aMeitinger, T.1 aMelander, O.1 aMeneton, P.1 aMeschia, J., F.1 aMiki, T.1 aMilaneschi, Y.1 aMohlke, K., L.1 aMooser, V.1 aMorken, M., A.1 aMorris, R., W.1 aMosley, T., H.1 aNajjar, S.1 aNarisu, N.1 aNewton-Cheh, C.1 aNguyen, K., D.1 aNilsson, P.1 aNyberg, F.1 aO'Donnell, C., J.1 aOgihara, T.1 aOhkubo, T.1 aOkamura, T.1 aOng, R., T.1 aOngen, H.1 aOnland-Moret, N., C.1 aO'Reilly, P., F.1 aOrg, E.1 aOrru, M.1 aPalmas, W.1 aPalmen, J.1 aPalmer, L., J.1 aPalmer, N., D.1 aParker, A., N.1 aPeden, J., F.1 aPeltonen, L.1 aPerola, M.1 aPihur, V.1 aPlatou, C., G.1 aPlump, A.1 aPrabhakaran, D.1 aPsaty, B., M.1 aRaffel, L., J.1 aRao, D., C.1 aRasheed, A.1 aRicceri, F.1 aRice, K., M.1 aRosengren, A.1 aRotter, J., I.1 aRudock, M., E.1 aS?ber, S.1 aSalako, T.1 aSaleheen, D.1 aSalomaa, V.1 aSamani, N., J.1 aSchwartz, S., M.1 aSchwarz, P., E.1 aScott, L., J.1 aScott, J.1 aScuteri, A.1 aSehmi, J., S.1 aSeielstad, M.1 aSeshadri, S.1 aSharma, P.1 aShaw-Hawkins, S.1 aShi, G.1 aShrine, N., R.1 aSijbrands, E., J.1 aSim, X.1 aSingleton, A.1 aSj?gren, M.1 aSmith, N., L.1 aArtigas, Soler1 aSpector, T., D.1 aStaessen, J., A.1 aStancakova, A.1 aSteinle, N., I.1 aStrachan, D., P.1 aStringham, H., M.1 aSun, Y., V.1 aSwift, A., J.1 aTabara, Y.1 aTai, E., S.1 aTalmud, P., J.1 aTaylor, A.1 aTerzic, J.1 aThelle, D., S.1 aTobin, M., D.1 aTomaszewski, M.1 aTripathy, V.1 aTuomilehto, J.1 aTzoulaki, I.1 aUda, M.1 aUeshima, H.1 aUiterwaal, C., S.1 aUmemura, S.1 avan der Harst, P.1 avan der Schouw, Y., T.1 avan Gilst, W., H.1 aVartiainen, E.1 aVasan, R., S.1 aVeldre, G.1 aVerwoert, G., C.1 aViigimaa, M.1 aVinay, D., G.1 aVineis, P.1 aVoight, B., F.1 aVollenweider, P.1 aWagenknecht, L., E.1 aWain, L., V.1 aWang, X.1 aWang, T., J.1 aWareham, N., J.1 aWatkins, H.1 aWeder, A., B.1 aWhincup, P., H.1 aWiggins, K., L.1 aWitteman, J., C.1 aWong, A.1 aWu, Y.1 aYajnik, C., S.1 aYao, J.1 aYoung, J., H.1 aZelenika, D.1 aZhai, G.1 aZhang, W.1 aZhang, F.1 aZhao, J., H.1 aZhu, H.1 aZhu, X.1 aZitting, P.1 aZukowska-Szczechowska, E.1 aOkada, Y.1 aWu, J., Y.1 aGu, D.1 aTakeuchi, F.1 aTakahashi, A.1 aMaeda, S.1 aTsunoda, T.1 aChen, P.1 aLim, S., C.1 aWong, T., Y.1 aLiu, J.1 aYoung, T., L.1 aAung, T.1 aTeo, Y., Y.1 aKim, Y., J.1 aKang, D.1 aChen, C., H.1 aTsai, F., J.1 aChang, L., C.1 aFann, S., J.1 aMei, H.1 aHixson, J., E.1 aChen, S.1 aKatsuya, T.1 aIsono, M.1 aAlbrecht, E.1 aYamamoto, K.1 aKubo, M.1 aNakamura, Y.1 aKamatani, N.1 aKato, N.1 aHe, J.1 aChen, Y., T.1 aTanaka, T.1 aReilly, M., P.1 aSchunkert, H.1 aAssimes, T., L.1 aHall, A.1 aHengstenberg, C.1 aK?nig, I., R.1 aLaaksonen, R.1 aMcPherson, R.1 aThompson, J., R.1 aThorsteinsdottir, U.1 aZiegler, A.1 aAbsher, D.1 aChen, L.1 aCupples, L., A.1 aHalperin, E.1 aLi, M.1 aMusunuru, K.1 aPreuss, M.1 aSchillert, A.1 aThorleifsson, G.1 aWells, G., A.1 aHolm, H.1 aRoberts, R.1 aStewart, A., F.1 aFortmann, S.1 aGo, A.1 aHlatky, M.1 aIribarren, C.1 aKnowles, J.1 aMyers, R.1 aQuertermous, T.1 aSidney, S.1 aRisch, N.1 aTang, H.1 aBlankenberg, S.1 aSchnabel, R.1 aSinning, C.1 aLackner, K., J.1 aTiret, L.1 aNicaud, V.1 aCambien, F.1 aBickel, C.1 aRupprecht, H., J.1 aPerret, C.1 aProust, C.1 aM?nzel, T., F.1 aBarbalic, M.1 aChen, I., Y.1 aDemissie-Banjaw, S.1 aFolsom, A.1 aLumley, T.1 aMarciante, K.1 aTaylor, K., D.1 aVolcik, K.1 aGretarsdottir, S.1 aGulcher, J., R.1 aKong, A.1 aStefansson, K.1 aThorgeirsson, G.1 aAndersen, K.1 aFischer, M.1 aGrosshennig, A.1 aLinsel-Nitschke, P.1 aStark, K.1 aSchreiber, S.1 aAherrahrou, Z.1 aBruse, P.1 aDoering, A.1 aKlopp, N.1 aDiemert, P.1 aLoley, C.1 aMedack, A.1 aNahrstedt, J.1 aPeters, A.1 aWagner, A., K.1 aWillenborg, C.1 aB?hm, B., O.1 aDobnig, H.1 aGrammer, T., B.1 aHoffmann, M., M.1 aMeinitzer, A.1 aWinkelmann, B., R.1 aPilz, S.1 aRenner, W.1 aScharnagl, H.1 aStojakovic, T.1 aTomaschitz, A.1 aWinkler, K.1 aGuiducci, C.1 aBurtt, N.1 aGabriel, S., B.1 aDandona, S.1 aJarinova, O.1 aQu, L.1 aWilensky, R.1 aMatthai, W.1 aHakonarson, H., H.1 aDevaney, J.1 aBurnett, M., S.1 aPichard, A., D.1 aKent, K., M.1 aSatler, L.1 aLindsay, J., M.1 aWaksman, R.1 aKnouff, C., W.1 aWaterworth, D., M.1 aWalker, M., C.1 aEpstein, S., E.1 aRader, D., J.1 aNelson, C., P.1 aWright, B., J.1 aBalmforth, A., J.1 aBall, S., G.1 aLoehr, L., R.1 aRosamond, W., D.1 aBenjamin, E.1 aHaritunians, T.1 aCouper, D.1 aMurabito, J.1 aWang, Y., A.1 aStricker, B., H.1 aChang, P., P.1 aWillerson, J., T.1 aFelix, S., B.1 aWatzinger, N.1 aAragam, J.1 aZweiker, R.1 aLind, L.1 aRodeheffer, R., J.1 aGreiser, K., H.1 aDeckers, J., W.1 aStritzke, J.1 aIngelsson, E.1 aKullo, I.1 aHaerting, J.1 aReffelmann, T.1 aRedfield, M., M.1 aWerdan, K.1 aMitchell, G., F.1 aArnett, D., K.1 aGottdiener, J., S.1 aBlettner, M.1 aFriedrich, N. uhttps://chs-nhlbi.org/node/856903570nas a2200349 4500008004100000022001400041245011100055210006900166260001500235300001100250490000600261520253900267100002202806700001602828700002302844700001902867700002302886700002202909700001702931700002002948700002202968700002202990700002003012700002503032700001903057700002903076700002203105700002003127700001403147700002303161856003603184 2016 eng d a2380-659100aGenetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.0 aGenetic Investigation Into the Differential Risk of Atrial Fibri c2016 Jul 1 a442-500 v13 aIMPORTANCE: White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors.
OBJECTIVES: To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon.
DESIGN, SETTING, AND PARTICIPANTS: Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015.
MAIN OUTCOMES AND MEASURES: Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data.
RESULTS: A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4%; 95% CI, 2.9%-29.9%) and ARIC (31.7%; 95% CI, 16.0%-53.0%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified.
CONCLUSIONS AND RELEVANCE: The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.
1 aRoberts, Jason, D1 aHu, Donglei1 aHeckbert, Susan, R1 aAlonso, Alvaro1 aDewland, Thomas, A1 aVittinghoff, Eric1 aLiu, Yongmei1 aPsaty, Bruce, M1 aOlgin, Jeffrey, E1 aMagnani, Jared, W1 aHuntsman, Scott1 aBurchard, Esteban, G1 aArking, Dan, E1 aBibbins-Domingo, Kirsten1 aHarris, Tamara, B1 aPerez, Marco, V1 aZiv, Elad1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/716503756nas a2200697 4500008004100000022001400041245007000055210006900125260001600194520179700210100003002007700002202037700002202059700002302081700002502104700001902129700001802148700001802166700001902184700002302203700002202226700002102248700002202269700001702291700002102308700002202329700001802351700001802369700002002387700001802407700001902425700002002444700001702464700001802481700001902499700002102518700002002539700001702559700002102576700002702597700001602624700002202640700002002662700002202682700002202704700001902726700002402745700002002769700002402789700002202813700001902835700002402854700002002878700001802898700001802916700002502934700002102959700002002980700002203000856003603022 2016 eng d a1533-345000aGenetic Variants Associated with Circulating Parathyroid Hormone.0 aGenetic Variants Associated with Circulating Parathyroid Hormone c2016 Dec 073 aParathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10(-53)), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10(-17)), rs219779 adjacent to CLDN14 (P=3.5 × 10(-16)), rs4443100 near RTDR1 (P=8.7 × 10(-9)), and rs73186030 near CASR (P=4.8 × 10(-8)). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
1 aRobinson-Cohen, Cassianne1 aLutsey, Pamela, L1 aKleber, Marcus, E1 aNielson, Carrie, M1 aMitchell, Braxton, D1 aBis, Joshua, C1 aEny, Karen, M1 aPortas, Laura1 aEriksson, Joel1 aLorentzon, Mattias1 aKoller, Daniel, L1 aMilaneschi, Yuri1 aTeumer, Alexander1 aPilz, Stefan1 aNethander, Maria1 aSelvin, Elizabeth1 aTang, Weihong1 aWeng, Lu-Chen1 aWong, Hoi, Suen1 aLai, Dongbing1 aPeacock, Munro1 aHannemann, Anke1 aVölker, Uwe1 aHomuth, Georg1 aNauk, Matthias1 aMurgia, Federico1 aPattee, Jack, W1 aOrwoll, Eric1 aZmuda, Joseph, M1 aRiancho, Jose, Antonio1 aWolf, Myles1 aWilliams, Frances1 aPenninx, Brenda1 aEcons, Michael, J1 aRyan, Kathleen, A1 aOhlsson, Claes1 aPaterson, Andrew, D1 aPsaty, Bruce, M1 aSiscovick, David, S1 aRotter, Jerome, I1 aPirastu, Mario1 aStreeten, Elizabeth1 aMärz, Winfried1 aFox, Caroline1 aCoresh, Josef1 aWallaschofski, Henri1 aPankow, James, S1 ade Boer, Ian, H1 aKestenbaum, Bryan uhttps://chs-nhlbi.org/node/725404625nas a2201021 4500008004100000022001400041245006600055210006500121260001300186300001200199490000700211520174100218100001601959700002501975700002502000700002802025700001502053700002402068700002202092700001602114700002402130700001802154700002502172700002302197700002602220700001902246700001602265700001802281700001902299700002102318700001802339700002302357700002202380700002302402700002002425700001602445700002102461700002002482700002002502700002402522700001902546700001802565700001702583700002602600700002002626700002002646700002302666700001202689700002402701700002502725700003002750700002402780700002402804700002302828700002802851700002602879700003002905700002502935700002502960700001902985700002403004700001903028700002003047700002403067700002103091700002603112700002103138700001903159700002303178700001903201700002003220700002103240700001903261700002303280700002403303700002303327700002403350700001603374700002203390700002803412700002303440700002103463700002203484700001703506700002103523700002303544856003603567 2016 eng d a1476-543800aGenetic variants in RBFOX3 are associated with sleep latency.0 aGenetic variants in RBFOX3 are associated with sleep latency c2016 Oct a1488-950 v243 aTime to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.
1 aAmin, Najaf1 aAllebrandt, Karla, V1 avan der Spek, Ashley1 aMüller-Myhsok, Bertram1 aHek, Karin1 aTeder-Laving, Maris1 aHayward, Caroline1 aEsko, Tõnu1 avan Mill, Josine, G1 aMbarek, Hamdi1 aWatson, Nathaniel, F1 aMelville, Scott, A1 aDel Greco, Fabiola, M1 aByrne, Enda, M1 aOole, Edwin1 aKolcic, Ivana1 aChen, Ting-Hsu1 aEvans, Daniel, S1 aCoresh, Josef1 aVogelzangs, Nicole1 aKarjalainen, Juha1 aWillemsen, Gonneke1 aGharib, Sina, A1 aZgaga, Lina1 aMihailov, Evelin1 aStone, Katie, L1 aCampbell, Harry1 aBrouwer, Rutger, Ww1 aDemirkan, Ayse1 aIsaacs, Aaron1 aDogas, Zoran1 aMarciante, Kristin, D1 aCampbell, Susan1 aBorovecki, Fran1 aLuik, Annemarie, I1 aLi, Man1 aHottenga, Jouke Jan1 aHuffman, Jennifer, E1 avan den Hout, Mirjam, Cgn1 aCummings, Steven, R1 aAulchenko, Yurii, S1 aGehrman, Philip, R1 aUitterlinden, André, G1 aWichmann, Heinz-Erich1 aMüller-Nurasyid, Martina1 aFehrmann, Rudolf, Sn1 aMontgomery, Grant, W1 aHofman, Albert1 aKao, Wen Hong Linda1 aOostra, Ben, A1 aWright, Alan, F1 aVink, Jacqueline, M1 aWilson, James, F1 aPramstaller, Peter, P1 aHicks, Andrew, A1 aPolasek, Ozren1 aPunjabi, Naresh, M1 aRedline, Susan1 aPsaty, Bruce, M1 aHeath, Andrew, C1 aMerrow, Martha1 aTranah, Gregory, J1 aGottlieb, Daniel, J1 aBoomsma, Dorret, I1 aMartin, Nicholas, G1 aRudan, Igor1 aTiemeier, Henning1 avan IJcken, Wilfred, Fj1 aPenninx, Brenda, W1 aMetspalu, Andres1 aMeitinger, Thomas1 aFranke, Lude1 aRoenneberg, Till1 aDuijn, Cornelia, M uhttps://chs-nhlbi.org/node/716810710nas a2203877 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2016 eng d00a{The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals0 agenetics of blood pressure regulation and its target organs from c10 a1171–11840 v483 aTo dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.1 aEhret, G., B.1 aFerreira, T.1 aChasman, D., I.1 aJackson, A., U.1 aSchmidt, E., M.1 aJohnson, T.1 aThorleifsson, G.1 aLuan, J.1 aDonnelly, L., A.1 aKanoni, S.1 aPetersen, A., K.1 aPihur, V.1 aStrawbridge, R., J.1 aShungin, D.1 aHughes, M., F.1 aMeirelles, O.1 aKaakinen, M.1 aBouatia-Naji, N.1 aKristiansson, K.1 aShah, S.1 aKleber, M., E.1 aGuo, X.1 aLyytik?inen, L., P.1 aFava, C.1 aEriksson, N.1 aNolte, I., M.1 aMagnusson, P., K.1 aSalfati, E., L.1 aRallidis, L., S.1 aTheusch, E.1 aSmith, A., J. P.1 aFolkersen, L.1 aWitkowska, K.1 aPers, T., H.1 aJoehanes, R.1 aKim, S., K.1 aLataniotis, L.1 aJansen, R.1 aJohnson, A., D.1 aWarren, H.1 aKim, Y., J.1 aZhao, W.1 aWu, Y.1 aTayo, B., O.1 aBochud, M.1 aAbsher, D.1 aAdair, L., S.1 aAmin, N.1 aArking, D., E.1 aAxelsson, T.1 aBaldassarre, D.1 aBalkau, B.1 aBandinelli, S.1 aBarnes, M., R.1 aBarroso, I.1 aBevan, S.1 aBis, J., C.1 aBjornsdottir, G.1 aBoehnke, M.1 aBoerwinkle, E.1 aBonnycastle, L., L.1 aBoomsma, D., I.1 aBornstein, S., R.1 aBrown, M., J.1 aBurnier, M.1 aCabrera, C., P.1 aChambers, J., C.1 aChang, I., S.1 aCheng, C., Y.1 aChines, P., S.1 aChung, R., H.1 aCollins, F., S.1 aConnell, J., M.1 aD?ring, A.1 aDallongeville, J.1 aDanesh, J.1 ade Faire, U.1 aDelgado, G.1 aDominiczak, A., F.1 aDoney, A., S. F.1 aDrenos, F.1 aEdkins, S.1 aEicher, J., D.1 aElosua, R.1 aEnroth, S.1 aErdmann, J.1 aEriksson, P.1 aEsko, T.1 aEvangelou, E.1 aEvans, A.1 aFall, T.1 aFarrall, M.1 aFelix, J., F.1 aFerri?res, J.1 aFerrucci, L.1 aFornage, M.1 aForrester, T.1 aFranceschini, N.1 aDuran, O., H. F.1 aFranco-Cereceda, A.1 aFraser, R., M.1 aGanesh, S., K.1 aGao, H.1 aGertow, K.1 aGianfagna, F.1 aGigante, B.1 aGiulianini, F.1 aGoel, A.1 aGoodall, A., H.1 aGoodarzi, M., O.1 aGorski, M.1 aGr??ler, J.1 aGroves, C.1 aGudnason, V.1 aGyllensten, U.1 aHallmans, G.1 aHartikainen, A., L.1 aHassinen, M.1 aHavulinna, A., S.1 aHayward, C.1 aHercberg, S.1 aHerzig, K., H.1 aHicks, A., A.1 aHingorani, A., D.1 aHirschhorn, J., N.1 aHofman, A.1 aHolmen, J.1 aHolmen, O., L.1 aHottenga, J., J.1 aHoward, P.1 aHsiung, C., A.1 aHunt, S., C.1 aIkram, M., A.1 aIllig, T.1 aIribarren, C.1 aJensen, R., A.1 aK?h?nen, M.1 aKang, H.1 aKathiresan, S.1 aKeating, B., J.1 aKhaw, K., T.1 aKim, Y., K.1 aKim, E.1 aKivimaki, M.1 aKlopp, N.1 aKolovou, G.1 aKomulainen, P.1 aKooner, J., S.1 aKosova, G.1 aKrauss, R., M.1 aKuh, D.1 aKutalik, Z.1 aKuusisto, J.1 aKval?y, K.1 aLakka, T., A.1 aLee, N., R.1 aLee, I., T.1 aLee, W., J.1 aLevy, D.1 aLi, X.1 aLiang, K., W.1 aLin, H.1 aLin, L.1 aLindstr?m, J.1 aLobbens, S.1 aM?nnist?, S.1 aM?ller, G.1 aM?ller-Nurasyid, M.1 aMach, F.1 aMarkus, H., S.1 aMarouli, E.1 aMcCarthy, M., I.1 aMcKenzie, C., A.1 aMeneton, P.1 aMenni, C.1 aMetspalu, A.1 aMijatovic, V.1 aMoilanen, L.1 aMontasser, M., E.1 aMorris, A., D.1 aMorrison, A., C.1 aMulas, A.1 aNagaraja, R.1 aNarisu, N.1 aNikus, K.1 aO'Donnell, C., J.1 aO'Reilly, P., F.1 aOng, K., K.1 aPaccaud, F.1 aPalmer, C., D.1 aParsa, A.1 aPedersen, N., L.1 aPenninx, B., W.1 aPerola, M.1 aPeters, A.1 aPoulter, N.1 aPramstaller, P., P.1 aPsaty, B., M.1 aQuertermous, T.1 aRao, D., C.1 aRasheed, A.1 aRayner, N., W. N. W. R1 aRenstr?m, F.1 aRettig, R.1 aRice, K., M.1 aRoberts, R.1 aRose, L., M.1 aRossouw, J.1 aSamani, N., J.1 aSanna, S.1 aSaramies, J.1 aSchunkert, H.1 aSebert, S.1 aSheu, W., H.1 aShin, Y., A.1 aSim, X.1 aSmit, J., H.1 aSmith, A., V.1 aSosa, M., X.1 aSpector, T., D.1 aStan??kov?, A.1 aStanton, A.1 aStirrups, K., E.1 aStringham, H., M.1 aSundstrom, J.1 aSwift, A., J.1 aSyv?nen, A., C.1 aTai, E., S.1 aTanaka, T.1 aTarasov, K., V.1 aTeumer, A.1 aThorsteinsdottir, U.1 aTobin, M., D.1 aTremoli, E.1 aUitterlinden, A., G.1 aUusitupa, M.1 aVaez, A.1 aVaidya, D.1 avan Duijn, C., M.1 avan Iperen, E., P. A.1 aVasan, R., S.1 aVerwoert, G., C.1 aVirtamo, J.1 aVitart, V.1 aVoight, B., F.1 aVollenweider, P.1 aWagner, A.1 aWain, L., V.1 aWareham, N., J.1 aWatkins, H.1 aWeder, A., B.1 aWestra, H., J.1 aWilks, R.1 aWilsgaard, T.1 aWilson, J., F.1 aWong, T., Y.1 aYang, T., P.1 aYao, J.1 aYengo, L.1 aZhang, W.1 aZhao, J., H.1 aZhu, X.1 aBovet, P.1 aCooper, R., S.1 aMohlke, K., L.1 aSaleheen, D.1 aLee, J., Y.1 aElliott, P.1 aGierman, H., J.1 aWiller, C., J.1 aFranke, L.1 aHovingh, G., K.1 aTaylor, K., D.1 aDedoussis, G.1 aSever, P.1 aWong, A.1 aLind, L.1 aAssimes, T., L.1 aNj?lstad, I.1 aSchwarz, P., E.1 aLangenberg, C.1 aSnieder, H.1 aCaulfield, M., J.1 aMelander, O.1 aLaakso, M.1 aSaltevo, J.1 aRauramaa, R.1 aTuomilehto, J.1 aIngelsson, E.1 aLehtim?ki, T.1 aHveem, K.1 aPalmas, W.1 aM?rz, W.1 aKumari, M.1 aSalomaa, V.1 aChen, Y., I.1 aRotter, J., I.1 aFroguel, P.1 aJarvelin, M., R.1 aLakatta, E., G.1 aKuulasmaa, K.1 aFranks, P., W.1 aHamsten, A.1 aWichmann, H., E.1 aPalmer, C., N. A.1 aStefansson, K.1 aRidker, P., M.1 aLoos, R., J. F.1 aChakravarti, A.1 aDeloukas, P.1 aMorris, A., P.1 aNewton-Cheh, C.1 aMunroe, P., B. uhttps://chs-nhlbi.org/node/856204818nas a2201141 4500008004100000022001400041245011000055210006900165260001300234300001100247490000700258520157500265653001001840653003901850653001701889653000901906653003701915653001901952653003201971653002402003653002002027653004002047653001102087653003802098653003402136653001102170653000902181653001602190653001502206653003602221653002602257653001102283100002002294700002002314700002302334700001902357700002102376700002202397700002702419700001802446700001602464700002302480700001802503700002602521700001702547700001802564700001402582700002102596700002702617700002302644700001802667700001702685700001902702700002002721700002302741700002402764700002302788700001702811700001702828700002302845700001902868700002202887700001902909700002402928700001602952700001502968700002002983700002103003700002103024700002103045700001903066700002003085700002203105700002303127700002403150700003003174700002203204700002603226700002003252700002503272700002003297700002003317700002203337700002003359700001903379700002203398700002003420700002203440700002103462700002803483700002003511700002303531700001703554700002103571700002503592710002303617856003603640 2016 eng d a1524-462800aGenome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.0 aGenomeWide Association Analysis of YoungOnset Stroke Identifies c2016 Feb a307-160 v473 aBACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.
METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.
RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.
CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
10aAdult10aAfrican Continental Ancestry Group10aAge of Onset10aAged10aAsian Continental Ancestry Group10aBrain Ischemia10aChromosomes, Human, Pair 1010aComputer Simulation10aDNA, Intergenic10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aOdds Ratio10aPolymorphism, Single Nucleotide10aSerine Endopeptidases10aStroke1 aCheng, Yu-Ching1 aStanne, Tara, M1 aGiese, Anne-Katrin1 aHo, Weang, Kee1 aTraylor, Matthew1 aAmouyel, Philippe1 aHolliday, Elizabeth, G1 aMalik, Rainer1 aXu, Huichun1 aKittner, Steven, J1 aCole, John, W1 aO'Connell, Jeffrey, R1 aDanesh, John1 aRasheed, Asif1 aZhao, Wei1 aEngelter, Stefan1 aGrond-Ginsbach, Caspar1 aKamatani, Yoichiro1 aLathrop, Mark1 aLeys, Didier1 aThijs, Vincent1 aMetso, Tiina, M1 aTatlisumak, Turgut1 aPezzini, Alessandro1 aParati, Eugenio, A1 aNorrving, Bo1 aBevan, Steve1 aRothwell, Peter, M1 aSudlow, Cathie1 aSlowik, Agnieszka1 aLindgren, Arne1 aWalters, Matthew, R1 aJannes, Jim1 aShen, Jess1 aCrosslin, David1 aDoheny, Kimberly1 aLaurie, Cathy, C1 aKanse, Sandip, M1 aBis, Joshua, C1 aFornage, Myriam1 aMosley, Thomas, H1 aHopewell, Jemma, C1 aStrauch, Konstantin1 aMüller-Nurasyid, Martina1 aGieger, Christian1 aWaldenberger, Melanie1 aPeters, Annette1 aMeisinger, Christine1 aIkram, Arfan, M1 aLongstreth, W T1 aMeschia, James, F1 aSeshadri, Sudha1 aSharma, Pankaj1 aWorrall, Bradford1 aJern, Christina1 aLevi, Christopher1 aDichgans, Martin1 aBoncoraglio, Giorgio, B1 aMarkus, Hugh, S1 aDebette, Stephanie1 aRolfs, Arndt1 aSaleheen, Danish1 aMitchell, Braxton, D1 aWTCCC-2 Consortium uhttps://chs-nhlbi.org/node/699105079nas a2201093 4500008004100000022001400041245015000055210006900205260000900274300001300283490000700296520193900303653000902242653001902251653002502270653002802295653001102323653003802334653003402372653001102406653000902417653001602426653002602442653003602468653002402504100001902528700001902547700002202566700002602588700002402614700002502638700002002663700002302683700001902706700001702725700002402742700002002766700002202786700002102808700002802829700002302857700001402880700001802894700002002912700002802932700002402960700002702984700002303011700001903034700001903053700002303072700002203095700002403117700002303141700002003164700002403184700002303208700001803231700002403249700002103273700002403294700002003318700001603338700001503354700002203369700001903391700002003410700001903430700001703449700002203466700001903488700002603507700001903533700002003552700001803572700002403590700001703614700002003631700002603651700002203677700001703699700001703716700001803733700001903751700001903770700002003789700002403809700002103833700002403854700002003878700002103898700003003919856003603949 2016 eng d a1932-620300aGenome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.0 aGenomeWide Association Study for Incident Myocardial Infarction c2016 ae01449970 v113 aBACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).
CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
10aAged10aCohort Studies10aCooperative Behavior10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies1 aDehghan, Abbas1 aBis, Joshua, C1 aWhite, Charles, C1 aSmith, Albert, Vernon1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aTrompet, Stella1 aChasman, Daniel, I1 aLumley, Thomas1 aVölker, Uwe1 aBuckley, Brendan, M1 aDing, Jingzhong1 aJensen, Majken, K1 aFolsom, Aaron, R1 aKritchevsky, Stephen, B1 aGirman, Cynthia, J1 aFord, Ian1 aDörr, Marcus1 aSalomaa, Veikko1 aUitterlinden, André, G1 aEiriksdottir, Gudny1 aVasan, Ramachandran, S1 aFranceschini, Nora1 aCarty, Cara, L1 aVirtamo, Jarmo1 aDemissie, Serkalem1 aAmouyel, Philippe1 aArveiler, Dominique1 aHeckbert, Susan, R1 aFerrieres, Jean1 aDucimetiere, Pierre1 aSmith, Nicholas, L1 aWang, Ying, A1 aSiscovick, David, S1 aRice, Kenneth, M1 aWiklund, Per-Gunnar1 aTaylor, Kent, D1 aEvans, Alun1 aKee, Frank1 aRotter, Jerome, I1 aKarvanen, Juha1 aKuulasmaa, Kari1 aHeiss, Gerardo1 aKraft, Peter1 aLauner, Lenore, J1 aHofman, Albert1 aMarkus, Marcello, R P1 aRose, Lynda, M1 aSilander, Kaisa1 aWagner, Peter1 aBenjamin, Emelia, J1 aLohman, Kurt1 aStott, David, J1 aRivadeneira, Fernando1 aHarris, Tamara, B1 aLevy, Daniel1 aLiu, Yongmei1 aRimm, Eric, B1 aJukema, Wouter1 aVölzke, Henry1 aRidker, Paul, M1 aBlankenberg, Stefan1 aFranco, Oscar, H1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/700403563nas a2200409 4500008004100000022001400041245010500055210006900160260001300229300001200242490000600254520239300260100002002653700002102673700002802694700002102722700001702743700001202760700001702772700002302789700002402812700001602836700002402852700001702876700002202893700002302915700002202938700002102960700001602981700002502997700001703022700002003039700001903059700002003078700001903098856003603117 2016 eng d a2352-187200aA genome-wide association study meta-analysis of clinical fracture in 10,012 African American women.0 agenomewide association study metaanalysis of clinical fracture i c2016 Dec a233-2420 v53 aBACKGROUND: Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50-70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis.
METHODS: Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10- 8.
RESULTS: One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10- 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed.
CONCLUSION: This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.
1 aTaylor, Kira, C1 aEvans, Daniel, S1 aEdwards, Digna, R Velez1 aEdwards, Todd, L1 aSofer, Tamar1 aLi, Guo1 aLiu, Youfang1 aFranceschini, Nora1 aJackson, Rebecca, D1 aGiri, Ayush1 aDonneyong, Macarius1 aPsaty, Bruce1 aRotter, Jerome, I1 aLaCroix, Andrea, Z1 aJordan, Joanne, M1 aRobbins, John, A1 aLewis, Beth1 aStefanick, Marcia, L1 aLiu, Yongmei1 aGarcia, Melissa1 aHarris, Tamara1 aCauley, Jane, A1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/759304555nas a2201081 4500008004100000022001400041245014800055210006900203260001300272300001200285490000700297520142500304100002501729700002301754700001701777700002501794700001401819700001801833700001901851700002301870700001401893700002201907700001801929700001801947700002101965700002201986700002202008700002602030700002102056700001902077700001802096700002102114700002202135700002202157700002002179700001802199700002502217700002302242700001602265700002302281700003602304700001902340700002202359700003002381700002102411700003502432700002202467700002002489700002502509700001702534700001502551700002202566700002102588700002202609700003602631700002602667700002202693700002402715700002102739700002102760700002602781700001502807700002302822700001902845700002602864700002202890700001902912700001702931700002402948700002102972700002502993700002203018700002503040700002003065700001603085700002303101700002103124700002403145700002403169700002103193700002303214700002003237700001803257700002203275700002003297700002203317700001903339700002003358700001903378700002003397700002003417856003603437 2016 eng d a1939-327X00aGenome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci.0 aGenomeWide Association Study of the Modified Stumvoll Insulin Se c2016 Oct a3200-110 v653 aGenome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
1 aWalford, Geoffrey, A1 aGustafsson, Stefan1 aRybin, Denis1 aStančáková, Alena1 aChen, Han1 aLiu, Ching-Ti1 aHong, Jaeyoung1 aJensen, Richard, A1 aRice, Ken1 aMorris, Andrew, P1 aMägi, Reedik1 aTönjes, Anke1 aProkopenko, Inga1 aKleber, Marcus, E1 aDelgado, Graciela1 aSilbernagel, Günther1 aJackson, Anne, U1 aAppel, Emil, V1 aGrarup, Niels1 aLewis, Joshua, P1 aMontasser, May, E1 aLandenvall, Claes1 aStaiger, Harald1 aLuan, Jian'an1 aFrayling, Timothy, M1 aWeedon, Michael, N1 aXie, Weijia1 aMorcillo, Sonsoles1 aMartínez-Larrad, María Teresa1 aBiggs, Mary, L1 aChen, Yii-Der Ida1 aCorbaton-Anchuelo, Arturo1 aFærch, Kristine1 aGómez-Zumaquero, Juan, Miguel1 aGoodarzi, Mark, O1 aKizer, Jorge, R1 aKoistinen, Heikki, A1 aLeong, Aaron1 aLind, Lars1 aLindgren, Cecilia1 aMachicao, Fausto1 aManning, Alisa, K1 aMartín-Núñez, Gracia, María1 aRojo-Martínez, Gemma1 aRotter, Jerome, I1 aSiscovick, David, S1 aZmuda, Joseph, M1 aZhang, Zhongyang1 aSerrano-Ríos, Manuel1 aSmith, Ulf1 aSoriguer, Federico1 aHansen, Torben1 aJørgensen, Torben, J1 aLinnenberg, Allan1 aPedersen, Oluf1 aWalker, Mark1 aLangenberg, Claudia1 aScott, Robert, A1 aWareham, Nicholas, J1 aFritsche, Andreas1 aHäring, Hans-Ulrich1 aStefan, Norbert1 aGroop, Leif1 aO'Connell, Jeff, R1 aBoehnke, Michael1 aBergman, Richard, N1 aCollins, Francis, S1 aMohlke, Karen, L1 aTuomilehto, Jaakko1 aMärz, Winfried1 aKovacs, Peter1 aStumvoll, Michael1 aPsaty, Bruce, M1 aKuusisto, Johanna1 aLaakso, Markku1 aMeigs, James, B1 aDupuis, Josée1 aIngelsson, Erik1 aFlorez, Jose, C uhttps://chs-nhlbi.org/node/716705092nas a2201189 4500008004100000022001400041245012100055210006900176260001300245300001100258490000700269520174700276100002202023700001402045700002102059700002002080700002502100700002002125700002102145700002502166700001702191700001802208700002202226700002102248700002002269700001702289700002202306700002002328700003502348700001902383700002002402700002002422700002102442700002202463700001802485700001702503700001702520700002202537700002102559700001902580700003602599700001402635700002102649700002202670700001802692700002102710700002702731700002302758700001902781700001902800700001702819700002102836700002802857700001802885700001702903700001302920700002102933700001702954700002002971700002302991700001803014700002103032700001803053700001703071700002003088700002003108700002003128700002303148700002603171700002103197700002003218700002003238700001803258700002203276700002403298700002303322700002003345700002003365700002003385700002503405700002203430700001603452700001203468700001803480700002003498700002003518700001803538700001803556700001603574700002303590700002203613700002403635700002703659700001703686700002103703700001903724700002503743700002203768710003503790710004103825856003603866 2016 eng d a1474-972600aGenomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.0 aGenomewide metaanalysis identifies loci associated with IGFI and c2016 Oct a811-240 v153 aThe growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.
1 aTeumer, Alexander1 aQi, Qibin1 aNethander, Maria1 aAschard, Hugues1 aBandinelli, Stefania1 aBeekman, Marian1 aBerndt, Sonja, I1 aBidlingmaier, Martin1 aBroer, Linda1 aCappola, Anne1 aCeda, Gian, Paolo1 aChanock, Stephen1 aChen, Ming-Huei1 aChen, Tai, C1 aChen, Yii-Der Ida1 aChung, Jonathan1 aMiglianico, Fabiola, Del Greco1 aEriksson, Joel1 aFerrucci, Luigi1 aFriedrich, Nele1 aGnewuch, Carsten1 aGoodarzi, Mark, O1 aGrarup, Niels1 aGuo, Tingwei1 aHammer, Elke1 aHayes, Richard, B1 aHicks, Andrew, A1 aHofman, Albert1 aHouwing-Duistermaat, Jeanine, J1 aHu, Frank1 aHunter, David, J1 aHusemoen, Lise, L1 aIsaacs, Aaron1 aJacobs, Kevin, B1 aJanssen, Joop, A M J L1 aJansson, John-Olov1 aJehmlich, Nico1 aJohnson, Simon1 aJuul, Anders1 aKarlsson, Magnus1 aKilpeläinen, Tuomas, O1 aKovacs, Peter1 aKraft, Peter1 aLi, Chao1 aLinneberg, Allan1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLorentzon, Mattias1 aLu, Yingchang1 aMaggio, Marcello1 aMägi, Reedik1 aMeigs, James1 aMellström, Dan1 aNauck, Matthias1 aNewman, Anne, B1 aPollak, Michael, N1 aPramstaller, Peter, P1 aProkopenko, Inga1 aPsaty, Bruce, M1 aReincke, Martin1 aRimm, Eric, B1 aRotter, Jerome, I1 aPierre, Aude, Saint1 aSchurmann, Claudia1 aSeshadri, Sudha1 aSjögren, Klara1 aSlagboom, Eline1 aStrickler, Howard, D1 aStumvoll, Michael1 aSuh, Yousin1 aSun, Qi1 aZhang, Cuilin1 aSvensson, Johan1 aTanaka, Toshiko1 aTare, Archana1 aTönjes, Anke1 aUh, Hae-Won1 aDuijn, Cornelia, M1 avan Heemst, Diana1 aVandenput, Liesbeth1 aVasan, Ramachandran, S1 aVölker, Uwe1 aWillems, Sara, M1 aOhlsson, Claes1 aWallaschofski, Henri1 aKaplan, Robert, C1 aCHARGE Longevity Working Group1 aBody Composition Genetics Consortium uhttps://chs-nhlbi.org/node/714703005nas a2200325 4500008004100000022001400041245019900055210006900254260001500323300001200338490000800350520192200358100002202280700002402302700002402326700001902350700002002369700001902389700002602408700002202434700002702456700002202483700002402505700001902529700002202548700002202570700002302592700002802615856003602643 2016 eng d a1524-453900aGlobal Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies.0 aGlobal Electric Heterogeneity Risk Score for Prediction of Sudde c2016 Jun 7 a2222-340 v1333 aBACKGROUND: Asymptomatic individuals account for the majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and noninvasive SCD risk stratification tools is necessary.
METHODS AND RESULTS: Participants from the Atherosclerosis Risk in Communities study and Cardiovascular Health Study (n=20 177; age, 59.3±10.1 years; age range, 44-100 years; 56% female; 77% white) were followed up for 14.0 years (median). Five ECG markers of global electric heterogeneity (GEH; sum absolute QRST integral, spatial QRST angle, spatial ventricular gradient [SVG] magnitude, SVG elevation, and SVG azimuth) were measured on standard 12-lead ECGs. Cox proportional hazards and competing risks models evaluated associations between GEH electrocardiographic parameters and SCD. An SCD competing risks score was derived from demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1000 person-years. After multivariable adjustment, baseline GEH parameters and large increases in GEH parameters over time were independently associated with SCD. Final SCD risk scores included age, sex, race, diabetes mellitus, hypertension, coronary heart disease, stroke, and GEH parameters as continuous variables. When GEH parameters were added to clinical/demographic factors, the C statistic increased from 0.777 to 0.790 (P=0.008), the risk score classified 10-year SCD risk as high (>5%) in 7.2% of participants, 10% of SCD victims were appropriately reclassified into a high-risk category, and only 1.4% of SCD victims were inappropriately reclassified from high to intermediate risk. The net reclassification index was 18.3%.
CONCLUSIONS: Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. The addition of GEH parameters to clinical characteristics improves SCD risk prediction.
1 aWaks, Jonathan, W1 aSitlani, Colleen, M1 aSoliman, Elsayed, Z1 aKabir, Muammar1 aGhafoori, Elyar1 aBiggs, Mary, L1 aHenrikson, Charles, A1 aSotoodehnia, Nona1 aBiering-Sørensen, Tor1 aAgarwal, Sunil, K1 aSiscovick, David, S1 aPost, Wendy, S1 aSolomon, Scott, D1 aBuxton, Alfred, E1 aJosephson, Mark, E1 aTereshchenko, Larisa, G uhttps://chs-nhlbi.org/node/713504458nas a2200937 4500008004100000022001400041245009600055210006900151260001300220300001200233490000700245520181500252100002102067700002002088700001902108700001602127700001802143700002002161700002302181700002102204700002602225700001702251700002102268700002202289700001702311700002402328700002102352700002102373700002302394700002202417700001202439700001902451700002102470700002202491700002402513700002002537700002102557700002302578700002702601700002402628700001902652700001902671700002002690700001902710700002202729700001702751700001702768700002602785700002202811700002802833700001902861700002102880700002302901700002802924700001702952700001902969700001902988700002003007700001403027700002403041700002103065700002203086700002403108700001803132700002003150700002203170700002403192700001903216700002803235700002003263700002003283700002403303700002603327700001803353700002503371700002003396700002303416700002103439700002403460856003603484 2016 eng d a1474-972600aGWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.0 aGWAS analysis of handgrip and lower body strength in older adult c2016 Oct a792-8000 v153 aDecline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
1 aMatteini, Amy, M1 aTanaka, Toshiko1 aKarasik, David1 aAtzmon, Gil1 aChou, Wen-Chi1 aEicher, John, D1 aJohnson, Andrew, D1 aArnold, Alice, M1 aCallisaya, Michele, L1 aDavies, Gail1 aEvans, Daniel, S1 aHoltfreter, Birte1 aLohman, Kurt1 aLunetta, Kathryn, L1 aMangino, Massimo1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTeumer, Alexander1 aYu, Lei1 aArking, Dan, E1 aBuchman, Aron, S1 aChibinik, Lori, B1 aDe Jager, Philip, L1 aEvans, Denis, A1 aFaul, Jessica, D1 aGarcia, Melissa, E1 aGillham-Nasenya, Irina1 aGudnason, Vilmundur1 aHofman, Albert1 aHsu, Yi-Hsiang1 aIttermann, Till1 aLahousse, Lies1 aLiewald, David, C1 aLiu, Yongmei1 aLopez, Lorna1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSiggeirsdottir, Kristin1 aStarr, John, M1 aThomson, Russell1 aTranah, Gregory, J1 aUitterlinden, André, G1 aVölker, Uwe1 aVölzke, Henry1 aWeir, David, R1 aYaffe, Kristine1 aZhao, Wei1 aZhuang, Wei, Vivian1 aZmuda, Joseph, M1 aBennett, David, A1 aCummings, Steven, R1 aDeary, Ian, J1 aFerrucci, Luigi1 aHarris, Tamara, B1 aKardia, Sharon, L R1 aKocher, Thomas1 aKritchevsky, Stephen, B1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aSpector, Timothy, D1 aSrikanth, Velandai, K1 aWindham, Gwen1 aZillikens, Carola, M1 aNewman, Anne, B1 aWalston, Jeremy, D1 aKiel, Douglas, P1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/714205902nas a2201657 4500008004100000022001400041245009300055210006900148260001300217300001100230490000700241520190600248100002602154700001602180700001502196700001402211700001502225700001302240700001402253700001502267700001602282700001202298700001802310700001102328700001402339700001302353700001602366700001502382700001302397700002102410700001602431700001902447700001302466700002002479700001802499700001702517700001602534700001102550700001802561700001502579700001702594700001502611700001602626700001602642700001202658700001602670700001702686700001802703700001602721700001802737700001202755700001602767700001402783700001602797700001502813700001402828700001202842700001602854700001702870700002102887700001002908700002102918700001302939700001302952700001202965700001602977700001302993700001403006700002203020700001903042700001803061700001603079700001303095700001903108700002003127700001403147700001603161700001203177700001403189700001403203700001403217700001603231700001803247700002003265700001703285700001803302700001803320700002003338700001603358700001703374700001503391700001503406700001903421700001403440700002003454700001603474700001003490700002003500700001403520700001403534700001603548700001803564700001403582700001903596700002303615700001803638700001503656700002203671700001503693700001603708700001803724700001703742700001703759700001903776700001703795700001903812700001603831700001803847700001603865700001603881700001303897700001503910700001603925700001603941700001403957700001403971700001503985700001204000700002104012700001504033700001804048700001604066700001604082700001604098700002204114700001604136700001504152700001704167710002404184856003604208 2016 eng d a1476-557800aGWAS for executive function and processing speed suggests involvement of the CADM2 gene.0 aGWAS for executive function and processing speed suggests involv c2016 Feb a189-970 v213 aTo identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
1 aIbrahim-Verbaas, C, A1 aBressler, J1 aDebette, S1 aSchuur, M1 aSmith, A V1 aBis, J C1 aDavies, G1 aTrompet, S1 aSmith, J, A1 aWolf, C1 aChibnik, L, B1 aLiu, Y1 aVitart, V1 aKirin, M1 aPetrovic, K1 aPolasek, O1 aZgaga, L1 aFawns-Ritchie, C1 aHoffmann, P1 aKarjalainen, J1 aLahti, J1 aLlewellyn, D, J1 aSchmidt, C, O1 aMather, K, A1 aChouraki, V1 aSun, Q1 aResnick, S, M1 aRose, L, M1 aOldmeadow, C1 aStewart, M1 aSmith, B, H1 aGudnason, V1 aYang, Q1 aMirza, S, S1 aJukema, J, W1 adeJager, P, L1 aHarris, T B1 aLiewald, D, C1 aAmin, N1 aCoker, L, H1 aStegle, O1 aLopez, O, L1 aSchmidt, R1 aTeumer, A1 aFord, I1 aKarbalai, N1 aBecker, J, T1 aJonsdottir, M, K1 aAu, R1 aFehrmann, R, S N1 aHerms, S1 aNalls, M1 aZhao, W1 aTurner, S T1 aYaffe, K1 aLohman, K1 avan Swieten, J, C1 aKardia, S, L R1 aKnopman, D, S1 aMeeks, W, M1 aHeiss, G1 aHolliday, E, G1 aSchofield, P, W1 aTanaka, T1 aStott, D, J1 aWang, J1 aRidker, P1 aGow, A, J1 aPattie, A1 aStarr, J, M1 aHocking, L, J1 aArmstrong, N, J1 aMcLachlan, S1 aShulman, J, M1 aPilling, L, C1 aEiriksdottir, G1 aScott, R, J1 aKochan, N, A1 aPalotie, A1 aHsieh, Y-C1 aEriksson, J, G1 aPenman, A1 aGottesman, R, F1 aOostra, B A1 aYu, L1 aDeStefano, A, L1 aBeiser, A1 aGarcia, M1 aRotter, J I1 aNöthen, M, M1 aHofman, A1 aSlagboom, P, E1 aWestendorp, R, G J1 aBuckley, B, M1 aWolf, P, A1 aUitterlinden, A G1 aPsaty, B M1 aGrabe, H, J1 aBandinelli, S1 aChasman, D I1 aGrodstein, F1 aRäikkönen, K1 aLambert, J-C1 aPorteous, D, J1 aPrice, J, F1 aSachdev, P, S1 aFerrucci, L1 aAttia, J, R1 aRudan, I1 aHayward, C1 aWright, A F1 aWilson, J F1 aCichon, S1 aFranke, L1 aSchmidt, H1 aDing, J1 ade Craen, A, J M1 aFornage, M1 aBennett, D, A1 aDeary, I, J1 aIkram, M, A1 aLauner, L J1 aFitzpatrick, A, L1 aSeshadri, S1 aDuijn, C M1 aMosley, T, H1 aGeneration Scotland uhttps://chs-nhlbi.org/node/679902724nas a2200265 4500008004100000022001400041245013800055210006900193260001300262300000900275490000800284520189600292100002202188700002302210700002202233700002402255700001902279700001702298700002002315700002202335700001902357700002302376700002302399856003602422 2016 eng d a1097-674400aImpact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.0 aImpact of genetic variants on the upstream efficacy of reninangi c2016 May a9-170 v1753 aBACKGROUND: Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.
METHODS: We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.
RESULTS: Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.
CONCLUSIONS: Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.
1 aRoberts, Jason, D1 aDewland, Thomas, A1 aGlidden, David, V1 aHoffmann, Thomas, J1 aArking, Dan, E1 aChen, Lin, Y1 aPsaty, Bruce, M1 aOlgin, Jeffrey, E1 aAlonso, Alvaro1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/716604416nas a2200793 4500008004100000022001400041245018200055210006900237260001300306300001200319490000700331520209900338100001902437700002302456700002002479700002302499700001802522700002602540700002102566700001902587700002602606700002002632700002102652700002302673700002202696700002002718700001502738700001402753700002602767700002402793700002202817700002702839700002002866700002102886700002002907700002002927700001502947700001802962700002302980700002103003700002103024700001903045700002103064700001803085700001603103700002403119700001703143700002103160700001903181700002003200700002503220700002203245700001903267700002303286700002003309700001903329700001703348700002303365700002603388700002303414700002103437700002203458700002003480700002003500700002403520700001703544710002503561856003603586 2016 eng d a2047-488100aInflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.0 aInflammatory markers and extent and progression of early atheros c2016 Jan a194-2050 v233 aBACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.
METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.
RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015).
CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.
1 aWilleit, Peter1 aThompson, Simon, G1 aAgewall, Stefan1 aBergström, Göran1 aBickel, Horst1 aCatapano, Alberico, L1 aChien, Kuo-Liong1 ade Groot, Eric1 aEmpana, Jean-Philippe1 aEtgen, Thorleif1 aFranco, Oscar, H1 aIglseder, Bernhard1 aJohnsen, Stein, H1 aKavousi, Maryam1 aLind, Lars1 aLiu, Jing1 aMathiesen, Ellisiv, B1 aNorata, Giuseppe, D1 aOlsen, Michael, H1 aPapagianni, Aikaterini1 aPoppert, Holger1 aPrice, Jackie, F1 aSacco, Ralph, L1 aYanez, David, N1 aZhao, Dong1 aSchminke, Ulf1 aBülbül, Alpaslan1 aPolak, Joseph, F1 aSitzer, Matthias1 aHofman, Albert1 aGrigore, Liliana1 aDörr, Marcus1 aSu, Ta-Chen1 aDucimetiere, Pierre1 aXie, Wuxiang1 aRonkainen, Kimmo1 aKiechl, Stefan1 aRundek, Tatjana1 aRobertson, Christine1 aFagerberg, Björn1 aBokemark, Lena1 aSteinmetz, Helmuth1 aIkram, Arfan, M1 aVölzke, Henry1 aLin, Hung-Ju1 aPlichart, Matthieu1 aTuomainen, Tomi-Pekka1 aDesvarieux, Moïse1 aMcLachlan, Stela1 aSchmidt, Caroline1 aKauhanen, Jussi1 aWilleit, Johann1 aLorenz, Matthias, W1 aSander, Dirk1 aPROG-IMT Study Group uhttps://chs-nhlbi.org/node/661202680nas a2200289 4500008004100000022001400041245011600055210006900171260001600240300001500256520179300271100002202064700002202086700002202108700002702130700002102157700002202178700001802200700002002218700001802238700002002256700001802276700002302294700002002317700001702337856003602354 2016 eng d a1945-719700aInsulinlike growth factor binding protein-1 and ghrelin predict health outcomes among older adults: CHS cohort.0 aInsulinlike growth factor binding protein1 and ghrelin predict h c2016 Nov 07 ajc201627793 aCONTEXT: Multiple diseases may explain the association of the growth hormone / insulinlike growth factor-I (GH/IGF-I) axis with longevity.
OBJECTIVE: To relate circulating GH/IGF-I system protein levels with major health events.
DESIGN: Cohort study Setting: Four US communities Participants: Adults (n=2268) 65 years and older free of diabetes and cardiovascular disease.
MEASUREMENTS: We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiologic covariates.
RESULTS: During 13,930 person-years of follow-up, 48.1% individuals sustained one or more components of the composite outcome and 31.8% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-h ghrelin were associated with a 27% higher (95% CI: 6%, 53%) and 39% higher (95% CI: 14%, 71%) risks of the composite outcome, respectively. The highest quartile of 2-h IGFBP-1 was associated with 35% higher (95% CI: 1%, 52%) risk of the composite endpoint. Similarly, higher mortality was significantly associated with higher fasting and 2-h ghrelin level, and with 2-h IGFBP-1 level. When examined together, 2-h post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels.
CONCLUSIONS: Circulating IGFBP-1 and ghrelin measured during an OGTT predict major health events and death in older adults, which may explain the influence of the GH-IGF-axis on lifespan and health.
1 aKaplan, Robert, C1 aStrizich, Garrett1 aAneke-Nash, Chino1 aDominguez-Islas, Clara1 aBůzková, Petra1 aStrickler, Howard1 aRohan, Thomas1 aPollak, Michael1 aKuller, Lewis1 aKizer, Jorge, R1 aCappola, Anne1 aLi, Christopher, I1 aPsaty, Bruce, M1 aNewman, Anne uhttps://chs-nhlbi.org/node/725805111nas a2200877 4500008004100000022001400041245025000055210006900305260001300374300001100387490000800398520248000406653002202886653003902908653002102947653001902968653000902987653002002996653002603016653002403042653001603066653003103082653001103113653001103124653003603135653003003171653001803201100001303219700002003232700002003252700002003272700002403292700001903316700002103335700001403356700001703370700001303387700001903400700002103419700002303440700002003463700002303483700002103506700002003527700002803547700002303575700001503598700002203613700002103635700001303656700002503669700002003694700002503714700001603739700002203755700002603777700002003803700001903823700002503842700002203867700002503889700002103914700002003935700002003955700002503975700001704000700002204017700003004039700002004069700002404089700001804113700002104131700002104152700002404173856003604197 2016 eng d a1938-320700aInteraction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.0 aInteraction of methylationrelated genetic variants with circulat c2016 Feb a567-780 v1033 aBACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.
OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.
DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.
RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).
CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.
10aApolipoproteins E10aATP Binding Cassette Transporter 110aCholesterol, HDL10aCohort Studies10aDiet10aDNA Methylation10aEicosapentaenoic Acid10aEpigenesis, Genetic10aFatty Acids10aGene Expression Regulation10aHumans10aLipids10aPolymorphism, Single Nucleotide10aPromoter Regions, Genetic10aTriglycerides1 aMa, Yiyi1 aFollis, Jack, L1 aSmith, Caren, E1 aTanaka, Toshiko1 aManichaikul, Ani, W1 aChu, Audrey, Y1 aSamieri, Cecilia1 aZhou, Xia1 aGuan, Weihua1 aWang, Lu1 aBiggs, Mary, L1 aChen, Yii-der, I1 aHernandez, Dena, G1 aBorecki, Ingrid1 aChasman, Daniel, I1 aRich, Stephen, S1 aFerrucci, Luigi1 aIrvin, Marguerite, Ryan1 aAslibekyan, Stella1 aZhi, Degui1 aTiwari, Hemant, K1 aClaas, Steven, A1 aSha, Jin1 aKabagambe, Edmond, K1 aLai, Chao-Qiang1 aParnell, Laurence, D1 aLee, Yu-Chi1 aAmouyel, Philippe1 aLambert, Jean-Charles1 aPsaty, Bruce, M1 aKing, Irena, B1 aMozaffarian, Dariush1 aMcKnight, Barbara1 aBandinelli, Stefania1 aTsai, Michael, Y1 aRidker, Paul, M1 aDing, Jingzhong1 aMstat, Kurt, Lohmant1 aLiu, Yongmei1 aSotoodehnia, Nona1 aBarberger-Gateau, Pascale1 aSteffen, Lyn, M1 aSiscovick, David, S1 aAbsher, Devin1 aArnett, Donna, K1 aOrdovas, Jose, M1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/695105543nas a2201657 4500008004100000022001400041245013300055210007000188260001600258300001600274490000800290520094500298100002101243700001601264700001901280700001201299700001901311700001301330700002101343700001601364700001601380700001701396700002601413700001801439700002301457700002601480700002101506700002101527700001901548700002001567700002101587700002101608700001901629700001701648700002401665700001901689700002001708700002101728700002001749700002101769700001701790700001801807700002801825700002101853700002101874700001801895700002101913700002201934700002101956700002401977700002402001700002002025700001802045700002302063700001602086700001702102700001902119700002202138700002302160700001802183700002602201700001902227700002202246700002002268700002802288700002402316700002602340700001802366700002202384700002202406700001902428700001602447700001302463700001802476700001902494700002302513700001902536700002302555700002102578700001702599700001502616700002302631700001602654700002202670700002102692700002202713700002202735700001902757700002402776700002002800700002202820700002802842700002102870700001902891700001902910700001902929700002702948700001902975700001902994700002203013700002103035700001603056700002403072700002203096700001703118700002403135700002103159700002103180700002003201700002003221700001703241700002003258700001703278700001803295700002203313700002203335700002003357700002003377700001703397700002003414700002103434700001503455700002303470700002503493700002403518700002503542700002303567700001803590700002503608700002103633700002503654700001303679700002103692700002603713700002303739700002603762700002603788700001703814700001803831856003603849 2016 eng d a1091-649000aKLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.0 aKLB is associated with alcohol drinking and its gene product βKl c2016 Dec 13 a14372-143770 v1133 aExcessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
1 aSchumann, Gunter1 aLiu, Chunyu1 aO'Reilly, Paul1 aGao, He1 aSong, Parkyong1 aXu, Bing1 aRuggeri, Barbara1 aAmin, Najaf1 aJia, Tianye1 aPreis, Sarah1 aLepe, Marcelo, Segura1 aAkira, Shizuo1 aBarbieri, Caterina1 aBaumeister, Sebastian1 aCauchi, Stephane1 aClarke, Toni-Kim1 aEnroth, Stefan1 aFischer, Krista1 aHällfors, Jenni1 aHarris, Sarah, E1 aHieber, Saskia1 aHofer, Edith1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJoshi, Peter, K1 aKaartinen, Niina1 aLaitinen, Jaana1 aLemaitre, Rozenn1 aLoukola, Anu1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMangino, Massimo1 aManichaikul, Ani1 aMbarek, Hamdi1 aMilaneschi, Yuri1 aMoayyeri, Alireza1 aMukamal, Kenneth1 aNelson, Christopher1 aNettleton, Jennifer1 aPartinen, Eemil1 aRawal, Rajesh1 aRobino, Antonietta1 aRose, Lynda1 aSala, Cinzia1 aSatoh, Takashi1 aSchmidt, Reinhold1 aSchraut, Katharina1 aScott, Robert1 aSmith, Albert, Vernon1 aStarr, John, M1 aTeumer, Alexander1 aTrompet, Stella1 aUitterlinden, André, G1 aVenturini, Cristina1 aVergnaud, Anne-Claire1 aVerweij, Niek1 aVitart, Veronique1 aVuckovic, Dragana1 aWedenoja, Juho1 aYengo, Loic1 aYu, Bing1 aZhang, Weihua1 aZhao, Jing Hua1 aBoomsma, Dorret, I1 aChambers, John1 aChasman, Daniel, I1 aDaniela, Toniolo1 ade Geus, Eco1 aDeary, Ian1 aEriksson, Johan, G1 aEsko, Tõnu1 aEulenburg, Volker1 aFranco, Oscar, H1 aFroguel, Philippe1 aGieger, Christian1 aGrabe, Hans, J1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHarris, Tamara, B1 aHartikainen, Anna-Liisa1 aHeath, Andrew, C1 aHocking, Lynne1 aHofman, Albert1 aHuth, Cornelia1 aJarvelin, Marjo-Riitta1 aJukema, Wouter1 aKaprio, Jaakko1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLahti, Jari1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLiu, Yongmei1 aMadden, Pamela, A F1 aMartin, Nicholas1 aMorrison, Alanna1 aPenninx, Brenda1 aPirastu, Nicola1 aPsaty, Bruce1 aRaitakari, Olli1 aRidker, Paul1 aRose, Richard1 aRotter, Jerome, I1 aSamani, Nilesh, J1 aSchmidt, Helena1 aSpector, Tim, D1 aStott, David1 aStrachan, David1 aTzoulaki, Ioanna1 aHarst, Pim1 aDuijn, Cornelia, M1 aMarques-Vidal, Pedro1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWilson, James1 aWolffenbuttel, Bruce1 aBakalkin, Georgy1 aEvangelou, Evangelos1 aLiu, Yun1 aRice, Kenneth, M1 aDesrivières, Sylvane1 aKliewer, Steven, A1 aMangelsdorf, David, J1 aMüller, Christian, P1 aLevy, Daniel1 aElliott, Paul uhttps://chs-nhlbi.org/node/725601946nas a2200193 4500008004100000022001400041245010100055210007000156260001300226300000900239490000800248520136100256100001701617700002301634700001801657700002001675700002101695856003601716 2016 eng d a1879-247200aLack of association of plasma gamma prime (γ') fibrinogen with incident cardiovascular disease.0 aLack of association of plasma gamma prime γ fibrinogen with inci c2016 Jul a50-20 v1433 aINTRODUCTION: The association of gamma prime (γ') fibrinogen; a fibrinogen γ chain variant generated via alternative mRNA processing, with cardiovascular disease (CVD) remains equivocal. We prospectively examine the association of plasma γ' fibrinogen with the incidence of multiple cardiovascular disease (CVD) endpoints, independent of established CVD risk factors and total fibrinogen.
MATERIALS AND METHODS: We measured plasma γ' fibrinogen on plasma samples collected in 1992-1993 from adults ≥65years (n=3219) enrolled in the Cardiovascular Health Study, who were followed through 2013 for incident CVD events.
RESULTS AND CONCLUSIONS: In multivariable Cox models adjusted for traditional CVD risk factors and total fibrinogen, the hazard ratio per 1 standard deviation (10.7mg/dl) increment of γ' fibrinogen was 1.02 (95%CI: 0.95-1.10) for coronary heart disease; 0.88 (0.77-1.00) for ischemic stroke; 1.07 (0.87-1.32) for peripheral artery disease; 1.00 (0.92-1.08) for heart failure and 1.01 (0.92-1.10) for CVD mortality. Likewise, we failed to show a statistically significant association of γ'/total fibrinogen ratio with any CVD endpoint. These results suggest that among the elderly, γ' fibrinogen does not add much to CVD prediction beyond traditional risk factors and total fibrinogen level.
1 aAppiah, Duke1 aHeckbert, Susan, R1 aCushman, Mary1 aPsaty, Bruce, M1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/711805559nas a2201297 4500008004100000022001400041245013800055210006900193260001500262300001000277490000700287520188700294100002402181700002202205700002002227700002002247700001602267700002302283700001602306700002002322700001202342700002802354700002102382700002102403700002802424700002102452700001702473700002102490700002602511700002302537700002702560700002402587700002502611700001902636700001602655700002002671700002602691700002002717700002402737700002202761700002502783700002102808700001702829700001802846700001902864700002302883700002602906700001702932700001902949700002402968700002102992700002803013700002003041700002003061700002103081700002103102700002303123700001903146700002003165700002003185700001203205700002403217700002403241700002103265700002403286700002103310700002103331700002103352700002003373700002403393700002203417700001903439700001803458700001703476700002203493700002203515700001803537700002103555700002403576700002403600700002103624700002403645700002003669700002603689700002303715700002303738700001803761700001803779700001803797700002203815700002403837700002003861700002003881700002203901700002203923700001903945700002103964700002203985700002004007700001604027700002004043700002104063700001804084700002304102700002104125700001904146700002204165700002004187700001804207856003604225 2016 eng d a1537-660500aLarge-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.0 aLargeScale Exomewide Association Analysis Identifies Loci for Wh c2016 Jul 7 a22-390 v993 aWhite blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aEicher, John, D1 aChami, Nathalie1 aGiri, Ayush1 aBrody, Jennifer, A1 aHill, David1 aKacprowski, Tim1 aLi, Jin1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMihailov, Evelin1 aO'Donoghue, Michelle, L1 aPankratz, Nathan1 aPazoki, Raha1 aPolfus, Linda, M1 aSmith, Albert, Vernon1 aSchurmann, Claudia1 aVacchi-Suzzi, Caterina1 aWaterworth, Dawn, M1 aEvangelou, Evangelos1 aYanek, Lisa, R1 aBurt, Amber1 aChen, Ming-Huei1 avan Rooij, Frank, J A1 aFloyd, James, S1 aGreinacher, Andreas1 aHarris, Tamara, B1 aHighland, Heather, M1 aLange, Leslie, A1 aLiu, Yongmei1 aMägi, Reedik1 aNalls, Mike, A1 aMathias, Rasika, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aStarr, John, M1 aTardif, Jean-Claude1 aTzoulaki, Ioanna1 aEdwards, Digna, R Velez1 aWallentin, Lars1 aBartz, Traci, M1 aBecker, Lewis, C1 aDenny, Joshua, C1 aRaffield, Laura, M1 aRioux, John, D1 aFriedrich, Nele1 aFornage, Myriam1 aGao, He1 aHirschhorn, Joel, N1 aLiewald, David, C M1 aRich, Stephen, S1 aUitterlinden, Andre1 aBastarache, Lisa1 aBecker, Diane, M1 aBoerwinkle, Eric1 ade Denus, Simon1 aBottinger, Erwin, P1 aHayward, Caroline1 aHofman, Albert1 aHomuth, Georg1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLu, Yingchang1 aMetspalu, Andres1 aO'Donnell, Chris, J1 aQuarells, Rakale, C1 aRichard, Melissa1 aTorstenson, Eric, S1 aTaylor, Kent, D1 aVergnaud, Anne-Claire1 aZonderman, Alan, B1 aCrosslin, David, R1 aDeary, Ian, J1 aDörr, Marcus1 aElliott, Paul1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKähönen, Mika1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aSlater, Andrew, J1 aDehghan, Abbas1 aWhite, Harvey, D1 aGanesh, Santhi, K1 aLoos, Ruth, J F1 aEsko, Tõnu1 aFaraday, Nauder1 aWilson, James, G1 aCushman, Mary1 aJohnson, Andrew, D1 aEdwards, Todd, L1 aZakai, Neil, A1 aLettre, Guillaume1 aReiner, Alex, P1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/714603252nas a2200817 4500008004100000022001400041245012800055210006900183260001600252520116200268100001601430700001801446700001601464700001501480700001001495700001501505700001901520700001001539700001301549700001601562700001501578700001601593700001801609700001701627700001801644700001301662700001601675700001401691700001501705700001601720700001401736700001401750700001901764700001801783700001701801700001601818700001301834700001501847700002201862700001701884700001601901700001801917700001601935700001601951700002501967700001901992700001802011700001002029700001202039700002002051700001902071700002102090700001702111700001602128700001802144700001702162700001502179700001702194700001702211700001102228700002402239700001602263700001702279700001602296700001702312700001502329700001802344700001802362700001802380856003602398 2016 eng d a1473-115000aLarge-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.0 aLargescale pharmacogenomic study of sulfonylureas and the QT JT c2016 Dec 133 aSulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10(-8)), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.The Pharmacogenomics Journal advance online publication, 13 December 2016; doi:10.1038/tpj.2016.90.
1 aFloyd, J, S1 aSitlani, C, M1 aAvery, C, L1 aNoordam, R1 aLi, X1 aSmith, A V1 aGogarten, S, M1 aLi, J1 aBroer, L1 aEvans, D, S1 aTrompet, S1 aBrody, J, A1 aStewart, J, D1 aEicher, J, D1 aSeyerle, A, A1 aRoach, J1 aLange, L, A1 aLin, H, J1 aKors, J, A1 aHarris, T B1 aLi-Gao, R1 aSattar, N1 aCummings, S, R1 aWiggins, K, L1 aNapier, M, D1 aStürmer, T1 aBis, J C1 aKerr, K, F1 aUitterlinden, A G1 aTaylor, K, D1 aStott, D, J1 ade Mutsert, R1 aLauner, L J1 aBusch, E, L1 aMéndez-Giráldez, R1 aSotoodehnia, N1 aSoliman, E, Z1 aLi, Y1 aDuan, Q1 aRosendaal, F, R1 aSlagboom, P, E1 aWilhelmsen, K, C1 aReiner, A, P1 aDI Chen, Y-1 aHeckbert, S R1 aKaplan, R, C1 aRice, K, M1 aJukema, J, W1 aJohnson, A D1 aLiu, Y1 aMook-Kanamori, D, O1 aGudnason, V1 aWilson, J, G1 aRotter, J I1 aLaurie, C, C1 aPsaty, B M1 aWhitsel, E, A1 aCupples, L, A1 aStricker, B H uhttps://chs-nhlbi.org/node/725301788nas a2200217 4500008004100000022001400041245013300055210006900188260001300257300001100270490000700281520111000288100002201398700001801420700002101438700001801459700001801477700001801495700002101513856003601534 2016 eng d a1552-688700aLongitudinal Relationship Between Loneliness and Social Isolation in Older Adults: Results From the Cardiovascular Health Study.0 aLongitudinal Relationship Between Loneliness and Social Isolatio c2016 Aug a775-950 v283 aOBJECTIVE: To understand the longitudinal relationship between loneliness and isolation.
METHOD: Participants included 5,870 adults 65 years and older (M = 72.89 ± 5.59 years) from the first 5 years of the Cardiovascular Health Study. Loneliness was assessed using a dichotomized loneliness question. Social isolation was assessed using six items from the Lubben Social Network Scale. Yearly life events were included to assess abrupt social network changes. Mixed effects logistic regression was employed to analyze the relationship between isolation and loneliness.
RESULTS: Higher levels of social isolation were associated with higher odds of loneliness, as was an increase (from median) in level of social isolation. Life events such as a friend dying were also associated with increased odds of loneliness.
DISCUSSION: These results suggest that average level of isolation and increases in the level of isolation are closely tied to loneliness, which has implications for future assessment or monitoring of loneliness in older adult populations.
1 aPetersen, Johanna1 aKaye, Jeffrey1 aJacobs, Peter, G1 aQuinones, Ana1 aDodge, Hiroko1 aArnold, Alice1 aThielke, Stephen uhttps://chs-nhlbi.org/node/687904937nas a2201345 4500008004100000022001400041245012400055210006900179260001300248300001200261490000700273520113500280100001601415700001901431700002301450700002301473700002301496700001901519700001801538700002401556700001801580700001801598700001701616700001901633700002001652700002201672700002301694700001901717700001901736700001801755700001901773700001601792700001401808700002601822700001501848700002601863700001601889700001301905700001301918700001901931700002201950700002001972700002101992700002002013700001402033700001902047700001802066700002402084700002202108700001902130700002402149700002002173700001202193700002702205700002202232700002002254700002402274700002802298700002402326700002102350700002402371700002102395700002202416700002802438700002102466700002702487700003002514700002002544700001502564700002402579700002002603700001702623700002302640700001902663700001902682700002202701700002202723700001802745700002202763700001902785700001902804700001402823700001802837700001402855700002102869700002302890700002802913700001702941700001902958700001902977700001702996700002003013700002103033700002403054700002503078700002303103700002303126700002103149700002603170700002203196700002003218700002003238700002003258700002003278700002903298700001703327700002303344710002603367710002303393710002603416710002503442710006603467710002203533856003603555 2016 eng d a1546-171800aMeta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.0 aMetaanalysis identifies common and rare variants influencing blo c2016 Oct a1162-700 v483 aMeta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
1 aLiu, Chunyu1 aKraja, Aldi, T1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aFranceschini, Nora1 aBis, Joshua, C1 aRice, Kenneth1 aMorrison, Alanna, C1 aLu, Yingchang1 aWeiss, Stefan1 aGuo, Xiuqing1 aPalmas, Walter1 aMartin, Lisa, W1 aChen, Yii-Der Ida1 aSurendran, Praveen1 aDrenos, Fotios1 aCook, James, P1 aAuer, Paul, L1 aChu, Audrey, Y1 aGiri, Ayush1 aZhao, Wei1 aJakobsdottir, Johanna1 aLin, Li-An1 aStafford, Jeanette, M1 aAmin, Najaf1 aMei, Hao1 aYao, Jie1 aVoorman, Arend1 aLarson, Martin, G1 aGrove, Megan, L1 aSmith, Albert, V1 aHwang, Shih-Jen1 aChen, Han1 aHuan, Tianxiao1 aKosova, Gulum1 aStitziel, Nathan, O1 aKathiresan, Sekar1 aSamani, Nilesh1 aSchunkert, Heribert1 aDeloukas, Panos1 aLi, Man1 aFuchsberger, Christian1 aPattaro, Cristian1 aGorski, Mathias1 aKooperberg, Charles1 aPapanicolaou, George, J1 aRossouw, Jacques, E1 aFaul, Jessica, D1 aKardia, Sharon, L R1 aBouchard, Claude1 aRaffel, Leslie, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aVasan, Ramachandran, S1 aO'Donnell, Christopher, J1 aTaylor, Kent, D1 aLiu, Kiang1 aBottinger, Erwin, P1 aGottesman, Omri1 aDaw, Warwick1 aGiulianini, Franco1 aGanesh, Santhi1 aSalfati, Elias1 aHarris, Tamara, B1 aLauner, Lenore, J1 aDörr, Marcus1 aFelix, Stephan, B1 aRettig, Rainer1 aVölzke, Henry1 aKim, Eric1 aLee, Wen-Jane1 aLee, I-Te1 aSheu, Wayne, H-H1 aTsosie, Krystal, S1 aEdwards, Digna, R Velez1 aLiu, Yongmei1 aCorrea, Adolfo1 aWeir, David, R1 aVölker, Uwe1 aRidker, Paul, M1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aReiner, Alexander, P1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aEdwards, Todd, L1 aChakravarti, Aravinda1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aLoos, Ruth, J F1 aFornage, Myriam1 aEhret, Georg, B1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aChasman, Daniel, I1 aCHD Exome+ Consortium1 aExomeBP Consortium1 aGoT2DGenes Consortium1 aT2D-GENES Consortium1 aMyocardial Infarction Genetics and CARDIoGRAM Exome Consortia1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/726405818nas a2201705 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520107200254100002201326700002301348700002501371700002001396700002501416700002201441700001801463700002201481700002501503700002001528700002301548700002001571700003001591700001901621700002301640700002201663700001701685700001901702700001801721700001901739700001901758700002801777700001601805700002401821700002001845700002401865700002001889700002301909700001801932700001701950700001901967700002701986700001802013700001902031700001702050700001502067700001602082700002102098700002302119700001602142700002202158700002502180700002102205700001802226700002002244700002502264700001302289700002002302700002402322700001802346700002002364700002302384700002302407700002102430700002502451700002402476700001602500700003202516700002002548700002102568700002202589700002402611700002002635700002102655700002502676700001902701700002002720700002802740700001902768700001902787700001702806700002602823700001802849700002202867700001502889700002002904700002702924700001502951700002002966700002102986700001903007700002303026700001903049700002303068700001703091700002003108700002003128700002603148700002203174700002003196700001803216700002103234700002003255700002303275700001703298700001903315700002803334700002003362700001903382700002103401700001903422700001603441700002903457700002103486700002403507700002003531700002003551700002303571700001903594700001803613700002103631700002103652700001903673700002003692700002103712700002003733700002403753700002103777700001903798700002303817700002203840700002103862700001903883700001803902700002003920700002103940700002003961700003003981700002304011700002304034700001904057856003604076 2016 eng d a1460-208300aA meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.0 ametaanalysis of 120 246 individuals identifies 18 new loci for f c2016 Jan 15 a358-700 v253 aGenome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
1 ade Vries, Paul, S1 aChasman, Daniel, I1 aSabater-Lleal, Maria1 aChen, Ming-Huei1 aHuffman, Jennifer, E1 aSteri, Maristella1 aTang, Weihong1 aTeumer, Alexander1 aMarioni, Riccardo, E1 aGrossmann, Vera1 aHottenga, Jouke, J1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aZhao, Jing Hua1 aBrody, Jennifer, A1 aKleber, Marcus, E1 aGuo, Xiuqing1 aWang, Jie, Jin1 aAuer, Paul, L1 aAttia, John, R1 aYanek, Lisa, R1 aAhluwalia, Tarunveer, S1 aLahti, Jari1 aVenturini, Cristina1 aTanaka, Toshiko1 aBielak, Lawrence, F1 aJoshi, Peter, K1 aRocanin-Arjo, Ares1 aKolcic, Ivana1 aNavarro, Pau1 aRose, Lynda, M1 aOldmeadow, Christopher1 aRiess, Helene1 aMazur, Johanna1 aBasu, Saonli1 aGoel, Anuj1 aYang, Qiong1 aGhanbari, Mohsen1 aWillemsen, Gonneke1 aRumley, Ann1 aFiorillo, Edoardo1 ade Craen, Anton, J M1 aGrotevendt, Anne1 aScott, Robert1 aTaylor, Kent, D1 aDelgado, Graciela, E1 aYao, Jie1 aKifley, Annette1 aKooperberg, Charles1 aQayyum, Rehan1 aLopez, Lorna, M1 aBerentzen, Tina, L1 aRäikkönen, Katri1 aMangino, Massimo1 aBandinelli, Stefania1 aPeyser, Patricia, A1 aWild, Sarah1 aTrégouët, David-Alexandre1 aWright, Alan, F1 aMarten, Jonathan1 aZemunik, Tatijana1 aMorrison, Alanna, C1 aSennblad, Bengt1 aTofler, Geoffrey1 ade Maat, Moniek, P M1 aGeus, Eco, J C1 aLowe, Gordon, D1 aZoledziewska, Magdalena1 aSattar, Naveed1 aBinder, Harald1 aVölker, Uwe1 aWaldenberger, Melanie1 aKhaw, Kay-Tee1 aMcKnight, Barbara1 aHuang, Jie1 aJenny, Nancy, S1 aHolliday, Elizabeth, G1 aQi, Lihong1 aMcevoy, Mark, G1 aBecker, Diane, M1 aStarr, John, M1 aSarin, Antti-Pekka1 aHysi, Pirro, G1 aHernandez, Dena, G1 aJhun, Min, A1 aCampbell, Harry1 aHamsten, Anders1 aRivadeneira, Fernando1 aMcArdle, Wendy, L1 aSlagboom, Eline1 aZeller, Tanja1 aKoenig, Wolfgang1 aPsaty, Bruce, M1 aHaritunians, Talin1 aLiu, Jingmin1 aPalotie, Aarno1 aUitterlinden, André, G1 aStott, David, J1 aHofman, Albert1 aFranco, Oscar, H1 aPolasek, Ozren1 aRudan, Igor1 aMorange, Pierre-Emmanuel1 aWilson, James, F1 aKardia, Sharon, L R1 aFerrucci, Luigi1 aSpector, Tim, D1 aEriksson, Johan, G1 aHansen, Torben1 aDeary, Ian, J1 aBecker, Lewis, C1 aScott, Rodney, J1 aMitchell, Paul1 aMärz, Winfried1 aWareham, Nick, J1 aPeters, Annette1 aGreinacher, Andreas1 aWild, Philipp, S1 aJukema, Wouter1 aBoomsma, Dorret, I1 aHayward, Caroline1 aCucca, Francesco1 aTracy, Russell1 aWatkins, Hugh1 aReiner, Alex, P1 aFolsom, Aaron, R1 aRidker, Paul, M1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aStrachan, David, P1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/693604981nas a2201333 4500008004100000022001400041245015700055210006900212260001300281300001000294490000700304520112400311100003001435700001601465700001901481700002501500700002101525700002101546700002101567700002301588700002001611700001501631700002101646700002401667700001701691700001901708700001801727700001801745700002001763700002001783700001801803700002501821700002801846700002201874700001801896700002701914700002801941700001901969700002101988700001902009700002102028700001902049700002602068700002302094700002802117700002602145700002102171700002202192700002502214700002302239700002102262700002202283700001902305700001802324700002002342700002102362700001602383700001802399700001702417700002202434700002002456700002102476700002202497700002002519700002202539700002002561700002002581700002102601700002702622700002302649700002302672700001402695700002302709700002802732700002302760700002202783700001702805700002402822700002302846700002502869700002602894700002302920700002002943700002902963700002002992700002303012700002003035700002203055700001803077700001503095700001903110700002903129700002303158700002203181700001903203700002003222700002603242700002203268700001903290700002203309700002103331700002103352700002403373700002103397700002003418700002303438700002103461700002203482700002503504700002303529710002703552710003203579856003603611 2016 eng d a1468-624400aMeta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.0 aMetaanalysis of 49 549 individuals imputed with the 1000 Genomes c2016 Jul a441-90 v533 aBACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.
METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.
RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.
CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
1 avan Leeuwen, Elisabeth, M1 aSabo, Aniko1 aBis, Joshua, C1 aHuffman, Jennifer, E1 aManichaikul, Ani1 aSmith, Albert, V1 aFeitosa, Mary, F1 aDemissie, Serkalem1 aJoshi, Peter, K1 aDuan, Qing1 aMarten, Jonathan1 avan Klinken, Jan, B1 aSurakka, Ida1 aNolte, Ilja, M1 aZhang, Weihua1 aMbarek, Hamdi1 aLi-Gao, Ruifang1 aTrompet, Stella1 aVerweij, Niek1 aEvangelou, Evangelos1 aLyytikäinen, Leo-Pekka1 aTayo, Bamidele, O1 aDeelen, Joris1 avan der Most, Peter, J1 avan der Laan, Sander, W1 aArking, Dan, E1 aMorrison, Alanna1 aDehghan, Abbas1 aFranco, Oscar, H1 aHofman, Albert1 aRivadeneira, Fernando1 aSijbrands, Eric, J1 aUitterlinden, André, G1 aMychaleckyj, Josyf, C1 aCampbell, Archie1 aHocking, Lynne, J1 aPadmanabhan, Sandosh1 aBrody, Jennifer, A1 aRice, Kenneth, M1 aWhite, Charles, C1 aHarris, Tamara1 aIsaacs, Aaron1 aCampbell, Harry1 aLange, Leslie, A1 aRudan, Igor1 aKolcic, Ivana1 aNavarro, Pau1 aZemunik, Tatijana1 aSalomaa, Veikko1 aKooner, Angad, S1 aKooner, Jaspal, S1 aLehne, Benjamin1 aScott, William, R1 aTan, Sian-Tsung1 ade Geus, Eco, J1 aMilaneschi, Yuri1 aPenninx, Brenda, W J H1 aWillemsen, Gonneke1 ade Mutsert, Renée1 aFord, Ian1 aGansevoort, Ron, T1 aSegura-Lepe, Marcelo, P1 aRaitakari, Olli, T1 aViikari, Jorma, S1 aNikus, Kjell1 aForrester, Terrence1 aMcKenzie, Colin, A1 ade Craen, Anton, J M1 ade Ruijter, Hester, M1 aPasterkamp, Gerard1 aSnieder, Harold1 aOldehinkel, Albertine, J1 aSlagboom, Eline1 aCooper, Richard, S1 aKähönen, Mika1 aLehtimäki, Terho1 aElliott, Paul1 aHarst, Pim1 aJukema, Wouter1 aMook-Kanamori, Dennis, O1 aBoomsma, Dorret, I1 aChambers, John, C1 aSwertz, Morris1 aRipatti, Samuli1 avan Dijk, Ko, Willems1 aVitart, Veronique1 aPolasek, Ozren1 aHayward, Caroline1 aWilson, James, G1 aWilson, James, F1 aGudnason, Vilmundur1 aRich, Stephen, S1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aCupples, Adrienne, L1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aCHARGE Lipids Working Group uhttps://chs-nhlbi.org/node/701104724nas a2201189 4500008004100000022001400041245009300055210006900148260001300217300001200230490000700242520135800249100001801607700002101625700002001646700002501666700002201691700001901713700002301732700002801755700002501783700002101808700001701829700001601846700002201862700002101884700001601905700002001921700002101941700002301962700002201985700002102007700002402028700002102052700002402073700001902097700002502116700002402141700002102165700002502186700002402211700002402235700001402259700001702273700002202290700002302312700001902335700001802354700002502372700002302397700001802420700001702438700001902455700002202474700002402496700001702520700002602537700002002563700001802583700003002601700001602631700001802647700002702665700001802692700002102710700002602731700001902757700001702776700002202793700002202815700002002837700002302857700002102880700002202901700001902923700002002942700002302962700001802985700002803003700001603031700002603047700002103073700002203094700002203116700002803138700002203166700002503188700002103213700002403234700001903258700002303277700002003300700002003320700002603340700002203366700002403388700002303412700001903435700002203454700002203476856003603498 2016 eng d a1468-624400aMeta-analysis of genome-wide association studies of HDL cholesterol response to statins.0 aMetaanalysis of genomewide association studies of HDL cholestero c2016 Dec a835-8450 v533 aBACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.
METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.
CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
1 aPostmus, Iris1 aWarren, Helen, R1 aTrompet, Stella1 aArsenault, Benoit, J1 aAvery, Christy, L1 aBis, Joshua, C1 aChasman, Daniel, I1 ade Keyser, Catherine, E1 aDeshmukh, Harshal, A1 aEvans, Daniel, S1 aFeng, QiPing1 aLi, Xiaohui1 aSmit, Roelof, A J1 aSmith, Albert, V1 aSun, Fangui1 aTaylor, Kent, D1 aArnold, Alice, M1 aBarnes, Michael, R1 aBarratt, Bryan, J1 aBetteridge, John1 aBoekholdt, Matthijs1 aBoerwinkle, Eric1 aBuckley, Brendan, M1 aChen, Y-D, Ida1 ade Craen, Anton, J M1 aCummings, Steven, R1 aDenny, Joshua, C1 aDubé, Marie, Pierre1 aDurrington, Paul, N1 aEiriksdottir, Gudny1 aFord, Ian1 aGuo, Xiuqing1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHofman, Albert1 aHovingh, Kees1 aKastelein, John, J P1 aLauner, Leonore, J1 aLiu, Ching-Ti1 aLiu, Yongmei1 aLumley, Thomas1 aMcKeigue, Paul, M1 aMunroe, Patricia, B1 aNeil, Andrew1 aNickerson, Deborah, A1 aNyberg, Fredrik1 aO'Brien, Eoin1 aO'Donnell, Christopher, J1 aPost, Wendy1 aPoulter, Neil1 aVasan, Ramachandran, S1 aRice, Kenneth1 aRich, Stephen, S1 aRivadeneira, Fernando1 aSattar, Naveed1 aSever, Peter1 aShaw-Hawkins, Sue1 aShields, Denis, C1 aSlagboom, Eline1 aSmith, Nicholas, L1 aSmith, Joshua, D1 aSotoodehnia, Nona1 aStanton, Alice1 aStott, David, J1 aStricker, Bruno, H1 aStürmer, Til1 aUitterlinden, André, G1 aWei, Wei-Qi1 aWestendorp, Rudi, G J1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aWilke, Russell, A1 aBallantyne, Christie, M1 aColhoun, Helen, M1 aCupples, Adrienne, L1 aFranco, Oscar, H1 aGudnason, Vilmundur1 aHitman, Graham1 aPalmer, Colin, N A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aStafford, Jeanette, M1 aStein, Charles, M1 aTardif, Jean-Claude1 aCaulfield, Mark, J1 aJukema, Wouter1 aRotter, Jerome, I1 aKrauss, Ronald, M uhttps://chs-nhlbi.org/node/735805480nas a2201321 4500008004100000022001400041245007700055210006900132260001600201520175400217100002301971700001901994700002402013700001902037700001802056700002102074700002302095700001702118700002002135700001802155700001702173700002002190700002002210700002802230700002502258700001802283700002402301700001702325700002402342700002102366700002002387700001902407700001302426700003102439700001602470700001702486700002302503700001802526700002202544700002502566700002002591700002102611700001902632700001902651700002102670700002102691700002202712700002202734700002302756700001902779700001802798700001902816700001802835700001902853700002002872700002402892700001902916700002202935700002002957700001902977700002502996700002203021700002303043700002003066700002303086700001903109700002603128700002203154700002103176700002003197700001603217700002503233700002303258700002303281700002203304700002603326700002103352700002203373700002003395700002203415700002003437700002303457700002803480700002203508700002203530700001703552700002303569700002503592700001803617700002403635700002103659700002103680700002103701700002203722700001803744700001903762700002203781700002403803700002203827700002003849700002903869700002003898700002103918700002203939700002103961700002303982700001904005700002204024700002404046700003004070710002204100856003604122 2016 eng d a1942-326800aMultiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.0 aMultiethnic ExomeWide Association Study of Subclinical Atheroscl c2016 Nov 213 aBACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.
METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).
CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.
1 aNatarajan, Pradeep1 aBis, Joshua, C1 aBielak, Lawrence, F1 aCox, Amanda, J1 aDörr, Marcus1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aIsaacs, Aaron1 aJhun, Min, A1 aKavousi, Maryam1 aLi-Gao, Ruifang1 aLyytikäinen, Leo-Pekka1 aMarioni, Riccardo, E1 aSchminke, Ulf1 aStitziel, Nathan, O1 aTada, Hayato1 avan Setten, Jessica1 aSmith, Albert, V1 aVojinovic, Dina1 aYanek, Lisa, R1 aYao, Jie1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aBaber, Usman1 aBorecki, Ingrid, B1 aCarr, Jeffrey1 aChen, Yii-Der Ida1 aCupples, Adrienne, L1 ade Jong, Pim, A1 ade Koning, Harry1 ade Vos, Bob, D1 aDemirkan, Ayse1 aFuster, Valentin1 aFranco, Oscar, H1 aGoodarzi, Mark, O1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHoffmann, Udo1 aHofman, Albert1 aIšgum, Ivana1 aJukema, Wouter1 aKähönen, Mika1 aKardia, Sharon, L R1 aKral, Brian, G1 aLauner, Lenore, J1 aMassaro, Joseph1 aMehran, Roxana1 aMitchell, Braxton, D1 aMosley, Thomas, H1 ade Mutsert, Renée1 aNewman, Anne, B1 aNguyen, Khanh-Dung1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOudkerk, Matthijs1 aPankow, James, S1 aPeloso, Gina, M1 aPost, Wendy1 aProvince, Michael, A1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRivadeneira, Fernando1 aRosendaal, Frits1 aSartori, Samantha1 aTaylor, Kent, D1 aTeumer, Alexander1 aTrompet, Stella1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Lugt, Aad1 aVölker, Uwe1 aWardlaw, Joanna, M1 aWassel, Christina, L1 aWeiss, Stefan1 aWojczynski, Mary, K1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBowden, Donald, W1 aDeary, Ian, J1 aDehghan, Abbas1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aLehtimäki, Terho1 aMathias, Rasika1 aMook-Kanamori, Dennis, O1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRotter, Jerome, I1 aWilson, James, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aKathiresan, Sekar1 aPeyser, Patricia, A1 aO'Donnell, Christopher, J1 aCHARGE Consortium uhttps://chs-nhlbi.org/node/725705631nas a2200937 4500008004100000022001400041245013000055210006900185260001200254300001000266490000600276520305400282653000903336653001503345653002803360653001103388653001103399653000903410653001603419653003103435653002203466653002403488653002003512100001903532700002103551700001603572700002203588700001903610700002003629700001903649700001303668700002103681700002003702700002203722700001703744700001603761700001803777700002003795700001703815700001903832700002103851700001503872700001903887700002003906700001703926700002003943700002003963700002003983700002404003700002204027700001804049700001504067700002204082700002004104700002004124700002204144700003004166700001804196700002004214700002104234700001704255700001904272700001904291700002204310700002004332700002504352700002104377700002304398700001904421700002504440700002704465700001704492700001804509700002004527700002004547700002404567700001904591700001704610700003004627856003604657 2016 eng d a2213-859500aNatriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.0 aNatriuretic peptides and integrated risk assessment for cardiova c2016 10 a840-90 v43 aBACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.
METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.
FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure.
INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.
FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.
10aAged10aBiomarkers10aCardiovascular Diseases10aFemale10aHumans10aMale10aMiddle Aged10aNatriuretic Peptide, Brain10aPeptide Fragments10aProspective Studies10aRisk Assessment1 aWilleit, Peter1 aKaptoge, Stephen1 aWelsh, Paul1 aButterworth, Adam1 aChowdhury, Raj1 aSpackman, Sarah1 aPennells, Lisa1 aGao, Pei1 aBurgess, Stephen1 aFreitag, Daniel1 aSweeting, Michael1 aWood, Angela1 aCook, Nancy1 aJudd, Suzanne1 aTrompet, Stella1 aNambi, Vijay1 aOlsen, Michael1 aEverett, Brendan1 aKee, Frank1 aArnlöv, Johan1 aSalomaa, Veikko1 aLevy, Daniel1 aKauhanen, Jussi1 aLaukkanen, Jari1 aKavousi, Maryam1 aNinomiya, Toshiharu1 aCasas, Juan-Pablo1 aDaniels, Lori1 aLind, Lars1 aKistorp, Caroline1 aRosenberg, Jens1 aMueller, Thomas1 aRubattu, Speranza1 aPanagiotakos, Demosthenes1 aFranco, Oscar1 ade Lemos, James1 aLuchner, Andreas1 aKizer, Jorge1 aKiechl, Stefan1 aSalonen, Jukka1 aWannamethee, Goya1 ade Boer, Rudolf1 aNordestgaard, Børge1 aAndersson, Jonas1 aJørgensen, Torben1 aMelander, Olle1 aBallantyne, Christie1 aDeFilippi, Christopher1 aRidker, Paul1 aCushman, Mary1 aRosamond, Wayne1 aThompson, Simon1 aGudnason, Vilmundur1 aSattar, Naveed1 aDanesh, John1 aDi Angelantonio, Emanuele uhttps://chs-nhlbi.org/node/856706633nas a2201633 4500008004100000022001400041245008000055210006900135260001300204300001100217490000700228520260200235653002202837653002202859653003202881653003402913653001102947653003602958653001702994100001103011700002603022700001703048700001703065700001303082700001403095700001703109700001403126700001303140700001803153700001403171700001803185700002003203700002103223700001203244700001803256700001503274700001603289700002603305700001603331700001503347700001503362700001703377700001503394700001603409700001803425700001803443700001503461700001603476700001503492700001703507700001403524700001403538700001403552700001703566700002203583700001603605700001603621700001403637700002203651700001303673700001203686700001403698700001603712700001503728700001203743700001803755700001203773700001203785700001903797700001803816700001603834700001903850700001403869700001903883700001603902700001503918700001303933700001603946700002003962700001703982700001403999700001304013700001704026700001704043700001404060700001304074700001604087700001604103700001904119700001404138700001704152700002404169700001504193700001404208700001704222700001604239700002004255700001804275700001604293700001204309700001704321700001804338700001404356700002704370700001304397700001604410700001904426700001504445700001404460700001804474700001704492700001904509700001804528700002104546700001804567700002104585700001504606700001804621700001404639700001304653700001704666700001504683700002304698700001504721700001604736700001404752700001504766700001604781700002004797700001604817700002404833700001504857700001604872700001504888700002304903700001704926710002004943856003604963 2016 eng d a1476-557800aA novel Alzheimer disease locus located near the gene encoding tau protein.0 anovel Alzheimer disease locus located near the gene encoding tau c2016 Jan a108-170 v213 aAPOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
10aAlzheimer Disease10aApolipoprotein E410aChromosomes, Human, Pair 1710aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10atau Proteins1 aJun, G1 aIbrahim-Verbaas, C, A1 aVronskaya, M1 aLambert, J-C1 aChung, J1 aNaj, A, C1 aKunkle, B, W1 aWang, L-S1 aBis, J C1 aBellenguez, C1 aHarold, D1 aLunetta, K, L1 aDeStefano, A, L1 aGrenier-Boley, B1 aSims, R1 aBeecham, G, W1 aSmith, A V1 aChouraki, V1 aHamilton-Nelson, K, L1 aIkram, M, A1 aFiévet, N1 aDenning, N1 aMartin, E, R1 aSchmidt, H1 aKamatani, Y1 aDunstan, M, L1 aValladares, O1 aLaza, A, R1 aZelenika, D1 aRamirez, A1 aForoud, T, M1 aChoi, S-H1 aBoland, A1 aBecker, T1 aKukull, W, A1 avan der Lee, S, J1 aPasquier, F1 aCruchaga, C1 aBeekly, D1 aFitzpatrick, A, L1 aHanon, O1 aGill, M1 aBarber, R1 aGudnason, V1 aCampion, D1 aLove, S1 aBennett, D, A1 aAmin, N1 aBerr, C1 aTsolaki, Magda1 aBuxbaum, J, D1 aLopez, O, L1 aDeramecourt, V1 aFox, N, C1 aCantwell, L, B1 aTárraga, L1 aDufouil, C1 aHardy, J1 aCrane, P, K1 aEiriksdottir, G1 aHannequin, D1 aClarke, R1 aEvans, D1 aMosley, T, H1 aLetenneur, L1 aBrayne, C1 aMaier, W1 aDe Jager, P1 aEmilsson, V1 aDartigues, J-F1 aHampel, H1 aKamboh, M, I1 ade Bruijn, R, F A G1 aTzourio, C1 aPastor, P1 aLarson, E, B1 aRotter, J I1 aO'Donovan, M, C1 aMontine, T, J1 aNalls, M, A1 aMead, S1 aReiman, E, M1 aJonsson, P, V1 aHolmes, C1 aSt George-Hyslop, P, H1 aBoada, M1 aPassmore, P1 aWendland, J, R1 aSchmidt, R1 aMorgan, K1 aWinslow, A, R1 aPowell, J, F1 aCarasquillo, M1 aYounkin, S, G1 aJakobsdóttir, J1 aKauwe, J, S K1 aWilhelmsen, K, C1 aRujescu, D1 aNöthen, M, M1 aHofman, A1 aJones, L1 aHaines, J, L1 aPsaty, B M1 aVan Broeckhoven, C1 aHolmans, P1 aLauner, L J1 aMayeux, R1 aLathrop, M1 aGoate, A, M1 aEscott-Price, V1 aSeshadri, S1 aPericak-Vance, M, A1 aAmouyel, P1 aWilliams, J1 aDuijn, C M1 aSchellenberg, G, D1 aFarrer, L, A1 aIGAP Consortium uhttps://chs-nhlbi.org/node/668003468nas a2200541 4500008004100000022001400041245007100055210006900126260001300195300001000208490000600218520192500224100002302149700001702172700002602189700001602215700002602231700002002257700002302277700002502300700002202325700001802347700001902365700002002384700002202404700002202426700002002448700002402468700002202492700001402514700002002528700002402548700002502572700001602597700001902613700002802632700001602660700001902676700001902695700002402714700002202738700002102760700002302781700002002804700001802824710004802842856003602890 2016 eng d a1942-326800aNovel Genetic Loci Associated With Retinal Microvascular Diameter.0 aNovel Genetic Loci Associated With Retinal Microvascular Diamete c2016 Feb a45-540 v93 aBACKGROUND: There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.
METHODS AND RESULTS: This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).
CONCLUSIONS: Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
1 aJensen, Richard, A1 aSim, Xueling1 aSmith, Albert, Vernon1 aLi, Xiaohui1 aJakobsdottir, Johanna1 aCheng, Ching-Yu1 aBrody, Jennifer, A1 aCotch, Mary, Frances1 aMcKnight, Barbara1 aKlein, Ronald1 aWang, Jie, Jin1 aKifley, Annette1 aHarris, Tamara, B1 aLauner, Lenore, J1 aTaylor, Kent, D1 aKlein, Barbara, E K1 aRaffel, Leslie, J1 aLi, Xiang1 aIkram, Arfan, M1 aKlaver, Caroline, C1 avan der Lee, Sven, J1 aMutlu, Unal1 aHofman, Albert1 aUitterlinden, André, G1 aLiu, Chunyu1 aKraja, Aldi, T1 aMitchell, Paul1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aWong, Tien, Y1 aCHARGE Exome Chip Blood Pressure Consortium uhttps://chs-nhlbi.org/node/690011779nas a2204225 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2016 eng d00a{Novel genetic loci underlying human intracranial volume identified through genome-wide association0 aNovel genetic loci underlying human intracranial volume identifi c12 a1569–15820 v193 aIntracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (Ïgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.1 aAdams, H., H.1 aHibar, D., P.1 aChouraki, V.1 aStein, J., L.1 aNyquist, P., A.1 aRenter?a, M., E.1 aTrompet, S.1 aArias-Vasquez, A.1 aSeshadri, S.1 aDesrivi?res, S.1 aBeecham, A., H.1 aJahanshad, N.1 aWittfeld, K.1 avan der Lee, S., J.1 aAbramovic, L.1 aAlhusaini, S.1 aAmin, N.1 aAndersson, M.1 aArfanakis, K.1 aAribisala, B., S.1 aArmstrong, N., J.1 aAthanasiu, L.1 aAxelsson, T.1 aBeiser, A.1 aBernard, M.1 aBis, J., C.1 aBlanken, L., M.1 aBlanton, S., H.1 aBohlken, M., M.1 aBoks, M., P.1 aBralten, J.1 aBrickman, A., M.1 aCarmichael, O.1 aChakravarty, M., M.1 aChauhan, G.1 aChen, Q.1 aChing, C., R.1 aCuellar-Partida, G.1 aBraber, A., D.1 aDoan, N., T.1 aEhrlich, S.1 aFilippi, I.1 aGe, T.1 aGiddaluru, S.1 aGoldman, A., L.1 aGottesman, R., F.1 aGreven, C., U.1 aGrimm, O.1 aGriswold, M., E.1 aGuadalupe, T.1 aHass, J.1 aHaukvik, U., K.1 aHilal, S.1 aHofer, E.1 aHoehn, D.1 aHolmes, A., J.1 aHoogman, M.1 aJanowitz, D.1 aJia, T.1 aKasperaviciute, D.1 aKim, S.1 aKlein, M.1 aKraemer, B.1 aLee, P., H.1 aLiao, J.1 aLiewald, D., C.1 aLopez, L., M.1 aLuciano, M.1 aMacare, C.1 aMarquand, A.1 aMatarin, M.1 aMather, K., A.1 aMattheisen, M.1 aMazoyer, B.1 aMcKay, D., R.1 aMcWhirter, R.1 aMilaneschi, Y.1 aMirza-Schreiber, N.1 aMuetzel, R., L.1 aManiega, S., M.1 aNho, K.1 aNugent, A., C.1 aLoohuis, L., M.1 aOosterlaan, J.1 aPapmeyer, M.1 aPappa, I.1 aPirpamer, L.1 aPudas, S.1 aP?tz, B.1 aRajan, K., B.1 aRamasamy, A.1 aRichards, J., S.1 aRisacher, S., L.1 aRoiz-Santia?ez, R.1 aRommelse, N.1 aRose, E., J.1 aRoyle, N., A.1 aRundek, T.1 aS?mann, P., G.1 aSatizabal, C., L.1 aSchmaal, L.1 aSchork, A., J.1 aShen, L.1 aShin, J.1 aShumskaya, E.1 aSmith, A., V.1 aSprooten, E.1 aStrike, L., T.1 aTeumer, A.1 aThomson, R.1 aTordesillas-Gutierrez, D.1 aToro, R.1 aTrabzuni, D.1 aVaidya, D.1 avan der Grond, J.1 avan der Meer, D.1 aVan Donkelaar, M., M.1 aVan Eijk, K., R.1 aVan Erp, T., G.1 avan Rooij, D.1 aWalton, E.1 aWestlye, L., T.1 aWhelan, C., D.1 aWindham, B., G.1 aWinkler, A., M.1 aWoldehawariat, G.1 aWolf, C.1 aWolfers, T.1 aXu, B.1 aYanek, L., R.1 aYang, J.1 aZijdenbos, A.1 aZwiers, M., P.1 aAgartz, I.1 aAggarwal, N., T.1 aAlmasy, L.1 aAmes, D.1 aAmouyel, P.1 aAndreassen, O., A.1 aArepalli, S.1 aAssareh, A., A.1 aBarral, S.1 aBastin, M., E.1 aBecker, D., M.1 aBecker, J., T.1 aBennett, D., A.1 aBlangero, J.1 avan Bokhoven, H.1 aBoomsma, D., I.1 aBrodaty, H.1 aBrouwer, R., M.1 aBrunner, H., G.1 aBuckner, R., L.1 aBuitelaar, J., K.1 aBulayeva, K., B.1 aCahn, W.1 aCalhoun, V., D.1 aCannon, D., M.1 aCavalleri, G., L.1 aChen, C.1 aCheng, C., Y.1 aCichon, S.1 aCookson, M., R.1 aCorvin, A.1 aCrespo-Facorro, B.1 aCurran, J., E.1 aCzisch, M.1 aDale, A., M.1 aDavies, G., E.1 aDe Geus, E., J.1 aDe Jager, P., L.1 ade Zubicaray, G., I.1 aDelanty, N.1 aDepondt, C.1 aDeStefano, A., L.1 aDillman, A.1 aDjurovic, S.1 aDonohoe, G.1 aDrevets, W., C.1 aDuggirala, R.1 aDyer, T., D.1 aErk, S.1 aEspeseth, T.1 aEvans, D., A.1 aFedko, I., O.1 aFern?ndez, G.1 aFerrucci, L.1 aFisher, S., E.1 aFleischman, D., A.1 aFord, I.1 aForoud, T., M.1 aFox, P., T.1 aFrancks, C.1 aFukunaga, M.1 aGibbs, J., R.1 aGlahn, D., C.1 aGollub, R., L.1 aG?ring, H., H.1 aGrabe, H., J.1 aGreen, R., C.1 aGruber, O.1 aGudnason, V.1 aGuelfi, S.1 aHansell, N., K.1 aHardy, J.1 aHartman, C., A.1 aHashimoto, R.1 aHegenscheid, K.1 aHeinz, A.1 aLe Hellard, S.1 aHernandez, D., G.1 aHeslenfeld, D., J.1 aHo, B., C.1 aHoekstra, P., J.1 aHoffmann, W.1 aHofman, A.1 aHolsboer, F.1 aHomuth, G.1 aHosten, N.1 aHottenga, J., J.1 aPol, H., E. Hulshof1 aIkeda, M.1 aIkram, M., K.1 aJack, C., R.1 aJenkinson, M.1 aJohnson, R.1 aJ?nsson, E., G.1 aJukema, J., W.1 aKahn, R., S.1 aKanai, R.1 aKloszewska, I.1 aKnopman, D., S.1 aKochunov, P.1 aKwok, J., B.1 aLawrie, S., M.1 aLema?tre, H.1 aLiu, X.1 aLongo, D., L.1 aLongstreth, W., T.1 aLopez, O., L.1 aLovestone, S.1 aMartinez, O.1 aMartinot, J., L.1 aMattay, V., S.1 aMcDonald, C.1 aMcIntosh, A., M.1 aMcMahon, K., L.1 aMcMahon, F., J.1 aMecocci, P.1 aMelle, I.1 aMeyer-Lindenberg, A.1 aMohnke, S.1 aMontgomery, G., W.1 aMorris, D., W.1 aMosley, T., H.1 aM?hleisen, T., W.1 aM?ller-Myhsok, B.1 aNalls, M., A.1 aNauck, M.1 aNichols, T., E.1 aNiessen, W., J.1 aN?then, M., M.1 aNyberg, L.1 aOhi, K.1 aOlvera, R., L.1 aOphoff, R., A.1 aPandolfo, M.1 aPaus, T.1 aPausova, Z.1 aPenninx, B., W.1 aPike, G., B.1 aPotkin, S., G.1 aPsaty, B., M.1 aReppermund, S.1 aRietschel, M.1 aRoffman, J., L.1 aRomanczuk-Seiferth, N.1 aRotter, J., I.1 aRyten, M.1 aSacco, R., L.1 aSachdev, P., S.1 aSaykin, A., J.1 aSchmidt, R.1 aSchofield, P., R.1 aSigurdsson, S.1 aSimmons, A.1 aSingleton, A.1 aSisodiya, S., M.1 aSmith, C.1 aSmoller, J., W.1 aSoininen, H.1 aSrikanth, V.1 aSteen, V., M.1 aStott, D., J.1 aSussmann, J., E.1 aThalamuthu, A.1 aTiemeier, H.1 aToga, A., W.1 aTraynor, B., J.1 aTroncoso, J.1 aTurner, J., A.1 aTzourio, C.1 aUitterlinden, A., G.1 aHern?ndez, M., C.1 aVan der Brug, M.1 avan der Lugt, A.1 aVan der Wee, N., J.1 avan Duijn, C., M.1 aVan Haren, N., E.1 aEnt, Van, T1 avan Tol, M., J.1 aVardarajan, B., N.1 aVeltman, D., J.1 aVernooij, M., W.1 aV?lzke, H.1 aWalter, H.1 aWardlaw, J., M.1 aWassink, T., H.1 aWeale, M., E.1 aWeinberger, D., R.1 aWeiner, M., W.1 aWen, W.1 aWestman, E.1 aWhite, T.1 aWong, T., Y.1 aWright, C., B.1 aZielke, H., R.1 aZonderman, A., B.1 aDeary, I., J.1 aDeCarli, C.1 aSchmidt, H.1 aMartin, N., G.1 aDe Craen, A., J.1 aWright, M., J.1 aLauner, L., J.1 aSchumann, G.1 aFornage, M.1 aFranke, B.1 aDebette, S.1 aMedland, S., E.1 aIkram, M., A.1 aThompson, P., M. uhttps://chs-nhlbi.org/node/856103031nas a2200385 4500008004100000022001400041245011800055210006900173260001600242300001100258490000800269520193400277653000902211653002202220653002102242653001102263653002202274653001802296653001102314653002302325653000902348653001902357653003202376653002402408653002102432653001102453653001802464653001202482100002602494700002402520700002002544700002002564700002502584856003602609 2016 ENG d a1524-453900aPhysical Activity and Risk of Coronary Heart Disease and Stroke in Older Adults: The Cardiovascular Health Study.0 aPhysical Activity and Risk of Coronary Heart Disease and Stroke c2016 Jan 12 a147-550 v1333 aBACKGROUND: Although guidelines suggest that older adults engage in regular physical activity (PA) to reduce cardiovascular disease (CVD), surprisingly few studies have evaluated this relationship, especially in those >75 years. In addition, with advancing age the ability to perform some types of PA might decrease, making light-moderate exercise such as walking especially important to meet recommendations.
METHODS AND RESULTS: Prospective cohort analysis among 4207 US men and women of a mean age of 73 years (standard deviation=6) who were free of CVD at baseline in the Cardiovascular Health Study were followed from 1989 to 1999. PA was assessed and cumulatively updated over time to minimize misclassification and assess the long-term effects of habitual activity. Walking (pace, blocks, combined walking score) was updated annually from baseline through 1999. Leisure-time activity and exercise intensity were updated at baseline, 1992, and 1996. Incident CVD (fatal or nonfatal myocardial infarction, coronary death, or stroke) was adjudicated using medical records. During 41,995 person-years of follow-up, 1182 CVD events occurred. After multivariable adjustment, greater PA was inversely associated with coronary heart disease, stroke (especially ischemic stroke), and total CVD, even in those ≥75 years. Walking pace, distance, and overall walking score, leisure-time activity, and exercise intensity were each associated with lower risk. For example, in comparison with a walking pace <2 mph, those that habitually walked at a pace >3 mph had a lower risk of coronary heart disease (0.50; confidence interval, 0.38-0.67), stroke (0.47; confidence interval, 033-0.66), and CVD (0.50; confidence interval, 0.40-0.62).
CONCLUSIONS: These data provide empirical evidence supporting PA recommendations, in particular, walking, to reduce the incidence of CVD among older adults.
10aAged10aAged, 80 and over10aCoronary Disease10aFemale10aFollow-Up Studies10aHealth Status10aHumans10aLeisure Activities10aMale10aMotor Activity10aProportional Hazards Models10aProspective Studies10aSampling Studies10aStroke10aUnited States10aWalking1 aSoares-Miranda, Luisa1 aSiscovick, David, S1 aPsaty, Bruce, M1 aLongstreth, W T1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/693306109nas a2201525 4500008004100000022001400041245009200055210006900147260001500216300001000231490000700241520179700248100002002045700002002065700002002085700002002105700002002125700001902145700002402164700002202188700002202210700002102232700001802253700002302271700001602294700002302310700002102333700002102354700001602375700001702391700001702408700002502425700002102450700001202471700002602483700002302509700002102532700002102553700001602574700002302590700002802613700001702641700002302658700002002681700002102701700001802722700002302740700002202763700001802785700001902803700002602822700002302848700002102871700002302892700002002915700002502935700002002960700002002980700002203000700002403022700002203046700002003068700002103088700002403109700001903133700002403152700002003176700001803196700002403214700002003238700002603258700002203284700002203306700002403328700002803352700002403380700001703404700002203421700002203443700002103465700002503486700002103511700001203532700001703544700002103561700002103582700001803603700002103621700002103642700001603663700002703679700001903706700002303725700002203748700002203770700002503792700001903817700002803836700002403864700002003888700002103908700002003929700002003949700002103969700002003990700001604010700002404026700002204050700001804072700002404090700001704114700001904131700001904150700002604169700002804195700002104223700001904244700002104263700002204284700002204306700002004328700001804348700002004366700002204386700002304408710003804431710003204469710004604501856003604547 2016 eng d a1537-660500aPlatelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.0 aPlateletRelated Variants Identified by Exomechip Metaanalysis in c2016 Jul 7 a40-550 v993 aPlatelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
1 aEicher, John, D1 aChami, Nathalie1 aKacprowski, Tim1 aNomura, Akihiro1 aChen, Ming-Huei1 aYanek, Lisa, R1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aSlater, Andrew, J1 aPankratz, Nathan1 aPolfus, Linda1 aSchurmann, Claudia1 aGiri, Ayush1 aBrody, Jennifer, A1 aLange, Leslie, A1 aManichaikul, Ani1 aHill, David1 aPazoki, Raha1 aElliot, Paul1 aEvangelou, Evangelos1 aTzoulaki, Ioanna1 aGao, He1 aVergnaud, Anne-Claire1 aMathias, Rasika, A1 aBecker, Diane, M1 aBecker, Lewis, C1 aBurt, Amber1 aCrosslin, David, R1 aLyytikäinen, Leo-Pekka1 aNikus, Kjell1 aHernesniemi, Jussi1 aKähönen, Mika1 aRaitoharju, Emma1 aMononen, Nina1 aRaitakari, Olli, T1 aLehtimäki, Terho1 aCushman, Mary1 aZakai, Neil, A1 aNickerson, Deborah, A1 aRaffield, Laura, M1 aQuarells, Rakale1 aWiller, Cristen, J1 aPeloso, Gina, M1 aAbecasis, Goncalo, R1 aLiu, Dajiang, J1 aDeloukas, Panos1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aFornage, Myriam1 aRichard, Melissa1 aTardif, Jean-Claude1 aRioux, John, D1 aDubé, Marie-Pierre1 ade Denus, Simon1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSmith, Albert, Vernon1 aHarris, Tamara, B1 aLauner, Lenore, J1 aGudnason, Vilmundur1 aEdwards, Digna, R Velez1 aTorstenson, Eric, S1 aLiu, Yongmei1 aTracy, Russell, P1 aRotter, Jerome, I1 aRich, Stephen, S1 aHighland, Heather, M1 aBoerwinkle, Eric1 aLi, Jin1 aLange, Ethan1 aWilson, James, G1 aMihailov, Evelin1 aMägi, Reedik1 aHirschhorn, Joel1 aMetspalu, Andres1 aEsko, Tõnu1 aVacchi-Suzzi, Caterina1 aNalls, Mike, A1 aZonderman, Alan, B1 aEvans, Michele, K1 aEngström, Gunnar1 aOrho-Melander, Marju1 aMelander, Olle1 aO'Donoghue, Michelle, L1 aWaterworth, Dawn, M1 aWallentin, Lars1 aWhite, Harvey, D1 aFloyd, James, S1 aBartz, Traci, M1 aRice, Kenneth, M1 aPsaty, Bruce, M1 aStarr, J, M1 aLiewald, David, C M1 aHayward, Caroline1 aDeary, Ian, J1 aGreinacher, Andreas1 aVölker, Uwe1 aThiele, Thomas1 aVölzke, Henry1 avan Rooij, Frank, J A1 aUitterlinden, André, G1 aFranco, Oscar, H1 aDehghan, Abbas1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aKathiresan, Sekar1 aFaraday, Nauder1 aAuer, Paul, L1 aReiner, Alex, P1 aLettre, Guillaume1 aJohnson, Andrew, D1 aGlobal Lipids Genetics Consortium1 aCARDIoGRAM Exome Consortium1 aMyocardial Infarction Genetics Consortium uhttps://chs-nhlbi.org/node/713903073nas a2200397 4500008004100000022001400041245013400055210006900189260001300258490000600271520187500277100002002152700002202172700002302194700002002217700002002237700002002257700002002277700003402297700002002331700001902351700001502370700002202385700002102407700001502428700001902443700001902462700002302481700002702504700002202531700001702553700002402570700002302594700002202617856003602639 2016 eng d a1941-329700aPredicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes.0 aPredicting Heart Failure With Preserved and Reduced Ejection Fra c2016 Jun0 v93 aBACKGROUND: Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF).
METHODS AND RESULTS: Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95% confidence interval [CI], 0.78-0.82) and validation samples (internal: 0.79; 95% CI, 0.77-0.82 and external: 0.76; 95% CI: 0.71-0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95% CI, 0.80-0.84) and validation samples (internal: 0.80; 95% CI, 0.78-0.83 and external: 0.76; 95% CI, 0.71-0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison ≤0.02).
CONCLUSIONS: We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.
1 aHo, Jennifer, E1 aEnserro, Danielle1 aBrouwers, Frank, P1 aKizer, Jorge, R1 aShah, Sanjiv, J1 aPsaty, Bruce, M1 aBartz, Traci, M1 aSanthanakrishnan, Rajalakshmi1 aLee, Douglas, S1 aChan, Cheeling1 aLiu, Kiang1 aBlaha, Michael, J1 aHillege, Hans, L1 aHarst, Pim1 aGilst, Wiek, H1 aKop, Willem, J1 aGansevoort, Ron, T1 aVasan, Ramachandran, S1 aGardin, Julius, M1 aLevy, Daniel1 aGottdiener, John, S1 ade Boer, Rudolf, A1 aLarson, Martin, G uhttps://chs-nhlbi.org/node/714010963nas a2203529 4500008004100000022001400041245011200055210006900167260001500236300001000251490000600261520104700267653001801314653001401332653003401346653001301380653001101393653002001404653003301424100002001457700002001477700001901497700003101516700002201547700002501569700002801594700001701622700001801639700001901657700001601676700002101692700001501713700002001728700002201748700002601770700002101796700001801817700002201835700002301857700002101880700001601901700001801917700001801935700002001953700002101973700002801994700001902022700001902041700001902060700002102079700001102100700001902111700001702130700002002147700002002167700002502187700001802212700002402230700002202254700002502276700001502301700002002316700002002336700001902356700002102375700001702396700001802413700001802431700003102449700002502480700002502505700002002530700001702550700001902567700002402586700001902610700001902629700002202648700002102670700002502691700002502716700002402741700002002765700002202785700002802807700002102835700002402856700002102880700002502901700002302926700001902949700002202968700002102990700002003011700002303031700002503054700002003079700002103099700002003120700002103140700002003161700002703181700002103208700002203229700002103251700001803272700002303290700001903313700002003332700002903352700002603381700002003407700002103427700002803448700002203476700002403498700001803522700001903540700002003559700001803579700002403597700001603621700002603637700001903663700001803682700002003700700002403720700001903744700002303763700002203786700001603808700002903824700002103853700002003874700002403894700001903918700003703937700002003974700001903994700002504013700001804038700002504056700002004081700001804101700002504119700001904144700002404163700002404187700002004211700002504231700002204256700002104278700002104299700002304320700001804343700002304361700002104384700001904405700002404424700002204448700002204470700002104492700002104513700001704534700001904551700002204570700002204592700002204614700002004636700001904656700001604675700001904691700001804710700001904728700002104747700002504768700002304793700001904816700002004835700001904855700002604874700002304900700002004923700001404943700002104957700002504978700001905003700002105022700002005043700002605063700001905089700001805108700002305126700002205149700002105171700002005192700002205212700002805234700003205262700002305294700002105317700002405338700002605362700002205388700001805410700001805428700002705446700002705473700003505500700002405535700002205559700002405581700001805605700002205623700002205645700002305667700002005690700002005710700002105730700002305751700001905774700002305793700002005816700003105836700002005867700002505887700002305912700002105935700002205956700002305978700001806001700002306019700002206042700001906064700002106083700001406104700002006118700002706138700001906165700002206184700001506206700002206221700001906243700001906262700002206281700002106303700002106324700001906345700002906364700002006393700001906413700001906432700002006451700002006471700002106491700002106512700001606533700002006549700002406569700002206593700001706615700002906632700002406661700002106685700002206706700002106728700002306749700002806772700002006800700001706820700002406837700002506861700001806886700002106904700002406925700002506949700002106974700002306995700002007018700002307038700001807061700001907079700001807098700002107116700002207137700002207159700001907181700002607200700002407226700002807250700002307278700002207301700002407323700003007347700002007377856003607397 2016 eng d a2041-172300aA principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.0 aprincipal component metaanalysis on multiple anthropometric trai c2016 11 23 a133570 v73 aLarge consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
10aAnthropometry10aBody Size10aGenome-Wide Association Study10aGenotype10aHumans10aModels, Genetic10aPrincipal Component Analysis1 aRied, Janina, S1 aM, Janina, Jeff1 aChu, Audrey, Y1 aBragg-Gresham, Jennifer, L1 avan Dongen, Jenny1 aHuffman, Jennifer, E1 aAhluwalia, Tarunveer, S1 aCadby, Gemma1 aEklund, Niina1 aEriksson, Joel1 aEsko, Tõnu1 aFeitosa, Mary, F1 aGoel, Anuj1 aGorski, Mathias1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aJackson, Anne, U1 aJokinen, Eero1 aKanoni, Stavroula1 aKristiansson, Kati1 aKutalik, Zoltán1 aLahti, Jari1 aLuan, Jian'an1 aMägi, Reedik1 aMahajan, Anubha1 aMangino, Massimo1 aMedina-Gómez, Carolina1 aMonda, Keri, L1 aNolte, Ilja, M1 aPerusse, Louis1 aProkopenko, Inga1 aQi, Lu1 aRose, Lynda, M1 aSalvi, Erika1 aSmith, Megan, T1 aSnieder, Harold1 aStančáková, Alena1 aSung, Yun, Ju1 aTachmazidou, Ioanna1 aTeumer, Alexander1 aThorleifsson, Gudmar1 aHarst, Pim1 aWalker, Ryan, W1 aWang, Sophie, R1 aWild, Sarah, H1 aWillems, Sara, M1 aWong, Andrew1 aZhang, Weihua1 aAlbrecht, Eva1 aAlves, Alexessander, Couto1 aBakker, Stephan, J L1 aBarlassina, Cristina1 aBartz, Traci, M1 aBeilby, John1 aBellis, Claire1 aBergman, Richard, N1 aBergmann, Sven1 aBlangero, John1 aBlüher, Matthias1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBruinenberg, Marcel1 aCampbell, Harry1 aChen, Yii-Der Ida1 aChiang, Charleston, W K1 aChines, Peter, S1 aCollins, Francis, S1 aCucca, Fracensco1 aCupples, Adrienne, L1 aD'Avila, Francesca1 aGeus, Eco, J C1 aDedoussis, George1 aDimitriou, Maria1 aDöring, Angela1 aEriksson, Johan, G1 aFarmaki, Aliki-Eleni1 aFarrall, Martin1 aFerreira, Teresa1 aFischer, Krista1 aForouhi, Nita, G1 aFriedrich, Nele1 aGjesing, Anette, Prior1 aGlorioso, Nicola1 aGraff, Mariaelisa1 aGrallert, Harald1 aGrarup, Niels1 aGräßler, Jürgen1 aGrewal, Jagvir1 aHamsten, Anders1 aHarder, Marie, Neergaard1 aHartman, Catharina, A1 aHassinen, Maija1 aHastie, Nicholas1 aHattersley, Andrew, Tym1 aHavulinna, Aki, S1 aHeliövaara, Markku1 aHillege, Hans1 aHofman, Albert1 aHolmen, Oddgeir1 aHomuth, Georg1 aHottenga, Jouke-Jan1 aHui, Jennie1 aHusemoen, Lise, Lotte1 aHysi, Pirro, G1 aIsaacs, Aaron1 aIttermann, Till1 aJalilzadeh, Shapour1 aJames, Alan, L1 aJørgensen, Torben1 aJousilahti, Pekka1 aJula, Antti1 aJustesen, Johanne, Marie1 aJustice, Anne, E1 aKähönen, Mika1 aKaraleftheri, Maria1 aKhaw, Kay, Tee1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKinnunen, Leena1 aKnekt, Paul, B1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooner, Ishminder, K1 aKoskinen, Seppo1 aKovacs, Peter1 aKyriakou, Theodosios1 aLaitinen, Tomi1 aLangenberg, Claudia1 aLewin, Alexandra, M1 aLichtner, Peter1 aLindgren, Cecilia, M1 aLindström, Jaana1 aLinneberg, Allan1 aLorbeer, Roberto1 aLorentzon, Mattias1 aLuben, Robert1 aLyssenko, Valeriya1 aMännistö, Satu1 aManunta, Paolo1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcKnight, Barbara1 aMohlke, Karen, L1 aMihailov, Evelin1 aMilani, Lili1 aMills, Rebecca1 aMontasser, May, E1 aMorris, Andrew, P1 aMüller, Gabriele1 aMusk, Arthur, W1 aNarisu, Narisu1 aOng, Ken, K1 aOostra, Ben, A1 aOsmond, Clive1 aPalotie, Aarno1 aPankow, James, S1 aPaternoster, Lavinia1 aPenninx, Brenda, W1 aPichler, Irene1 aPilia, Maria, G1 aPolasek, Ozren1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRankinen, Tuomo1 aRao, D, C1 aRayner, Nigel, W1 aRibel-Madsen, Rasmus1 aRice, Treva, K1 aRichards, Marcus1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRyan, Kathy, A1 aSanna, Serena1 aSarzynski, Mark, A1 aScholtens, Salome1 aScott, Robert, A1 aSebert, Sylvain1 aSoutham, Lorraine1 aSparsø, Thomas, Hempel1 aSteinthorsdottir, Valgerdur1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStrauch, Konstantin1 aStringham, Heather, M1 aSwertz, Morris, A1 aSwift, Amy, J1 aTönjes, Anke1 aTsafantakis, Emmanouil1 avan der Most, Peter, J1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aVartiainen, Erkki1 aVenturini, Cristina1 aVerweij, Niek1 aViikari, Jorma, S1 aVitart, Veronique1 aVohl, Marie-Claude1 aVonk, Judith, M1 aWaeber, Gérard1 aWiden, Elisabeth1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWinkler, Thomas, W1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZhao, Jing, Hua1 aZillikens, Carola, M1 aBoomsma, Dorret, I1 aBouchard, Claude1 aChambers, John, C1 aChasman, Daniel, I1 aCusi, Daniele1 aGansevoort, Ron, T1 aGieger, Christian1 aHansen, Torben1 aHicks, Andrew, A1 aHu, Frank1 aHveem, Kristian1 aJarvelin, Marjo-Riitta1 aKajantie, Eero1 aKooner, Jaspal, S1 aKuh, Diana1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMetspalu, Andres1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aPalmer, Lyle, J1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPsaty, Bruce, M1 aPuolijoki, Hannu1 aRauramaa, Rainer1 aRudan, Igor1 aSalomaa, Veikko1 aSchwarz, Peter, E H1 aShudiner, Alan, R1 aSmit, Jan, H1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aStumvoll, Michael1 aTremblay, Angelo1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aVölker, Uwe1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWilson, James, F1 aZeggini, Eleftheria1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aDuijn, Cornelia, M1 aFox, Caroline1 aGroop, Leif, C1 aHeid, Iris, M1 aHunter, David, J1 aKaplan, Robert, C1 aMcCarthy, Mark, I1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aThorsteinsdottir, Unnur1 aStrachan, David, P1 aFrayling, Timothy1 aHirschhorn, Joel, N1 aMüller-Nurasyid, Martina1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/857002162nas a2200217 4500008004100000022001400041245014400055210007000199260001300269300000900282490000800291520145900299100002101758700001801779700002301797700002301820700002601843700001801869700002101887856003601908 2016 eng d a1879-247200aProspective study of γ' fibrinogen and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).0 aProspective study of γ fibrinogen and incident venous thromboemb c2016 Mar a44-90 v1393 aINTRODUCTION: Epidemiological studies generally have not found plasma total fibrinogen to be a risk factor for venous thromboembolism (VTE), but several have reported associations between variants in the fibrinogen gamma gene (FGG) and VTE. A case-control study in whites suggested plasma γ' fibrinogen concentration may be associated inversely with VTE, but this was not replicated in African Americans.
OBJECTIVE: To examine the prospective association between γ' fibrinogen concentrations and occurrence of VTE.
METHODS: We used the Longitudinal Investigation of Thromboembolism Etiology (LITE), involving two pooled population-based cohorts in the United States including 16,234 participants. The cohorts comprised white and African American men and women, aged 50years and older at study onset in the early 1990s. We identified VTEs during follow-up and documented they met standardized diagnostic criteria.
RESULTS: During two decades of follow-up, neither γ' fibrinogen nor total fibrinogen nor their ratio was associated with VTE overall (n=521 VTEs), in subgroups defined by race, or in other subgroups. In both race groups, the minor allele of FGG rs2066865 was associated with lower γ' fibrinogen concentrations, but this allele was not associated with VTE.
CONCLUSIONS: A lower plasma concentration of γ' fibrinogen in healthy adults does not appear to increase VTE risk.
1 aFolsom, Aaron, R1 aTang, Weihong1 aGeorge, Kristen, M1 aHeckbert, Susan, R1 aMacLehose, Richard, F1 aCushman, Mary1 aPankow, James, S uhttps://chs-nhlbi.org/node/699303283nas a2200565 4500008004100000022001400041245009400055210006900149260001300218300001000231490000600241520164500247100001301892700001901905700002001924700002301944700001601967700001801983700001902001700002102020700002202041700002602063700001902089700002502108700002102133700002002154700002302174700001902197700001602216700002302232700002302255700001702278700001902295700001902314700001702333700001402350700002202364700002902386700001502415700001702430700001902447700002202466700002302488700002002511700001702531700002902548700002402577710008002601856003602681 2016 eng d a1942-326800aRare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.0 aRare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Leve c2016 Feb a64-700 v93 aBACKGROUND: Rare genetic variants influence blood pressure (BP).
METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).
CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.
1 aYu, Bing1 aPulit, Sara, L1 aHwang, Shih-Jen1 aBrody, Jennifer, A1 aAmin, Najaf1 aAuer, Paul, L1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBurke, Gregory, L1 aChakravarti, Aravinda1 aCorrea, Adolfo1 aDreisbach, Albert, W1 aFranco, Oscar, H1 aEhret, Georg, B1 aFranceschini, Nora1 aHofman, Albert1 aLin, Dan-Yu1 aMetcalf, Ginger, A1 aMusani, Solomon, K1 aMuzny, Donna1 aPalmas, Walter1 aRaffel, Leslie1 aReiner, Alex1 aRice, Ken1 aRotter, Jerome, I1 aVeeraraghavan, Narayanan1 aFox, Ervin1 aGuo, Xiuqing1 aNorth, Kari, E1 aGibbs, Richard, A1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aLevy, Daniel1 aNewton-Cheh, Christopher1 aMorrison, Alanna, C1 aCHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP* uhttps://chs-nhlbi.org/node/693703298nas a2200793 4500008004100000022001400041245008800055210006900143260001300212300001300225490000700238520090200245100002601147700002501173700001901198700002201217700002201239700002101261700002001282700001401302700002101316700002101337700002401358700002301382700002101405700001601426700001801442700003001460700002101490700002601511700002001537700001801557700002001575700002301595700002201618700002001640700002001660700002001680700002101700700002101721700002401742700002301766700002001789700002401809700002101833700002001854700001701874700002801891700002001919700002201939700001901961700003001980700002802010700002202038700001902060700001802079700002002097700002802117700002102145700002002166700002002186700002302206700002402229700002302253710007602276710004502352710007102397856003602468 2016 eng d a1553-740400aRare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.0 aRare Functional Variant in TM2D3 is Associated with LateOnset Al c2016 Oct ae10063270 v123 aWe performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
1 aJakobsdottir, Johanna1 avan der Lee, Sven, J1 aBis, Joshua, C1 aChouraki, Vincent1 aLi-Kroeger, David1 aYamamoto, Shinya1 aGrove, Megan, L1 aNaj, Adam1 aVronskaya, Maria1 aSalazar, Jose, L1 aDeStefano, Anita, L1 aBrody, Jennifer, A1 aSmith, Albert, V1 aAmin, Najaf1 aSims, Rebecca1 aIbrahim-Verbaas, Carla, A1 aChoi, Seung-Hoan1 aSatizabal, Claudia, L1 aLopez, Oscar, L1 aBeiser, Alexa1 aIkram, Arfan, M1 aGarcia, Melissa, E1 aHayward, Caroline1 aVarga, Tibor, V1 aRipatti, Samuli1 aFranks, Paul, W1 aHallmans, Göran1 aRolandsson, Olov1 aJansson, Jan-Håkon1 aPorteous, David, J1 aSalomaa, Veikko1 aEiriksdottir, Gudny1 aRice, Kenneth, M1 aBellen, Hugo, J1 aLevy, Daniel1 aUitterlinden, André, G1 aEmilsson, Valur1 aRotter, Jerome, I1 aAspelund, Thor1 aO'Donnell, Christopher, J1 aFitzpatrick, Annette, L1 aLauner, Lenore, J1 aHofman, Albert1 aSan Wang, Li-1 aWilliams, Julie1 aSchellenberg, Gerard, D1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aShulman, Joshua, M1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium1 aAlzheimer’s Disease Genetic Consortium1 aGenetic and Environmental Risk in Alzheimer’s Disease consortium uhttps://chs-nhlbi.org/node/726003859nas a2200769 4500008004100000022001400041245014200055210006900197260001300266300001000279490000700289520193000296100001402226700001802240700001802258700001402276700001902290700001402309700001602323700001102339700001902350700001302369700001502382700001702397700001402414700001202428700001402440700001502454700001602469700001702485700001802502700001602520700001702536700001502553700001802568700001402586700002002600700001702620700001602637700001102653700001402664700001902678700001902697700001702716700001502733700001402748700001702762700001202779700001602791700001502807700001702822700001702839700002202856700001702878700001402895700001502909700001402924700001102938700001202949700001502961700001702976700001802993700001203011700001303023700001703036856003603053 2016 eng d a1476-557800aRare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.0 aRare low frequency and common coding variants in CHRNA5 and thei c2016 May a601-70 v213 aThe common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.
1 aOlfson, E1 aSaccone, N, L1 aJohnson, E, O1 aChen, L-S1 aCulverhouse, R1 aDoheny, K1 aFoltz, S, M1 aFox, L1 aGogarten, S, M1 aHartz, S1 aHetrick, K1 aLaurie, C, C1 aMarosy, B1 aAmin, N1 aArnett, D1 aBarr, R, G1 aBartz, T, M1 aBertelsen, S1 aBorecki, I, B1 aBrown, M, R1 aChasman, D I1 aDuijn, C M1 aFeitosa, M, F1 aFox, E, R1 aFranceschini, N1 aFranco, O, H1 aGrove, M, L1 aGuo, X1 aHofman, A1 aKardia, S, L R1 aMorrison, A, C1 aMusani, S, K1 aPsaty, B M1 aRao, D, C1 aReiner, A, P1 aRice, K1 aRidker, P M1 aRose, L, M1 aSchick, U, M1 aSchwander, K1 aUitterlinden, A G1 aVojinovic, D1 aWang, J-C1 aWare, E, B1 aWilson, G1 aYao, J1 aZhao, W1 aBreslau, N1 aHatsukami, D1 aStitzel, J, A1 aRice, J1 aGoate, A1 aBierut, L, J uhttps://chs-nhlbi.org/node/679301877nas a2200181 4500008004100000022001400041245012000055210006900175260001600244520127500260100001701535700002601552700002201578700001801600700002001618700002101638856003601659 2016 eng d a1473-573300aRelation of coagulation factor XI with incident coronary heart disease and stroke: the Cardiovascular Health Study.0 aRelation of coagulation factor XI with incident coronary heart d c2016 Dec 223 aThe role of coagulation factor XI (FXI) in the cause of arterial thrombotic events remains uncertain. We examined the association of FXI with incident coronary heart disease (CHD), ischemic stroke, and hemorrhagic stroke. Data were from 3394 adults (mean age: 74.5 years) enrolled in the Cardiovascular Health Study who had FXI antigen from plasma samples drawn in 1992-1993 and were followed for cardiovascular events until 30 June 2013. Approximately 63% of participants were women and 17% were black. FXI levels were higher in blacks and women, showed positive associations with high-density lipoprotein and total cholesterol, BMI and diabetes, and negative associations with age and alcohol intake. During median follow-up of 13 years, we identified 1232 incident CHD, 473 ischemic stroke, and 84 hemorrhagic stroke events. In multivariable Cox models adjusted for traditional cardiovascular disease risk factors, the hazard ratio per one SD (32.2 mg/dl) increment of FXI was 1.02 (95% confidence interval: 0.96-1.08) for CHD; 0.94 (0.85-1.04) for ischemic stroke, and 0.85 (0.65-1.10) for hemorrhagic stroke. In this prospective cohort of elderly adults, there was no statistically significant association of higher FXI levels with incident CHD and stroke.
1 aAppiah, Duke1 aFashanu, Oluwaseun, E1 aHeckbert, Susa, R1 aCushman, Mary1 aPsaty, Bruce, M1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/736803152nas a2200529 4500008004100000022001400041245014400055210006900199260001300268300001000281490000700291520165800298653000901956653001001965653001801975653002801993653001202021653001102033653002202044653001202066653002702078653001902105653001102124653001402135653000902149653003202158653002402190653002002214653001702234653001802251653001802269100002402287700002002311700002102331700002402352700001902376700002102395700002402416700001802440700001902458700002302477700002202500700002402522700002002546700002002566856003602586 2016 eng d a1758-535X00aRelations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study.0 aRelations of Postload and Fasting Glucose With Incident Cardiova c2016 Mar a370-70 v713 aBACKGROUND: Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse.
METHODS: Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic.
RESULTS: Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models.
CONCLUSION: In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life.
10aAged10aAging10aBlood Glucose10aCardiovascular Diseases10aFasting10aFemale10aFollow-Up Studies10aGlucose10aGlucose Tolerance Test10aHealth Surveys10aHumans10aIncidence10aMale10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aSurvival Rate10aUnited States1 aBrutsaert, Erika, F1 aShitole, Sanyog1 aBiggs, Mary, Lou1 aMukamal, Kenneth, J1 adeBoer, Ian, H1 aThacker, Evan, L1 aBarzilay, Joshua, I1 aDjoussé, Luc1 aIx, Joachim, H1 aSmith, Nicholas, L1 aKaplan, Robert, C1 aSiscovick, David, S1 aPsaty, Bruce, M1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/685002682nas a2200253 4500008004100000022001400041245011600055210006900171260001600240300001200256490000600268520189400274100002102168700002102189700002302210700001902233700002202252700002702274700002402301700002702325700002102352700001902373856003602392 2016 eng d a1664-545600aRisk Factors for Incident Carotid Artery Revascularization among Older Adults: The Cardiovascular Health Study.0 aRisk Factors for Incident Carotid Artery Revascularization among c2016 Nov 16 a129-1390 v63 aBACKGROUND: Population-based risk factors for carotid artery revascularization are not known. We investigated the association between demographic and clinical characteristics and incident carotid artery revascularization in a cohort of older adults.
METHODS: Among Cardiovascular Health Study participants, a population-based cohort of 5,888 adults aged 65 years or older enrolled in two waves (1989-1990 and 1992-1993), 5,107 participants without a prior history of carotid endarterectomy (CEA) or cerebrovascular disease had a carotid ultrasound at baseline and were included in these analyses. Cox proportional hazards multivariable analysis was used to determine independent risk factors for incident carotid artery revascularization.
RESULTS: Over a mean follow-up of 13.5 years, 141 participants underwent carotid artery revascularization, 97% were CEA. Baseline degree of stenosis and incident ischemic cerebral events occurring during follow-up were the strongest predictors of incident revascularization. After adjustment for these, factors independently associated with an increased risk of incident revascularization were: hypertension (HR 1.53; 95% CI: 1.05-2.23), peripheral arterial disease (HR 2.57; 95% CI: 1.34-4.93), and low-density lipoprotein cholesterol (HR 1.23 per standard deviation [SD] increment [35.4 mg/dL]; 95% CI: 1.04-1.46). Factors independently associated with a lower risk of incident revascularization were: female gender (HR 0.51; 95% CI: 0.34-0.77) and older age (HR 0.69 per SD increment [5.5 years]; 95% CI: 0.56-0.86).
CONCLUSIONS: Even after accounting for carotid stenosis and incident cerebral ischemic events, carotid revascularization is related to age, gender, and cardiovascular risk factors. Further study of these demographic disparities and the role of risk factor control is warranted.
1 aGarg, Parveen, K1 aKoh, Willam, J H1 aDelaney, Joseph, A1 aHalm, Ethan, A1 aHirsch, Calvin, H1 aLongstreth, William, T1 aMukamal, Kenneth, J1 aKucharska-Newton, Anna1 aPolak, Joseph, F1 aCurtis, Lesley uhttps://chs-nhlbi.org/node/724402216nas a2200397 4500008004100000022001400041245018200055210006900237260001200306300001400318490000700332520093100339653002101270653003801291653001101329653005101340653002101391653003601412653001801448100002101466700001801487700002001505700002301525700001801548700002501566700002301591700002501614700002201639700002201661700001601683700002001699700002201719700002201741700001901763856003601782 2016 eng d a1744-804200aRooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment.0 aRooted in risk genetic predisposition for lowdensity lipoprotein c2016 10 a1621-16280 v173 aAIMS: To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response.
METHODS: We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia.
RESULTS: Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels.
CONCLUSION: Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.
10aCholesterol, LDL10aGenetic Predisposition to Disease10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aPharmacogenetics10aPolymorphism, Single Nucleotide10aTriglycerides1 aSmit, Roelof, Aj1 aPostmus, Iris1 aTrompet, Stella1 aBarnes, Michael, R1 aWarren, Helen1 aArsenault, Benoit, J1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aHitman, Graham, A1 aKrauss, Ronald, M1 aLi, Xiaohui1 aPsaty, Bruce, M1 aStein, Charles, M1 aRotter, Jerome, I1 aJukema, Wouter uhttps://chs-nhlbi.org/node/857102516nas a2200193 4500008004100000022001400041245011900055210006900174260001300243490000600256520188200262100002002144700002402164700002402188700002402212700002002236700003002256856003602286 2016 eng d a2047-998000aSoluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community-Dwelling Population.0 aSoluble ST2 for Prediction of Heart Failure and Cardiovascular D c2016 Aug0 v53 aBACKGROUND: Soluble ST2 (sST2), a marker of myocyte stretch and fibrosis, has prognostic value in many cardiovascular diseases. We hypothesized that sST2 levels are associated with incident heart failure (HF), including subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fraction, and cardiovascular death.
METHODS AND RESULTS: Baseline serum sST2 was measured in 3915 older, community-dwelling subjects from the Cardiovascular Health Study without prevalent HF. sST2 levels were associated with older age, male sex, black race, traditional cardiovascular risk factors, other biomarkers of inflammation, cardiac stretch, myocardial injury, and fibrosis, and abnormal echocardiographic parameters. In longitudinal analysis, greater sST2 was associated with a higher risk of incident HF and cardiovascular death; however, in multivariate models adjusting for other cardiac risk factors and the cardiac-specific biomarker, N-terminal pro-type B natriuretic peptide, these associations were attenuated. In these models, an sST2 level above the US Food and Drug Administration-approved cut-off value (>35 ng/mL) was significantly associated with incident HF (hazard ratio [HR], 1.20; 95% CI, 1.02-1.43) and cardiovascular death (HR, 1.21; 95% CI, 1.02-1.44), and greater sST2 was continuously associated with cardiovascular death (per 1-ln increment: HR, 1.24; 95% CI, 1.02-1.50). sST2 was not associated with the HF subtypes of HFpEF and HFrEF in adjusted analysis. Addition of sST2 to existing risk models of HF and cardiovascular death modestly improved discrimination and reclassification into a higher risk.
CONCLUSIONS: The predictive value of sST2 for HF of all subtypes and cardiovascular death is modest in an elderly population despite strong cross-sectional associations with risk factors and underlying cardiac pathology.
1 aParikh, Ravi, H1 aSeliger, Stephen, L1 aChristenson, Robert1 aGottdiener, John, S1 aPsaty, Bruce, M1 adeFilippi, Christopher, R uhttps://chs-nhlbi.org/node/713006988nas a2201993 4500008004100000022001400041245011600055210006900171260001600240520137500256100001201631700001301643700001801656700002201674700002201696700002501718700001801743700002701761700002001788700002801808700001901836700002001855700002101875700001801896700001601914700002801930700001901958700002501977700002302002700002302025700002302048700002502071700001902096700002102115700002102136700002202157700002102179700002302200700001502223700001802238700001902256700002102275700001702296700001702313700001602330700002002346700002802366700001802394700001902412700002002431700001702451700001802468700001802486700002202504700002102526700002102547700002902568700002302597700002202620700001702642700002202659700003202681700002102713700002302734700002102757700003102778700001402809700002202823700001902845700001602864700002102880700002102901700002302922700002302945700002402968700001902992700002103011700002303032700002103055700002003076700002403096700001803120700001703138700002003155700001803175700002003193700002403213700002103237700002103258700002503279700002203304700001603326700002103342700001703363700002203380700002303402700002003425700001803445700002403463700002203487700002203509700001903531700001903550700001703569700002803586700002403614700002303638700002503661700002003686700002403706700002103730700002403751700002203775700002203797700002303819700002203842700001703864700002103881700002103902700001703923700002003940700001803960700002503978700001904003700002104022700001904043700002004062700002104082700002504103700001804128700001904146700002004165700001904185700001904204700002004223700002904243700002004272700001104292700002304303700002004326700001904346700002004365700002604385700002404411700001904435700002104454700002004475700002404495700002104519700002304540700002804563700001804591700002304609700001704632700001904649700002604668700001904694700001904713700001804732700002304750700002104773700002304794700002304817700001904840700001904859710003904878710004104917856003604958 2016 eng d a1533-345000aSOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.0 aSOS2 and ACP1 Loci Identified through LargeScale Exome Chip Anal c2016 Dec 053 aGenome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
1 aLi, Man1 aLi, Yong1 aWeeks, Olivia1 aMijatovic, Vladan1 aTeumer, Alexander1 aHuffman, Jennifer, E1 aTromp, Gerard1 aFuchsberger, Christian1 aGorski, Mathias1 aLyytikäinen, Leo-Pekka1 aNutile, Teresa1 aSedaghat, Sanaz1 aSorice, Rossella1 aTin, Adrienne1 aYang, Qiong1 aAhluwalia, Tarunveer, S1 aArking, Dan, E1 aBihlmeyer, Nathan, A1 aBöger, Carsten, A1 aCarroll, Robert, J1 aChasman, Daniel, I1 aCornelis, Marilyn, C1 aDehghan, Abbas1 aFaul, Jessica, D1 aFeitosa, Mary, F1 aGambaro, Giovanni1 aGasparini, Paolo1 aGiulianini, Franco1 aHeid, Iris1 aHuang, Jinyan1 aImboden, Medea1 aJackson, Anne, U1 aJeff, Janina1 aJhun, Min, A1 aKatz, Ronit1 aKifley, Annette1 aKilpeläinen, Tuomas, O1 aKumar, Ashish1 aLaakso, Markku1 aLi-Gao, Ruifang1 aLohman, Kurt1 aLu, Yingchang1 aMägi, Reedik1 aMalerba, Giovanni1 aMihailov, Evelin1 aMohlke, Karen, L1 aMook-Kanamori, Dennis, O1 aRobino, Antonietta1 aRuderfer, Douglas1 aSalvi, Erika1 aSchick, Ursula, M1 aSchulz, Christina-Alexandra1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTraglia, Michela1 aYerges-Armstrong, Laura, M1 aZhao, Wei1 aGoodarzi, Mark, O1 aKraja, Aldi, T1 aLiu, Chunyu1 aWessel, Jennifer1 aBoerwinkle, Eric1 aBorecki, Ingrid, B1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBraga, Daniele1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarey, David, J1 aChristensen, Cramer1 aCoresh, Josef1 aCrook, Errol1 aCurhan, Gary, C1 aCusi, Daniele1 ade Boer, Ian, H1 ade Vries, Aiko, P J1 aDenny, Joshua, C1 aDevuyst, Olivier1 aDreisbach, Albert, W1 aEndlich, Karlhans1 aEsko, Tõnu1 aFranco, Oscar, H1 aFulop, Tibor1 aGerhard, Glenn, S1 aGlümer, Charlotte1 aGottesman, Omri1 aGrarup, Niels1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHayward, Caroline1 aHocking, Lynne1 aHofman, Albert1 aHu, Frank, B1 aHusemoen, Lise, Lotte N1 aJackson, Rebecca, D1 aJørgensen, Torben1 aJørgensen, Marit, E1 aKähönen, Mika1 aKardia, Sharon, L R1 aKönig, Wolfgang1 aKooperberg, Charles1 aKriebel, Jennifer1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLehtimäki, Terho1 aLevy, Daniel1 aLinksted, Pamela1 aLinneberg, Allan1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLupo, Antonio1 aMeisinger, Christine1 aMelander, Olle1 aMetspalu, Andres1 aMitchell, Paul1 aNauck, Matthias1 aNürnberg, Peter1 aOrho-Melander, Marju1 aParsa, Afshin1 aPedersen, Oluf1 aPeters, Annette1 aPeters, Ulrike1 aPolasek, Ozren1 aPorteous, David1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aQi, Lu1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRettig, Rainer1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRossouw, Jacques, E1 aSchmidt, Frank1 aSiscovick, David1 aSoranzo, Nicole1 aStrauch, Konstantin1 aToniolo, Daniela1 aTurner, Stephen, T1 aUitterlinden, André, G1 aUlivi, Sheila1 aVelayutham, Dinesh1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWang, Jie, Jin1 aWeir, David, R1 aWitte, Daniel1 aKuivaniemi, Helena1 aFox, Caroline, S1 aFranceschini, Nora1 aGoessling, Wolfram1 aKöttgen, Anna1 aChu, Audrey, Y1 aCHARGE Glycemic-T2D Working Group,1 aCHARGE Blood Pressure Working Group, uhttps://chs-nhlbi.org/node/725503259nas a2200481 4500008004100000022001400041245010400055210006900159260001600228300001100244490000800255520187600263653001802139653002802157653001102185653002202196653001902218653002002237653002402257653001102281653002702292653004502319653001102364653000902375653002602384653001302410653001702423653002102440653002202461653001802483100002002501700002302521700002102544700002202565700002802587700002302615700002202638700001602660700002402676700002102700700002002721856003602741 2016 ENG d a1524-453900aStudy of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.0 aStudy of Cardiovascular Health Outcomes in the Era of Claims Dat c2016 Jan 12 a156-640 v1333 aBACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.
METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare & Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6%, but this code identified only 53.8% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.
CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.
10aBlood Glucose10aCardiovascular Diseases10aFemale10aFollow-Up Studies10aHealth Surveys10aHospitalization10aHospitals, Veterans10aHumans10aInsurance Claim Review10aInternational Classification of Diseases10aLipids10aMale10aManaged Care Programs10aMedicare10aRisk Factors10aSampling Studies10aTreatment Outcome10aUnited States1 aPsaty, Bruce, M1 aDelaney, Joseph, A1 aArnold, Alice, M1 aCurtis, Lesley, H1 aFitzpatrick, Annette, L1 aHeckbert, Susan, R1 aMcKnight, Barbara1 aIves, Diane1 aGottdiener, John, S1 aKuller, Lewis, H1 aLongstreth, W T uhttps://chs-nhlbi.org/node/693202995nas a2200385 4500008004100000022001400041245024500055210006900300260001600369520171800385100001902103700001202122700001802134700002302152700001902175700001802194700002302212700002702235700001702262700001902279700001802298700002202316700001702338700002202355700001902377700002602396700001902422700002402441700002402465700002002489700002102509700002202530700002102552856003602573 2016 eng d a1460-208300aTargeted Sequencing of Genome Wide Significant Loci Associated with Bone Mineral Density (BMD) Reveals Significant Novel and Rare Variants: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.0 aTargeted Sequencing of Genome Wide Significant Loci Associated w c2016 Sep 113 aBACKGROUND: Bone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis.
METHODS AND RESULTS: Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study (n=925) and Cardiovascular Health Study (n=366), including 206 women and men with extreme low femoral neck (FN) BMD. A total of 4,964 sequence variants (SNVs) were observed and 80% were rare with MAF <1%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find protein-coding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS, ARHGAP1, and 5' of MEF2C (p-values < 8x10(-5); false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements.
CONCLUSIONS: Our findings suggest that protein-coding variants in selected GWAS loci did not contribute to GWAS signals. By performing targeted sequencing in GWAS loci, we identified less-common and rare non-coding SNVs associated with BMD independently from GWAS common SNPs, suggesting both common and less-common variants may associate with disease risks and phenotypes in the same loci.
1 aHsu, Yi-Hsiang1 aLi, Guo1 aLiu, Ching-Ti1 aBrody, Jennifer, A1 aKarasik, David1 aChou, Wen-Chi1 aDemissie, Serkalem1 aNandakumar, Kannabiran1 aZhou, Yanhua1 aCheng, Chia-Ho1 aGill, Richard1 aGibbs, Richard, A1 aMuzny, Donna1 aSantibanez, Jireh1 aEstrada, Karol1 aRivadeneira, Fernando1 aHarris, Tamara1 aGudnason, Vilmundur1 aUitterlinden, Andre1 aPsaty, Bruce, M1 aRobbins, John, A1 aCupples, Adrienne1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/724603627nas a2200637 4500008004100000022001400041245011300055210006900168260001300237300001400250490000800264520178200272100001802054700002702072700002602099700002102125700002002146700002002166700001902186700002602205700002102231700002902252700002102281700001802302700002002320700002302340700001402363700002302377700002002400700002202420700002102442700001802463700002002481700002002501700002002521700002102541700002402562700001902586700002302605700001902628700001902647700002502666700002302691700001802714700002202732700001902754700001802773700002402791700001902815700002102834700002102855700002102876700002202897710003402919856003602953 2016 eng d a1945-719700aThyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis.0 aThyroid Function Within the Reference Range and the Risk of Stro c2016 Nov a4270-42820 v1013 aCONTEXT: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.
DESIGN AND SETTING: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L.
RESULTS: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes.
CONCLUSION: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.
1 aChaker, Layal1 aBaumgartner, Christine1 aElzen, Wendy, P J den1 aCollet, Tinh-Hai1 aIkram, Arfan, M1 aBlum, Manuel, R1 aDehghan, Abbas1 aDrechsler, Christiane1 aLuben, Robert, N1 aPortegies, Marileen, L P1 aIervasi, Giorgio1 aMedici, Marco1 aStott, David, J1 aDullaart, Robin, P1 aFord, Ian1 aBremner, Alexandra1 aNewman, Anne, B1 aWanner, Christoph1 aSgarbi, José, A1 aDörr, Marcus1 aLongstreth, W T1 aPsaty, Bruce, M1 aFerrucci, Luigi1 aMaciel, Rui, M B1 aWestendorp, Rudi, G1 aJukema, Wouter1 aCeresini, Graziano1 aImaizumi, Misa1 aHofman, Albert1 aBakker, Stephan, J L1 aFranklyn, Jayne, A1 aKhaw, Kay-Tee1 aBauer, Douglas, C1 aWalsh, John, P1 aRazvi, Salman1 aGussekloo, Jacobijn1 aVölzke, Henry1 aFranco, Oscar, H1 aCappola, Anne, R1 aRodondi, Nicolas1 aPeeters, Robin, P1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/723805835nas a2201585 4500008004100000022001400041245012700055210006900182260001500251300001000266490000700276520141400283100001801697700002401715700001901739700002801758700001901786700001901805700002501824700001801849700001301867700002001880700002001900700002101920700001701941700002401958700002501982700001202007700002202019700002002041700002002061700002202081700002602103700001902129700001802148700001802166700002502184700002102209700002102230700002202251700002102273700001702294700001702311700001702328700001502345700002102360700002402381700003102405700002402436700002402460700002002484700001902504700001402523700002102537700002402558700001902582700002402601700002202625700001802647700001902665700002102684700002202705700001802727700002002745700002002765700002302785700001602808700002202824700002002846700001602866700002202882700002302904700002302927700001702950700002202967700002302989700001703012700002003029700002203049700002303071700001603094700002003110700001503130700002103145700002203166700001903188700002503207700002403232700002103256700002103277700002203298700001603320700002303336700002403359700002203383700001803405700001303423700001803436700002203454700002103476700002303497700002603520700002303546700002103569700002003590700002003610700002403630700001903654700002103673700002303694700002203717700002603739700002103765700002203786700002203808700002503830700002003855700002403875700002003899700002103919700002003940700001903960700002103979700002004000700002204020700002204042700002004064710002004084710002004104710002504124710002204149710002104171710002104192856003604213 2016 eng d a1537-660500aTrans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.0 aTransethnic Metaanalysis and Functional Annotation Illuminates t c2016 Jul 7 a56-750 v993 aKnowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
1 aLiu, Ching-Ti1 aRaghavan, Sridharan1 aMaruthur, Nisa1 aKabagambe, Edmond, Kato1 aHong, Jaeyoung1 aC Y Ng, Maggie1 aHivert, Marie-France1 aLu, Yingchang1 aAn, Ping1 aBentley, Amy, R1 aDrolet, Anne, M1 aGaulton, Kyle, J1 aGuo, Xiuqing1 aArmstrong, Loren, L1 aIrvin, Marguerite, R1 aLi, Man1 aLipovich, Leonard1 aRybin, Denis, V1 aTaylor, Kent, D1 aAgyemang, Charles1 aPalmer, Nicholette, D1 aCade, Brian, E1 aChen, Wei-Min1 aDauriz, Marco1 aDelaney, Joseph, A C1 aEdwards, Todd, L1 aEvans, Daniel, S1 aEvans, Michele, K1 aLange, Leslie, A1 aLeong, Aaron1 aLiu, Jingmin1 aLiu, Yongmei1 aNayak, Uma1 aPatel, Sanjay, R1 aPorneala, Bianca, C1 aRasmussen-Torvik, Laura, J1 aSnijder, Marieke, B1 aStallings, Sarah, C1 aTanaka, Toshiko1 aYanek, Lisa, R1 aZhao, Wei1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBiggs, Mary, L1 aBottinger, Erwin, P1 aBowden, Donald, W1 aChen, Guanjie1 aCorrea, Adolfo1 aCouper, David, J1 aCrawford, Dana, C1 aCushman, Mary1 aEicher, John, D1 aFornage, Myriam1 aFranceschini, Nora1 aFu, Yi-Ping1 aGoodarzi, Mark, O1 aGottesman, Omri1 aHara, Kazuo1 aHarris, Tamara, B1 aJensen, Richard, A1 aJohnson, Andrew, D1 aJhun, Min, A1 aKarter, Andrew, J1 aKeller, Margaux, F1 aKho, Abel, N1 aKizer, Jorge, R1 aKrauss, Ronald, M1 aLangefeld, Carl, D1 aLi, Xiaohui1 aLiang, Jingling1 aLiu, Simin1 aLowe, William, L1 aMosley, Thomas, H1 aNorth, Kari, E1 aPacheco, Jennifer, A1 aPeyser, Patricia, A1 aPatrick, Alan, L1 aRice, Kenneth, M1 aSelvin, Elizabeth1 aSims, Mario1 aSmith, Jennifer, A1 aTajuddin, Salman, M1 aVaidya, Dhananjay1 aWren, Mary, P1 aYao, Jie1 aZhu, Xiaofeng1 aZiegler, Julie, T1 aZmuda, Joseph, M1 aZonderman, Alan, B1 aZwinderman, Aeilko, H1 aAdeyemo, Adebowale1 aBoerwinkle, Eric1 aFerrucci, Luigi1 aHayes, Geoffrey1 aKardia, Sharon, L R1 aMiljkovic, Iva1 aPankow, James, S1 aRotimi, Charles, N1 aSale, Michèle, M1 aWagenknecht, Lynne, E1 aArnett, Donna, K1 aChen, Yii-Der Ida1 aNalls, Michael, A1 aProvince, Michael, A1 aKao, Linda, W H1 aSiscovick, David, S1 aPsaty, Bruce, M1 aWilson, James, G1 aLoos, Ruth, J F1 aDupuis, Josée1 aRich, Stephen, S1 aFlorez, Jose, C1 aRotter, Jerome, I1 aMorris, Andrew, P1 aMeigs, James, B1 aAAAG Consortium1 aCARe Consortium1 aCOGENT-BP Consortium1 aeMERGE Consortium1 aMEDIA Consortium1 aMAGIC Consortium uhttps://chs-nhlbi.org/node/714103045nas a2200709 4500008004100000022001400041245009300055210006900148260001500217300001400232490000700246520089300253653004101146653002501187653004901212653002101261653003801282653002701320653002401347653001101371653003801382653003401420653002801454653001101482653000901493653004001502653003601542653002301578653002801601653002801629100001801657700002401675700001801699700001901717700001901736700001801755700002801773700002801801700001801829700001801847700002401865700002301889700002001912700002801932700001701960700002301977700002202000700002202022700002102044700002402065700002102089700001902110700001902129700002202148700002202170700002302192700002502215700001702240700001502257710002702272856003602299 2016 eng d a1460-208300aTwenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram.0 aTwentyeight genetic loci associated with STTwave amplitudes of t c2016 05 15 a2093-21030 v253 aThe ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
10aAdaptor Proteins, Signal Transducing10aArrhythmias, Cardiac10aBasic Helix-Loop-Helix Transcription Factors10aBrugada Syndrome10aCardiac Conduction System Disease10aDeath, Sudden, Cardiac10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMale10aNAV1.5 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aRepressor Proteins10aShab Potassium Channels10aShal Potassium Channels1 aVerweij, Niek1 aLeach, Irene, Mateo1 aIsaacs, Aaron1 aArking, Dan, E1 aBis, Joshua, C1 aPers, Tune, H1 avan den Berg, Marten, E1 aLyytikäinen, Leo-Pekka1 aBarnett, Phil1 aWang, Xinchen1 aSoliman, Elsayed, Z1 aDuijn, Cornelia, M1 aKähönen, Mika1 avan Veldhuisen, Dirk, J1 aKors, Jan, A1 aRaitakari, Olli, T1 aSilva, Claudia, T1 aLehtimäki, Terho1 aHillege, Hans, L1 aHirschhorn, Joel, N1 aBoyer, Laurie, A1 aGilst, Wiek, H1 aAlonso, Alvaro1 aSotoodehnia, Nona1 aEijgelsheim, Mark1 ade Boer, Rudolf, A1 ade Bakker, Paul, I W1 aFranke, Lude1 aHarst, Pim1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/760403189nas a2200433 4500008004100000022001400041245005100055210005000106260001300156300001300169490000700182520196300189100002202152700002302174700002502197700002202222700001802244700003002262700001902292700002102311700002202332700001902354700002502373700002102398700002602419700001702445700002002462700002002482700002402502700002202526700002402548700002402572700002302596700001902619700002402638700001902662710003802681856003602719 2016 eng d a1553-740400aWhole Exome Sequencing in Atrial Fibrillation.0 aWhole Exome Sequencing in Atrial Fibrillation c2016 Sep ae10062840 v123 aAtrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.
1 aLubitz, Steven, A1 aBrody, Jennifer, A1 aBihlmeyer, Nathan, A1 aRoselli, Carolina1 aWeng, Lu-Chen1 aChristophersen, Ingrid, E1 aAlonso, Alvaro1 aBoerwinkle, Eric1 aGibbs, Richard, A1 aBis, Joshua, C1 aCupples, Adrienne, L1 aMohler, Peter, J1 aNickerson, Deborah, A1 aMuzny, Donna1 aPerez, Marco, V1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aLunetta, Kathryn, L1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aArking, Dan, E1 aEllinor, Patrick, T1 aLin, Honghuang1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/725002324nas a2200793 4500008004100000022001400041245015800055210006900213260001600282300000800298490000700306100002100313700002300334700002200357700002100379700001700400700002300417700002000440700001800460700002000478700001500498700001800513700002600531700002200557700002000579700001700599700002900616700002000645700001300665700001600678700002100694700002000715700002100735700001500756700002100771700001600792700001500808700002000823700002300843700002000866700002100886700002000907700002800927700002000955700002200975700002300997700002001020700002901040700002201069700002301091700002101114700002101135700002601156700001901182700002801201700002101229700002001250700002001270700001901290700002101309700002001330700002301350700003001373700002101403700002501424700002201449700002301471856003601494 2016 eng d a1537-660500aWhole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.0 aWholeExome Sequencing Identifies Loci Associated with Blood Cell c2016 Sep 01 a7850 v991 aPolfus, Linda, M1 aKhajuria, Rajiv, K1 aSchick, Ursula, M1 aPankratz, Nathan1 aPazoki, Raha1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aAuer, Paul, L1 aFloyd, James, S1 aHuang, Jie1 aLange, Leslie1 avan Rooij, Frank, J A1 aGibbs, Richard, A1 aMetcalf, Ginger1 aMuzny, Donna1 aVeeraraghavan, Narayanan1 aWalter, Klaudia1 aChen, Lu1 aYanek, Lisa1 aBecker, Lewis, C1 aPeloso, Gina, M1 aWakabayashi, Aoi1 aKals, Mart1 aMetspalu, Andres1 aEsko, Tõnu1 aFox, Keolu1 aWallace, Robert1 aFranceschini, Nora1 aMatijevic, Nena1 aRice, Kenneth, M1 aBartz, Traci, M1 aLyytikäinen, Leo-Pekka1 aKähönen, Mika1 aLehtimäki, Terho1 aRaitakari, Olli, T1 aLi-Gao, Ruifang1 aMook-Kanamori, Dennis, O1 aLettre, Guillaume1 aDuijn, Cornelia, M1 aFranco, Oscar, H1 aRich, Stephen, S1 aRivadeneira, Fernando1 aHofman, Albert1 aUitterlinden, André, G1 aWilson, James, G1 aPsaty, Bruce, M1 aSoranzo, Nicole1 aDehghan, Abbas1 aBoerwinkle, Eric1 aZhang, Xiaoling1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aJohnsen, Jill, M1 aReiner, Alexander, P1 aGanesh, Santhi, K1 aSankaran, Vijay, G uhttps://chs-nhlbi.org/node/726303877nas a2200313 4500008004100000022001400041245014800055210006900203260001600272300001200288490000600300520290500306100001803211700001603229700003003245700002303275700002203298700002403320700002003344700002403364700001903388700002003407700002203427700001903449700002103468700001803489700002003507856003603527 2017 eng d a2380-659100aAbsolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-Based Cohort Studies.0 aAbsolute Rates of Heart Failure Coronary Heart Disease and Strok c2017 Mar 01 a314-3180 v23 aImportance: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes.
Objective: To determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD.
Design, Setting and Participants: We pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012.
Exposures: Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine-cystatin C CKD-Epidemiology Collaboration Equation.
Main Outcomes and Measures: Poisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD.
Results: Among 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, and 44% (n = 6363) were African American. Overall, 1461 (10%) had CKD (mean [SD] estimated glomerular filtration rate, 49 [10] mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively.
Conclusions and Relevance: Among 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention.
1 aBansal, Nisha1 aKatz, Ronit1 aRobinson-Cohen, Cassianne1 aOdden, Michelle, C1 aDalrymple, Lorien1 aShlipak, Michael, G1 aSarnak, Mark, J1 aSiscovick, David, S1 aZelnick, Leila1 aPsaty, Bruce, M1 aKestenbaum, Bryan1 aCorrea, Adolfo1 aAfkarian, Maryam1 aYoung, Bessie1 ade Boer, Ian, H uhttps://chs-nhlbi.org/node/733701086nas a2200409 4500008004100000022001400041245008300055210006900138260001300207300000900220490000600229100002100235700001300256700001700269700001400286700002000300700001500320700001500335700001800350700001800368700001700386700001400403700001500417700001500432700001500447700001700462700001500479700001700494700001300511700001700524700003100541700001800572700001400590700001600604700002000620856003600640 2017 eng d a2376-783900aThe Alzheimer's Disease Sequencing Project: Study design and sample selection.0 aAlzheimers Disease Sequencing Project Study design and sample se c2017 Oct ae1940 v31 aBeecham, Gary, W1 aBis, J C1 aMartin, E, R1 aChoi, S-H1 aDeStefano, A, L1 aDuijn, C M1 aFornage, M1 aGabriel, S, B1 aKoboldt, D, C1 aLarson, D, E1 aNaj, A, C1 aPsaty, B M1 aSalerno, W1 aBush, W, S1 aForoud, T, M1 aWijsman, E1 aFarrer, L, A1 aGoate, A1 aHaines, J, L1 aPericak-Vance, Margaret, A1 aBoerwinkle, E1 aMayeux, R1 aSeshadri, S1 aSchellenberg, G uhttps://chs-nhlbi.org/node/755101904nas a2200577 4500008004100000022001400041245010300055210006900158260001600227300001400243490000700257100002300264700002400287700001900311700002600330700002200356700002500378700002000403700002000423700002400443700002000467700002200487700002700509700001900536700002400555700002300579700002100602700001800623700002200641700002800663700003000691700002100721700002100742700002400763700002300787700002300810700002100833700002500854700002700879700002100906700002200927700002100949700002100970700002000991700002501011710006501036710008501101710005101186710005301237856003601290 2017 eng d a1546-171800aAnalysis commons, a team approach to discovery in a big-data environment for genetic epidemiology.0 aAnalysis commons a team approach to discovery in a bigdata envir c2017 Oct 27 a1560-15630 v491 aBrody, Jennifer, A1 aMorrison, Alanna, C1 aBis, Joshua, C1 aO'Connell, Jeffrey, R1 aBrown, Michael, R1 aHuffman, Jennifer, E1 aAmes, Darren, C1 aCarroll, Andrew1 aConomos, Matthew, P1 aGabriel, Stacey1 aGibbs, Richard, A1 aGogarten, Stephanie, M1 aGupta, Namrata1 aJaquish, Cashell, E1 aJohnson, Andrew, D1 aLewis, Joshua, P1 aLiu, Xiaoming1 aManning, Alisa, K1 aPapanicolaou, George, J1 aPitsillides, Achilleas, N1 aRice, Kenneth, M1 aSalerno, William1 aSitlani, Colleen, M1 aSmith, Nicholas, L1 aHeckbert, Susan, R1 aLaurie, Cathy, C1 aMitchell, Braxton, D1 aVasan, Ramachandran, S1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium1 aTOPMed Hematology and Hemostasis Working Group1 aCHARGE Analysis and Bioinformatics Working Group uhttps://chs-nhlbi.org/node/755303488nas a2200481 4500008004100000022001400041245014400055210006900199260001600268300001400284490000800298520209000306653000902396653002202405653001502427653001802442653002802460653001902488653002202507653001102529653001102540653001402551653004902565653003302614653002502647653000902672653001602681653002402697653000902721100002502730700001702755700001402772700001902786700001802805700001802823700002002841700002002861700002102881700002102902700002502923700002202948856003602970 2017 eng d a1945-719700aThe Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study.0 aAssociation Between IGFI and IGFBP3 and Incident Diabetes in an c2017 Dec 01 a4541-45470 v1023 aContext: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I.
Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults.
Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged ≥65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates.
Setting: General community.
Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up.
Interventions: Not applicable.
Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) ≥126 mg/dL, non-FPG ≥200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare & Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx.
Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes.
Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.
10aAged10aAged, 80 and over10aBiomarkers10aBlood Glucose10aCardiovascular Diseases10aCohort Studies10aDiabetes Mellitus10aFemale10aHumans10aIncidence10aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aLongitudinal Studies10aMale10aNew England10aProspective Studies10aRisk1 aAneke-Nash, Chino, S1 aXue, XiaoNan1 aQi, Qibin1 aBiggs, Mary, L1 aCappola, Anne1 aKuller, Lewis1 aPollak, Michael1 aPsaty, Bruce, M1 aSiscovick, David1 aMukamal, Kenneth1 aStrickler, Howard, D1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/754710307nas a2202725 4500008004100000022001400041245012100055210006900176260001600245300001200261490000600273520278700279653001003066653000903076653002203085653002803107653001103135653003803146653003403184653002303218653001103241653000903252653003703261653001603298653001403314653003603328653002003364653001303384653002503397110005203422700002303474700002103497700001703518700001503535700002103550700001703571700002503588700002503613700002003638700001903658700001803677700001803695700001903713700002103732700002803753700002503781700002103806700002303827700002003850700001903870700001703889700002003906700002103926700001803947700001603965700002503981700002604006700002104032700001904053700002304072700002504095700002104120700001804141700002504159700003304184700002604217700003104243700001404274700001904288700002204307700002104329700001704350700002004367700002004387700002004407700001904427700002104446700002104467700002204488700002604510700001804536700002204554700002304576700002104599700002304620700001704643700002104660700002804681700002304709700001804732700002104750700002104771700001904792700002204811700001604833700002404849700002104873700002104894700001504915700002404930700002204954700002204976700001904998700001905017700002705036700002305063700002105086700001905107700002205126700001605148700002005164700002205184700002505206700001805231700002505249700002805274700001305302700002205315700001905337700001805356700002405374700002505398700002005423700002305443700001605466700001905482700002005501700002205521700001605543700002105559700002005580700001605600700002405616700002205640700002005662700001605682700002405698700002405722700002405746700002105770700002305791700002605814700002005840700002005860700001405880700001805894700001705912700002305929700002305952700001705975700001205992700002306004700002106027700002206048700002506070700002306095700001906118700002106137700002206158700001406180700002106194700002106215700001806236700002306254700001806277700001506295700001706310700001606327700001806343700002306361700002206384700001906406700002006425700002706445700001806472700001406490700002706504700001706531700001706548700001806565700001706583700001906600700001806619700002206637700002206659700001906681700001506700700001706715700001806732700001706750700001806767700001806785700002206803700002206825700002606847700001906873700002606892700002006918700001606938700001806954700002406972700001806996700002007014700001907034700001907053700002007072700002107092700001707113700002107130700002007151700001707171700001707188700002007205700002407225700001707249700002007266700002507286700003107311700002007342700001907362700002007381700001907401700001507420700002007435700001807455700002407473700002307497700002507520856003607545 2017 eng d a2374-244500aAssociation Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.0 aAssociation Between Telomere Length and Risk of Cancer and NonNe c2017 May 01 a636-6510 v33 aImportance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.
Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.
Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.
Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.
Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.
Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.
Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).
Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGerm-Line Mutation10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aNeoplasms10aPolymorphism, Single Nucleotide10aRisk Assessment10aTelomere10aTelomere Homeostasis1 aTelomeres Mendelian Randomization Collaboration1 aHaycock, Philip, C1 aBurgess, Stephen1 aNounu, Aayah1 aZheng, Jie1 aOkoli, George, N1 aBowden, Jack1 aWade, Kaitlin, Hazel1 aTimpson, Nicholas, J1 aEvans, David, M1 aWilleit, Peter1 aAviv, Abraham1 aGaunt, Tom, R1 aHemani, Gibran1 aMangino, Massimo1 aEllis, Hayley, Patricia1 aKurian, Kathreena, M1 aPooley, Karen, A1 aEeles, Rosalind, A1 aLee, Jeffrey, E1 aFang, Shenying1 aChen, Wei, V1 aLaw, Matthew, H1 aBowdler, Lisa, M1 aIles, Mark, M1 aYang, Qiong1 aWorrall, Bradford, B1 aMarkus, Hugh, Stephen1 aHung, Rayjean, J1 aAmos, Chris, I1 aSpurdle, Amanda, B1 aThompson, Deborah, J1 aO'Mara, Tracy, A1 aWolpin, Brian1 aAmundadottir, Laufey1 aStolzenberg-Solomon, Rachael1 aTrichopoulou, Antonia1 aOnland-Moret, Charlotte, N1 aLund, Eil1 aDuell, Eric, J1 aCanzian, Federico1 aSeveri, Gianluca1 aOvervad, Kim1 aGunter, Marc, J1 aTumino, Rosario1 aSvenson, Ulrika1 avan Rij, Andre1 aBaas, Annette, F1 aBown, Matthew, J1 aSamani, Nilesh, J1 avan t'Hof, Femke, N G1 aTromp, Gerard1 aJones, Gregory, T1 aKuivaniemi, Helena1 aElmore, James, R1 aJohansson, Mattias1 aMckay, James1 aScelo, Ghislaine1 aCarreras-Torres, Robert1 aGaborieau, Valerie1 aBrennan, Paul1 aBracci, Paige, M1 aNeale, Rachel, E1 aOlson, Sara, H1 aGallinger, Steven1 aLi, Donghui1 aPetersen, Gloria, M1 aRisch, Harvey, A1 aKlein, Alison, P1 aHan, Jiali1 aAbnet, Christian, C1 aFreedman, Neal, D1 aTaylor, Philip, R1 aMaris, John, M1 aAben, Katja, K1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aWiencke, John, K1 aWalsh, Kyle, M1 aWrensch, Margaret1 aRice, Terri1 aTurnbull, Clare1 aLitchfield, Kevin1 aPaternoster, Lavinia1 aStandl, Marie1 aAbecasis, Goncalo, R1 aSanGiovanni, John, Paul1 aLi, Yong1 aMijatovic, Vladan1 aSapkota, Yadav1 aLow, Siew-Kee1 aZondervan, Krina, T1 aMontgomery, Grant, W1 aNyholt, Dale, R1 avan Heel, David, A1 aHunt, Karen1 aArking, Dan, E1 aAshar, Foram, N1 aSotoodehnia, Nona1 aWoo, Daniel1 aRosand, Jonathan1 aComeau, Mary, E1 aBrown, Mark1 aSilverman, Edwin, K1 aHokanson, John, E1 aCho, Michael, H1 aHui, Jennie1 aFerreira, Manuel, A1 aThompson, Philip, J1 aMorrison, Alanna, C1 aFelix, Janine, F1 aSmith, Nicholas, L1 aChristiano, Angela, M1 aPetukhova, Lynn1 aBetz, Regina, C1 aFan, Xing1 aZhang, Xuejun1 aZhu, Caihong1 aLangefeld, Carl, D1 aThompson, Susan, D1 aWang, Feijie1 aLin, Xu1 aSchwartz, David, A1 aFingerlin, Tasha1 aRotter, Jerome, I1 aCotch, Mary, Frances1 aJensen, Richard, A1 aMunz, Matthias1 aDommisch, Henrik1 aSchaefer, Arne, S1 aHan, Fang1 aOllila, Hanna, M1 aHillary, Ryan, P1 aAlbagha, Omar1 aRalston, Stuart, H1 aZeng, Chenjie1 aZheng, Wei1 aShu, Xiao-Ou1 aReis, Andre1 aUebe, Steffen1 aHüffmeier, Ulrike1 aKawamura, Yoshiya1 aOtowa, Takeshi1 aSasaki, Tsukasa1 aHibberd, Martin, Lloyd1 aDavila, Sonia1 aXie, Gang1 aSiminovitch, Katherine1 aBei, Jin-Xin1 aZeng, Yi-Xin1 aFörsti, Asta1 aChen, Bowang1 aLandi, Stefano1 aFranke, Andre1 aFischer, Annegret1 aEllinghaus, David1 aFlores, Carlos1 aNoth, Imre1 aMa, Shwu-Fan1 aFoo, Jia, Nee1 aLiu, Jianjun1 aKim, Jong-Won1 aCox, David, G1 aDelattre, Olivier1 aMirabeau, Olivier1 aSkibola, Christine, F1 aTang, Clara, S1 aGarcia-Barcelo, Merce1 aChang, Kai-Ping1 aSu, Wen-Hui1 aChang, Yu-Sun1 aMartin, Nicholas, G1 aGordon, Scott1 aWade, Tracey, D1 aLee, Chaeyoung1 aKubo, Michiaki1 aCha, Pei-Chieng1 aNakamura, Yusuke1 aLevy, Daniel1 aKimura, Masayuki1 aHwang, Shih-Jen1 aHunt, Steven1 aSpector, Tim1 aSoranzo, Nicole1 aManichaikul, Ani, W1 aBarr, Graham1 aKahali, Bratati1 aSpeliotes, Elizabeth1 aYerges-Armstrong, Laura, M1 aCheng, Ching-Yu1 aJonas, Jost, B1 aWong, Tien, Yin1 aFogh, Isabella1 aLin, Kuang1 aPowell, John, F1 aRice, Kenneth1 aRelton, Caroline, L1 aMartin, Richard, M1 aSmith, George, Davey uhttps://chs-nhlbi.org/node/759402583nas a2200205 4500008004100000022001400041245014800055210006900203260001600272520187300288100002802161700002202189700002402211700002002235700002002255700002002275700002302295700002302318856003602341 2017 eng d a1941-722500aAssociation of Blood Pressure Trajectory With Mortality, Incident Cardiovascular Disease, and Heart Failure in the Cardiovascular Health Study.0 aAssociation of Blood Pressure Trajectory With Mortality Incident c2017 Mar 103 aBACKGROUND: Common blood pressure (BP) trajectories are not well established in elderly persons, and their association with clinical outcomes is uncertain.
METHODS: We used hierarchical cluster analysis to identify discrete BP trajectories among 4,067 participants in the Cardiovascular Health Study using repeated BP measures from years 0 to 7. We then evaluated associations of each BP trajectory cluster with all-cause mortality, incident cardiovascular disease (CVD, defined as stroke or myocardial infarction) (N = 2,837), and incident congestive heart failure (HF) (N = 3,633) using Cox proportional hazard models.
RESULTS: Median age was 77 years at year 7. Over a median 9.3 years of follow-up, there were 2,475 deaths, 659 CVD events, and 1,049 HF events. The cluster analysis identified 3 distinct trajectory groups. Participants in cluster 1 (N = 1,838) had increases in both systolic (SBP) and diastolic (DBP) BPs, whereas persons in cluster 2 (N = 1,109) had little change in SBP but declines in DBP. Persons in cluster 3 (N = 1,120) experienced declines in both SBP and DBP. After multivariable adjustment, clusters 2 and 3 were associated with increased mortality risk relative to cluster 1 (hazard ratio = 1.21, 95% confidence interval: 1.06-1.37 and hazard ratio = 1.20, 95% confidence interval: 1.05-1.36, respectively). Compared to cluster 1, cluster 3 had higher rates of incident CVD but associations were not statistically significant in demographic-adjusted models (hazard ratio = 1.16, 95% confidence interval: 0.96-1.39). Findings were similar when stratified by use of antihypertensive therapy.
CONCLUSIONS: Among community-dwelling elders, distinct BP trajectories were identified by integrating both SBP and DBP. These clusters were found to have differential associations with outcomes.
1 aSmitson, Christopher, C1 aScherzer, Rebecca1 aShlipak, Michael, G1 aPsaty, Bruce, M1 aNewman, Anne, B1 aSarnak, Mark, J1 aOdden, Michelle, C1 aPeralta, Carmen, A uhttps://chs-nhlbi.org/node/736202603nas a2200181 4500008004100000022001400041245015300055210006900208260001600277520196400293100002302257700002102280700002302301700002002324700001902344700002202363856003602385 2017 eng d a2213-178700aAssociation of Holter-Derived Heart Rate Variability Parameters With the Development of Congestive Heart Failure in the Cardiovascular Health Study.0 aAssociation of HolterDerived Heart Rate Variability Parameters W c2017 Mar 303 aOBJECTIVES: This study sought to determine whether Holter-based parameters of heart rate variability (HRV) are independently associated with incident heart failure among older adults in the CHS (Cardiovascular Health Study) as evidenced by an improvement in the predictive power of the Health Aging and Body Composition Heart Failure (Health ABC) score.
BACKGROUND: Abnormal HRV, a marker of autonomic dysfunction, has been associated with multiple adverse cardiovascular outcomes but not the development of congestive heart failure (CHF).
METHODS: Asymptomatic CHS participants with interpretable 24-h baseline Holter recordings were included (n = 1,401). HRV measures and premature ventricular contraction (PVC) counts were compared between participants with (n = 260) and without (n = 1,141) incident CHF on follow-up. Significantly different parameters between groups were added to the components of the Health ABC score, a validated CHF prediction tool, using stepwise Cox regression.
RESULTS: The final model included components of the Health ABC score, In PVC counts (adjusted hazard ratio [aHR]: 1.12; 95% confidence interval [CI]: 1.07 to 1.19; p < 0.001) and the following HRV measures: abnormal heart rate turbulence onset (aHR: 1.52; 95% CI: 1.11 to 2.08; p = 0.009), short-term fractal scaling exponent (aHR: 0.27; 95% CI: 0.14 to 0.53; p < 0.001), in very low frequency power (aHR: 1.28; 95% CI: 1.02 to 1.60; p = 0.037), and coefficient of variance of N-N intervals (aHR: 0.94; 95% CI: 0.90 to 0.99; p = 0.009). The C-statistic for the final model was significantly improved over the Health ABC model alone (0.77 vs. 0.73; p = 0.0002).
CONCLUSIONS: Abnormal HRV parameters were significantly and independently associated with incident CHF in asymptomatic, older adults. When combined with increased PVCs, HRV improved the predictive power of the Health ABC score.
1 aPatel, Vaiibhav, N1 aPierce, Brian, R1 aBodapati, Rohan, K1 aBrown, David, L1 aIves, Diane, G1 aStein, Phyllis, K uhttps://chs-nhlbi.org/node/735703651nas a2200301 4500008004100000022001400041245007800055210006900133260001600202300001400218490000600232520279800238100002003036700001603056700002403072700001503096700001503111700002003126700002603146700002003172700001803192700002203210700002103232700002103253700002003274700001903294856003603313 2017 eng d a2380-659100aAssociation of Mitochondrial DNA Copy Number With Cardiovascular Disease.0 aAssociation of Mitochondrial DNA Copy Number With Cardiovascular c2017 Nov 01 a1247-12550 v23 aImportance: Mitochondrial dysfunction is a core component of the aging process and may play a key role in atherosclerotic cardiovascular disease. Mitochondrial DNA copy number (mtDNA-CN), which represents the number of mitochondria per cell and number of mitochondrial genomes per mitochondrion, is an indirect biomarker of mitochondrial function.
Objective: To determine whether mtDNA-CN, measured in an easily accessible tissue (buffy coat/circulating leukocytes), can improve risk classification for cardiovascular disease (CVD) and help guide initiation of statin therapy for primary prevention of CVD.
Design, Setting, and Participants: Prospective, population-based cohort analysis including 21 870 participants (20 163 free from CVD at baseline) from 3 studies: Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities Study (ARIC), and Multiethnic Study of Atherosclerosis (MESA). The mean follow-up was 13.5 years. The study included 11 153 participants from ARIC, 4830 from CHS, and 5887 from MESA. Analysis of the data was conducted from March 10, 2014, to January 29, 2017.
Exposures: Mitochondrial DNA-CN measured from buffy coat/circulating leukocytes.
Main Outcomes and Measures: Incident CVD, which combines coronary heart disease, defined as the first incident myocardial infarction or death owing to coronary heart disease, and stroke, defined as the first nonfatal stroke or death owing to stroke.
Results: Of the 21 870 participants, the mean age was 62.4 years (ARIC, 57.9 years; MESA, 62.4 years; and CHS, 72.5 years), and 54.7% of participants were women. The hazard ratios for incident coronary heart disease, stroke, and CVD associated with a 1-SD decrease in mtDNA-CN were 1.29 (95% CI, 1.24-1.33), 1.11 (95% CI, 1.06-1.16), and 1.23 (95% CI, 1.19-1.26). The associations persisted after adjustment for traditional CVD risk factors. Addition of mtDNA-CN to the 2013 American College of Cardiology/American Heart Association Pooled Cohorts Equations for estimating 10-year hard atherosclerosis CVD risk was associated with improved risk classification (continuous net reclassification index, 0.194; 95% CI, 0.130-0.258; P < .001). Mitochondrial DNA-CN further improved sensitivity and specificity for the 2013 American College of Cardiology/American Heart Association recommendations on initiating statin therapy for primary prevention of ASCVD (net 221 individuals appropriately downclassified and net 15 individuals appropriately upclassified).
Conclusions and Relevance: Mitochondrial DNA-CN was independently associated with incident CVD in 3 large prospective studies and may have potential clinical utility in improving CVD risk classification.
1 aAshar, Foram, N1 aZhang, Yiyi1 aLongchamps, Ryan, J1 aLane, John1 aMoes, Anna1 aGrove, Megan, L1 aMychaleckyj, Josyf, C1 aTaylor, Kent, D1 aCoresh, Josef1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aPankratz, Nathan1 aGuallar, Eliseo1 aArking, Dan, E uhttps://chs-nhlbi.org/node/754802588nas a2200253 4500008004100000022001400041245008900055210006900144260001300213300001400226490000700240520182000247100002802067700002202095700002202117700002402139700002402163700002302187700002202210700002002232700002302252700002302275856003602298 2017 eng d a1556-387100aAtrial ectopy as a mediator of the association between race and atrial fibrillation.0 aAtrial ectopy as a mediator of the association between race and c2017 Dec a1856-18610 v143 aBACKGROUND: Blacks have a lower risk of atrial fibrillation (AF) despite having more AF risk factors, but the mechanism remains unknown. Premature atrial contraction (PAC) burden is a recently identified risk factor for AF.
OBJECTIVE: The purpose of this study was to determine whether the burden of PACs explains racial differences in AF risk.
METHODS: PAC burden (number per hour) was assessed by 24-hour ambulatory electrocardiographic (ECG) monitoring in a randomly selected subset of patients in the Cardiovascular Health Study. Participants were followed prospectively for the development of AF, diagnosed by study ECG and hospital admission records.
RESULTS: Among 938 participants (median age 73 years; 34% black; 58% female), 206 (22%) developed AF over a median follow-up of 11.0 years (interquartile range 6.1-13.4). After adjusting for age, sex, body mass index, coronary disease, congestive heart failure, diabetes, hypertension, alcohol consumption, smoking status, and study site, black race was associated with a 42% lower risk of AF (hazard ratio 0.58, 95% confidence interval [CI] 0.40-0.85; P = .005). The baseline PAC burden was 2.10 times (95% CI 1.57-2.83; P <.001) higher in whites than blacks. There was no detectable difference in premature ventricular contraction (PVC) burden by race. PAC burden mediated 19.5% (95% CI 6.3-52.5) of the adjusted association between race and AF.
CONCLUSION: On average, whites exhibited more PACs than blacks, and this difference statistically explains a modest proportion of the differential risk of AF by race. The differential PAC burden, without differences in PVCs, by race suggests that identifiable common exposures or genetic influences might be important to atrial pathophysiology.
1 aChristensen, Matthew, A1 aNguyen, Kaylin, T1 aStein, Phyllis, K1 aFohtung, Raymond, B1 aSoliman, Elsayed, Z1 aDewland, Thomas, A1 aVittinghoff, Eric1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/755502626nas a2200277 4500008004100000022001400041245009400055210006900149260001600218300000700234490000700241520180500248100002402053700002602077700002402103700001602127700002302143700002602166700002002192700001702212700002102229700001902250700001802269710002502287856003602312 2017 eng d a1472-694700aAutomatic identification of variables in epidemiological datasets using logic regression.0 aAutomatic identification of variables in epidemiological dataset c2017 Apr 13 a400 v173 aBACKGROUND: For an individual participant data (IPD) meta-analysis, multiple datasets must be transformed in a consistent format, e.g. using uniform variable names. When large numbers of datasets have to be processed, this can be a time-consuming and error-prone task. Automated or semi-automated identification of variables can help to reduce the workload and improve the data quality. For semi-automation high sensitivity in the recognition of matching variables is particularly important, because it allows creating software which for a target variable presents a choice of source variables, from which a user can choose the matching one, with only low risk of having missed a correct source variable.
METHODS: For each variable in a set of target variables, a number of simple rules were manually created. With logic regression, an optimal Boolean combination of these rules was searched for every target variable, using a random subset of a large database of epidemiological and clinical cohort data (construction subset). In a second subset of this database (validation subset), this optimal combination rules were validated.
RESULTS: In the construction sample, 41 target variables were allocated on average with a positive predictive value (PPV) of 34%, and a negative predictive value (NPV) of 95%. In the validation sample, PPV was 33%, whereas NPV remained at 94%. In the construction sample, PPV was 50% or less in 63% of all variables, in the validation sample in 71% of all variables.
CONCLUSIONS: We demonstrated that the application of logic regression in a complex data management task in large epidemiological IPD meta-analyses is feasible. However, the performance of the algorithm is poor, which may require backup strategies.
1 aLorenz, Matthias, W1 aAbdi, Negin, Ashtiani1 aScheckenbach, Frank1 aPflug, Anja1 aBülbül, Alpaslan1 aCatapano, Alberico, L1 aAgewall, Stefan1 aEzhov, Marat1 aBots, Michiel, L1 aKiechl, Stefan1 aOrth, Andreas1 aPROG-IMT Study Group uhttps://chs-nhlbi.org/node/757403194nas a2200469 4500008004100000022001400041245014600055210006900201260001300270300001400283490000700297520186100304653001602165653000902181653002802190653001902218653002402237653002402261653001102285653001502296653001102311653001702322653001402339653001802353653002502371653003102396653000902427653002402436653001902460653001702479653001702496653001802513100002102531700002002552700001802572700001702590700001702607700002002624700002002644700002402664856003602688 2017 eng d a1524-463600aBlood Pressure and Heart Rate Measures Associated With Increased Risk of Covert Brain Infarction and Worsening Leukoaraiosis in Older Adults.0 aBlood Pressure and Heart Rate Measures Associated With Increased c2017 Aug a1579-15860 v373 aOBJECTIVE: In people without previous stroke, covert findings on serial magnetic resonance imaging (MRI) of incident brain infarcts and worsening leukoaraiosis are associated with increased risk for ischemic stroke and dementia. We evaluated whether various measures of blood pressure (BP) and heart rate are associated with these MRI findings.
APPROACH AND RESULTS: In the CHS (Cardiovascular Health Study), a longitudinal cohort study of older adults, we used relative risk regression to assess the associations of mean, variability, and trend in systolic BP, diastolic BP, and heart rate measured at 4 annual clinic visits between 2 brain MRIs with incident covert brain infarction and worsening white matter grade (using a 10-point scale to characterize leukoaraiosis). We included participants who had both brain MRIs, no stroke before the follow-up MRI, and no change in antihypertensive medication status during follow-up. Among 878 eligible participants, incident covert brain infarction occurred in 15% and worsening white matter grade in 27%. Mean systolic BP was associated with increased risk for incident covert brain infarction (relative risk per 10 mm Hg, 1.28; 95% confidence interval, 1.12-1.47), and mean diastolic BP was associated with increased risk for worsening white matter grade (relative risk per 10 mm Hg, 1.45; 95% confidence interval, 1.24-1.69). These findings persisted in secondary and sensitivity analyses.
CONCLUSIONS: Elevated mean systolic BP is associated with increased risk for covert brain infarction, and elevated mean diastolic BP is associated with increased risk for worsening leukoaraiosis. These findings reinforce the importance of hypertension in the development of silent cerebrovascular diseases, but the pathophysiologic relationships to BP for each may differ.
10aAge Factors10aAged10aAntihypertensive Agents10aBlood Pressure10aCerebral Infarction10aDisease Progression10aFemale10aHeart Rate10aHumans10aHypertension10aIncidence10aLeukoaraiosis10aLongitudinal Studies10aMagnetic Resonance Imaging10aMale10aProspective Studies10aPulsatile Flow10aRisk Factors10aTime Factors10aUnited States1 aLeung, Lester, Y1 aBartz, Traci, M1 aRice, Kenneth1 aFloyd, James1 aPsaty, Bruce1 aGutierrez, Jose1 aLongstreth, W T1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/746602209nas a2200193 4500008004100000022001400041245011400055210006900169260001600238520157000254100002001824700002101844700002001865700002901885700002201914700002001936700002301956856003601979 2017 eng d a1464-368500aComparing methods to address bias in observational data: statin use and cardiovascular events in a US cohort.0 aComparing methods to address bias in observational data statin u c2017 Sep 083 aBackground: The theoretical conditions under which causal estimates can be derived from observational data are challenging to achieve in the real world. Applied examples can help elucidate the practical limitations of methods to estimate randomized-controlled trial effects from observational data.
Methods: We used six methods with varying design and analytic features to compare the 5-year risk of incident myocardial infarction among statin users and non-users, and used non-cardiovascular mortality as a negative control outcome. Design features included restriction to a statin-eligible population and new users only; analytic features included multivariable adjustment and propensity score matching.
Results: We used data from 5294 participants in the Cardiovascular Health Study from 1989 to 2004. For non-cardiovascular mortality, most methods produced protective estimates with confidence intervals that crossed the null. The hazard ratio (HR) was 0.92, 95% confidence interval: 0.58, 1.46 using propensity score matching among eligible new users. For myocardial infarction, all estimates were strongly protective; the propensity score-matched analysis among eligible new users resulted in a HR of 0.55 (0.29, 1.05)-a much stronger association than observed in randomized controlled trials.
Conclusions: In designs that compare active treatment with non-treated participants to evaluate effectiveness, methods to address bias in observational data may be limited in real-world settings by residual bias.
1 aKaiser, Paulina1 aArnold, Alice, M1 aBenkeser, David1 aHazzouri, Adina, Zeki Al1 aHirsch, Calvin, H1 aPsaty, Bruce, M1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/750204941nas a2201165 4500008004100000022001400041245010700055210006900162260000900231300001300240490000700253520165900260100002201919700002501941700002301966700002001989700002802009700002202037700002202059700002002081700001902101700001902120700002502139700002202164700001802186700001502204700002002219700002302239700002402262700002002286700001902306700002702325700001902352700001702371700002302388700001602411700002002427700002302447700001602470700002102486700002502507700002102532700002002553700002502573700002002598700002002618700002302638700002102661700002502682700002402707700002002731700002102751700002502772700002502797700002002822700002802842700001902870700002102889700001702910700002202927700001502949700002702964700002002991700001903011700001903030700002303049700001703072700002603089700002203115700002003137700001803157700002003175700002803195700001903223700002003242700001903262700001903281700002103300700002203321700002003343700002003363700001803383700002003401700002403421700002103445700002103466700002303487700001803510700001803528700002003546700001903566700002103585700001903606700001903625700003003644700002303674700002303697700001903720856003603739 2017 eng d a1932-620300aComparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.0 aComparison of HapMap and 1000 Genomes Reference Panels in a Larg c2017 ae01677420 v123 aAn increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.
1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aChasman, Daniel, I1 aTrompet, Stella1 aAhluwalia, Tarunveer, S1 aTeumer, Alexander1 aKleber, Marcus, E1 aChen, Ming-Huei1 aWang, Jie, Jin1 aAttia, John, R1 aMarioni, Riccardo, E1 aSteri, Maristella1 aWeng, Lu-Chen1 aPool, Rene1 aGrossmann, Vera1 aBrody, Jennifer, A1 aVenturini, Cristina1 aTanaka, Toshiko1 aRose, Lynda, M1 aOldmeadow, Christopher1 aMazur, Johanna1 aBasu, Saonli1 aFrånberg, Mattias1 aYang, Qiong1 aLigthart, Symen1 aHottenga, Jouke, J1 aRumley, Ann1 aMulas, Antonella1 ade Craen, Anton, J M1 aGrotevendt, Anne1 aTaylor, Kent, D1 aDelgado, Graciela, E1 aKifley, Annette1 aLopez, Lorna, M1 aBerentzen, Tina, L1 aMangino, Massimo1 aBandinelli, Stefania1 aMorrison, Alanna, C1 aHamsten, Anders1 aTofler, Geoffrey1 ade Maat, Moniek, P M1 aDraisma, Harmen, H M1 aLowe, Gordon, D1 aZoledziewska, Magdalena1 aSattar, Naveed1 aLackner, Karl, J1 aVölker, Uwe1 aMcKnight, Barbara1 aHuang, Jie1 aHolliday, Elizabeth, G1 aMcEvoy, Mark, A1 aStarr, John, M1 aHysi, Pirro, G1 aHernandez, Dena, G1 aGuan, Weihua1 aRivadeneira, Fernando1 aMcArdle, Wendy, L1 aSlagboom, Eline1 aZeller, Tanja1 aPsaty, Bruce, M1 aUitterlinden, André, G1 aGeus, Eco, J C1 aStott, David, J1 aBinder, Harald1 aHofman, Albert1 aFranco, Oscar, H1 aRotter, Jerome, I1 aFerrucci, Luigi1 aSpector, Tim, D1 aDeary, Ian, J1 aMärz, Winfried1 aGreinacher, Andreas1 aWild, Philipp, S1 aCucca, Francesco1 aBoomsma, Dorret, I1 aWatkins, Hugh1 aTang, Weihong1 aRidker, Paul, M1 aJukema, Jan, W1 aScott, Rodney, J1 aMitchell, Paul1 aHansen, Torben1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aStrachan, David, P1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/734304071nas a2200973 4500008004100000022001400041245007600055210006800131260001600199300001200215490000600227520134400233100002101577700001901598700001801617700002401635700002301659700002001682700001701702700001801719700002101737700002101758700002001779700002101799700002101820700002001841700002001861700002101881700002601902700002101928700001201949700002401961700002001985700002402005700001902029700001902048700001802067700002202085700002202107700001802129700002302147700002502170700002002195700002102215700001902236700002402255700002202279700003602301700001902337700001902356700002602375700002002401700002602421700002102447700002002468700002302488700001702511700002102528700002302549700002802572700001902600700001402619700001902633700002302652700002002675700002202695700002402717700001802741700002202759700002402781700002202805700002602827700002402853700001902877700002302896700001702919700002102936700002302957700002002980700002103000700002403021700001603045856003603061 2017 eng d a1945-458900aThe complex genetics of gait speed: genome-wide meta-analysis approach.0 acomplex genetics of gait speed genomewide metaanalysis approach c2017 Jan 10 a209-2460 v93 aEmerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
1 aBen-Avraham, Dan1 aKarasik, David1 aVerghese, Joe1 aLunetta, Kathryn, L1 aSmith, Jennifer, A1 aEicher, John, D1 aVered, Rotem1 aDeelen, Joris1 aArnold, Alice, M1 aBuchman, Aron, S1 aTanaka, Toshiko1 aFaul, Jessica, D1 aNethander, Maria1 aFornage, Myriam1 aAdams, Hieab, H1 aMatteini, Amy, M1 aCallisaya, Michele, L1 aSmith, Albert, V1 aYu, Lei1 aDe Jager, Philip, L1 aEvans, Denis, A1 aGudnason, Vilmundur1 aHofman, Albert1 aPattie, Alison1 aCorley, Janie1 aLauner, Lenore, J1 aKnopman, Davis, S1 aParimi, Neeta1 aTurner, Stephen, T1 aBandinelli, Stefania1 aBeekman, Marian1 aGutman, Danielle1 aSharvit, Lital1 aMooijaart, Simon, P1 aLiewald, David, C1 aHouwing-Duistermaat, Jeanine, J1 aOhlsson, Claes1 aMoed, Matthijs1 aVerlinden, Vincent, J1 aMellström, Dan1 avan der Geest, Jos, N1 aKarlsson, Magnus1 aHernandez, Dena1 aMcWhirter, Rebekah1 aLiu, Yongmei1 aThomson, Russell1 aTranah, Gregory, J1 aUitterlinden, André, G1 aWeir, David, R1 aZhao, Wei1 aStarr, John, M1 aJohnson, Andrew, D1 aIkram, Arfan, M1 aBennett, David, A1 aCummings, Steven, R1 aDeary, Ian, J1 aHarris, Tamara, B1 aKardia, Sharon, L R1 aMosley, Thomas, H1 aSrikanth, Velandai, K1 aWindham, Beverly, G1 aNewman, Ann, B1 aWalston, Jeremy, D1 aDavies, Gail1 aEvans, Daniel, S1 aSlagboom, Eline, P1 aFerrucci, Luigi1 aKiel, Douglas, P1 aMurabito, Joanne, M1 aAtzmon, Gil uhttps://chs-nhlbi.org/node/734003000nas a2200517 4500008004100000022001400041245014300055210006900198260001600267300001400283490000800297520149600305653000901801653002201810653002801832653003101860653002001891653002801911653001901939653000901958653001301967653001101980653002401991653002202015653001102037653001402048653002502062653000902087653001402096653003302110653002402143653001802167100002202185700002202207700002002229700002202249700001902271700002302290700002102313700002202334700002802356700002202384700002002406700002002426856003602446 2017 eng d a1476-625600aConcordance With Prevention Guidelines and Subsequent Cancer, Cardiovascular Disease, and Mortality: A Longitudinal Study of Older Adults.0 aConcordance With Prevention Guidelines and Subsequent Cancer Car c2017 Nov 15 a1168-11790 v1863 aReports on the associations between multiple clinical and behavioral health indicators and major health outcomes among older adults are scarce. We prospectively examined concordance with guidelines from the American Cancer Society and American Heart Association for disease prevention in relation to cancer, cardiovascular disease (CVD), and mortality among Cardiovascular Health Study enrollees aged 65-98 years who, at baseline assessment in 1989-1996 (n = 3,491), were free of CVD and cancer. Total and cause-specific mortality, as well as incidence of cancer and CVD, were lower with higher guideline concordance. Independent of body mass index, blood pressure, total cholesterol, and fasting plasma glucose, better health behaviors (diet, physical activity, and alcohol consumption) were associated with lower mortality (2-sided P < 0.0001). Among individuals with ideal levels for 3-4 of these 4 cardiometabolic biomarkers, those with poor concordance with health behavior recommendations had higher mortality compared with those who had the highest concordance with these behavioral recommendations (adjusted mortality hazard ratio = 1.82, 95% confidence interval: 1.25, 2.67). Older adults who are concordant with recommendations for cancer and CVD prevention have reduced rates of chronic disease and mortality. Interventions to achieve and maintain healthy lifestyle behaviors may offer benefits both in the presence and absence of adverse traditional clinical risk factors.
10aAged10aAged, 80 and over10aAmerican Cancer Society10aAmerican Heart Association10aBody Mass Index10aCardiovascular Diseases10aCause of Death10aDiet10aExercise10aFemale10aGuideline Adherence10aHealthy Lifestyle10aHumans10aIncidence10aLongitudinal Studies10aMale10aNeoplasms10aPractice Guidelines as Topic10aProspective Studies10aUnited States1 aGreenlee, Heather1 aStrizich, Garrett1 aLovasi, Gina, S1 aKaplan, Robert, C1 aBiggs, Mary, L1 aLi, Christopher, I1 aRichardson, John1 aBurke, Gregory, L1 aFitzpatrick, Annette, L1 aFretts, Amanda, M1 aPsaty, Bruce, M1 aFried, Linda, P uhttps://chs-nhlbi.org/node/756303099nas a2200481 4500008004100000022001400041245014200055210006900197260001600266520168500282100002201967700002301989700002402012700001702036700001302053700001202066700002202078700001702100700002002117700002002137700001802157700002402175700002002199700002102219700002202240700002002262700001902282700001402301700002202315700002202337700002002359700002102379700001702400700002202417700002402439700001802463700001702481700002702498700001602525700002102541700001902562856003602581 2017 eng d a1460-208300aDetection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium.0 aDetection of genetic loci associated with plasma fetuinA A metaa c2017 Apr 033 aPlasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies.We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (p < 0.05x10-8) SNPs near the AHSG locus, the top SNP was rs4917 (p = 1.27x10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/L (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.
1 aJensen, Majken, K1 aJensen, Richard, A1 aMukamal, Kenneth, J1 aGuo, Xiuqing1 aYao, Jie1 aSun, Qi1 aCornelis, Marilyn1 aLiu, Yongmei1 aChen, Ming-Huei1 aKizer, Jorge, R1 aDjoussé, Luc1 aSiscovick, David, S1 aPsaty, Bruce, M1 aZmuda, Joseph, M1 aRotter, Jerome, I1 aGarcia, Melissa1 aHarris, Tamara1 aChen, Ida1 aGoodarzi, Mark, O1 aNalls, Michael, A1 aKeller, Margaux1 aArnold, Alice, M1 aNewman, Anne1 aHoogeeven, Ron, C1 aRexrode, Kathryn, M1 aRimm, Eric, B1 aHu, Frank, B1 aVasan, Ramachandran, S1 aKatz, Ronit1 aPankow, James, S1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/732806485nas a2201489 4500008004100000022001400041245020200055210006900257260001600326300001300342490000700355520221400362100001902576700002202595700001802617700002102635700001902656700001802675700001902693700001902712700002102731700002402752700001802776700002302794700001902817700002402836700001502860700001702875700002102892700002202913700002002935700002402955700002202979700002203001700002703023700001803050700001803068700002203086700002503108700002703133700002303160700001503183700002403198700002803222700002203250700002003272700002103292700002203313700002103335700002403356700001803380700002403398700002203422700002003444700002303464700002003487700002303507700002003530700002403550700001903574700001703593700001803610700001903628700002003647700001803667700001603685700001203701700002203713700001503735700002203750700002203772700001903794700002203813700001903835700002503854700002203879700002303901700001703924700002403941700002303965700002503988700001604013700001904029700002204048700001904070700001304089700001804102700002304120700002304143700002304166700001704189700001804206700002104224700002204245700002104267700002804288700001804316700001904334700001404353700001504367700002104382700002304403700002404426700002904450700001404479700002304493700002204516700002004538700002204558700002104580700002304601700002204624700002204646700002404668700001204692700002104704700002004725700002204745700002104767700002204788700002504810700002704835700002004862700001904882710005804901856003604959 2017 eng d a1553-740400aDiscovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium.0 aDiscovery and finemapping of adiposity loci using high density i c2017 Apr 21 ae10067190 v133 aGenome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
1 aC Y Ng, Maggie1 aGraff, Mariaelisa1 aLu, Yingchang1 aJustice, Anne, E1 aMudgal, Poorva1 aLiu, Ching-Ti1 aYoung, Kristin1 aYanek, Lisa, R1 aFeitosa, Mary, F1 aWojczynski, Mary, K1 aRand, Kristin1 aBrody, Jennifer, A1 aCade, Brian, E1 aDimitrov, Latchezar1 aDuan, Qing1 aGuo, Xiuqing1 aLange, Leslie, A1 aNalls, Michael, A1 aOkut, Hayrettin1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aVedantam, Sailaja1 aBradfield, Jonathan, P1 aChen, Guanjie1 aChen, Wei-Min1 aChesi, Alessandra1 aIrvin, Marguerite, R1 aPadhukasahasram, Badri1 aSmith, Jennifer, A1 aZheng, Wei1 aAllison, Matthew, A1 aAmbrosone, Christine, B1 aBandera, Elisa, V1 aBartz, Traci, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBottinger, Erwin, P1 aCarpten, John1 aChanock, Stephen, J1 aChen, Yii-Der Ida1 aConti, David, V1 aCooper, Richard, S1 aFornage, Myriam1 aFreedman, Barry, I1 aGarcia, Melissa1 aGoodman, Phyllis, J1 aHsu, Yu-Han, H1 aHu, Jennifer1 aHuff, Chad, D1 aIngles, Sue, A1 aJohn, Esther, M1 aKittles, Rick1 aKlein, Eric1 aLi, Jin1 aMcKnight, Barbara1 aNayak, Uma1 aNemesure, Barbara1 aOgunniyi, Adesola1 aOlshan, Andrew1 aPress, Michael, F1 aRohde, Rebecca1 aRybicki, Benjamin, A1 aSalako, Babatunde1 aSanderson, Maureen1 aShao, Yaming1 aSiscovick, David, S1 aStanford, Janet, L1 aStevens, Victoria, L1 aStram, Alex1 aStrom, Sara, S1 aVaidya, Dhananjay1 aWitte, John, S1 aYao, Jie1 aZhu, Xiaofeng1 aZiegler, Regina, G1 aZonderman, Alan, B1 aAdeyemo, Adebowale1 aAmbs, Stefan1 aCushman, Mary1 aFaul, Jessica, D1 aHakonarson, Hakon1 aLevin, Albert, M1 aNathanson, Katherine, L1 aWare, Erin, B1 aWeir, David, R1 aZhao, Wei1 aZhi, Degui1 aArnett, Donna, K1 aGrant, Struan, F A1 aKardia, Sharon, L R1 aOloapde, Olufunmilayo, I1 aRao, D, C1 aRotimi, Charles, N1 aSale, Michèle, M1 aWilliams, Keoki1 aZemel, Babette, S1 aBecker, Diane, M1 aBorecki, Ingrid, B1 aEvans, Michele, K1 aHarris, Tamara, B1 aHirschhorn, Joel, N1 aLi, Yun1 aPatel, Sanjay, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aWilson, James, G1 aBowden, Donald, W1 aCupples, Adrienne, L1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aNorth, Kari, E1 aBone Mineral Density in Childhood Study (BMDCS) Group uhttps://chs-nhlbi.org/node/735203246nas a2200505 4500008004100000022001400041245015500055210006900210260001600279520174700295100001202042700002002054700001702074700001702091700001802108700002002126700002202146700001902168700001202187700002102199700002102220700002802241700002502269700002102294700002102315700002002336700002502356700002102381700002102402700001802423700002402441700002102465700002102486700002002507700001702527700001802544700002202562700002402584700002502608700002002633700002202653700001702675700001202692856003602704 2017 eng d a1539-726200aDiscovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations.0 aDiscovery and finemapping of loci associated with monounsaturate c2017 Mar 153 aMonounsaturated fatty acids (MUFAs) are unsaturated fatty acids with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels were associated with cardiometabolic disorders including cardiovascular disease (CVD), type 2 diabetes (T2D) and metabolic syndrome (MS). Previous genome-wide association studies (GWAS) have identified seven loci for plasma and erythrocyte palmitoleic acid and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential causal variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in over 15,000 participants of Chinese- and European-ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log10(Bayes factor)>=8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor)>=61619;6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering ~95kb) to five (covering ~20kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were enriched in unsaturated fatty acids metabolism and signaling pathways. Our findings provided novel insight into the genetic basis relevant to MUFA metabolism and biology.
1 aHu, Yao1 aTanaka, Toshiko1 aZhu, Jingwen1 aGuan, Weihua1 aH Y Wu, Jason1 aPsaty, Bruce, M1 aMcKnight, Barbara1 aKing, Irena, B1 aSun, Qi1 aRichard, Melissa1 aManichaikul, Ani1 aFrazier-Wood, Alexis, C1 aKabagambe, Edmond, K1 aHopkins, Paul, N1 aOrdovas, Jose, M1 aFerrucci, Luigi1 aBandinelli, Stefania1 aArnett, Donna, K1 aChen, Yii-der, I1 aLiang, Shuang1 aSiscovick, David, S1 aTsai, Michael, Y1 aRich, Stephen, S1 aFornage, Myriam1 aHu, Frank, B1 aRimm, Eric, B1 aJensen, Majken, K1 aLemaitre, Rozenn, N1 aMozaffarian, Dariush1 aSteffen, Lyn, M1 aMorris, Andrew, P1 aLi, Huaixing1 aLin, Xu uhttps://chs-nhlbi.org/node/734603683nas a2200757 4500008004100000022001400041245011200055210006900167260000900236300000700245490000700252520150800259100002401767700002201791700002101813700001601834700001601850700002701866700002501893700002101918700002201939700001601961700001901977700001701996700002402013700001802037700002302055700001802078700002802096700002302124700002602147700002002173700002202193700002302215700002002238700002302258700002302281700002002304700003102324700001802355700001802373700002702391700002002418700002402438700001802462700002202480700002202502700001802524700002102542700002102563700002002584700001902604700002802623700002002651700002402671700002202695700002102717700001902738700001802757700002002775700001902795700002702814700002402841700002402865856003602889 2017 eng d a1756-038100aDiscovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.0 aDiscovery and replication of SNPSNP interactions for quantitativ c2017 a250 v103 aBACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).
RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.
CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
1 aHolzinger, Emily, R1 aVerma, Shefali, S1 aMoore, Carrie, B1 aHall, Molly1 aDe, Rishika1 aGilbert-Diamond, Diane1 aLanktree, Matthew, B1 aPankratz, Nathan1 aAmuzu, Antoinette1 aBurt, Amber1 aDale, Caroline1 aDudek, Scott1 aFurlong, Clement, E1 aGaunt, Tom, R1 aKim, Daniel, Seung1 aRiess, Helene1 aSivapalaratnam, Suthesh1 aTragante, Vinicius1 avan Iperen, Erik, P A1 aBrautbar, Ariel1 aCarrell, David, S1 aCrosslin, David, R1 aJarvik, Gail, P1 aKuivaniemi, Helena1 aKullo, Iftikhar, J1 aLarson, Eric, B1 aRasmussen-Torvik, Laura, J1 aTromp, Gerard1 aBaumert, Jens1 aCruickshanks, Karen, J1 aFarrall, Martin1 aHingorani, Aroon, D1 aHovingh, G, K1 aKleber, Marcus, E1 aKlein, Barbara, E1 aKlein, Ronald1 aKoenig, Wolfgang1 aLange, Leslie, A1 aMӓrz, Winfried1 aNorth, Kari, E1 aOnland-Moret, Charlotte1 aReiner, Alex, P1 aTalmud, Philippa, J1 aSchouw, Yvonne, T1 aWilson, James, G1 aKivimaki, Mika1 aKumari, Meena1 aMoore, Jason, H1 aDrenos, Fotios1 aAsselbergs, Folkert, W1 aKeating, Brendan, J1 aRitchie, Marylyn, D uhttps://chs-nhlbi.org/node/756606088nas a2201561 4500008004100000022001400041245007200055210006900127260001600196520173100212100002801943700002101971700002401992700001802016700002002034700002202054700002502076700001602101700001802117700001802135700001802153700002002171700002002191700001502211700002302226700003002249700001902279700001302298700002102311700002802332700002002360700002402380700002002404700001902424700001802443700002102461700002102482700002102503700001702524700002202541700001902563700001902582700002002601700002502621700002302646700002202669700002402691700002102715700002402736700002202760700002202782700001702804700002302821700001902844700002202863700002302885700001902908700002002927700002002947700002402967700001802991700002203009700001203031700001303043700002103056700001503077700002503092700002103117700002203138700002103160700002203181700002703203700001703230700002503247700002003272700002303292700001803315700002003333700001503353700002303368700002603391700002203417700001603439700001903455700001703474700002203491700002403513700002403537700002203561700002603583700002003609700002103629700002403650700002103674700001803695700002403713700001703737700002603754700001603780700002803796700001903824700001903843700002103862700002003883700002303903700002403926700001903950700002703969700002203996700002204018700002404040700001804064700002204082700001904104700002204123700002304145700002304168700001804191700002904209700002004238700001904258700002204277700001804299700002404317700002204341700001904363700002404382700001504406700002204421700002304443700002404466856003604490 2017 eng d a1460-208300aDiscovery of novel heart rate-associated loci using the Exome Chip.0 aDiscovery of novel heart rateassociated loci using the Exome Chi c2017 Apr 033 aBackground Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
1 avan den Berg, Marten, E1 aWarren, Helen, R1 aCabrera, Claudia, P1 aVerweij, Niek1 aMifsud, Borbala1 aHaessler, Jeffrey1 aBihlmeyer, Nathan, A1 aFu, Yi-Ping1 aWeiss, Stefan1 aLin, Henry, J1 aGrarup, Niels1 aLi-Gao, Ruifang1 aPistis, Giorgio1 aShah, Nabi1 aBrody, Jennifer, A1 aMüller-Nurasyid, Martina1 aLin, Honghuang1 aMei, Hao1 aSmith, Albert, V1 aLyytikäinen, Leo-Pekka1 aHall, Leanne, M1 avan Setten, Jessica1 aTrompet, Stella1 aPrins, Bram, P1 aIsaacs, Aaron1 aRadmanesh, Farid1 aMarten, Jonathan1 aEntwistle, Aiman1 aKors, Jan, A1 aSilva, Claudia, T1 aAlonso, Alvaro1 aBis, Joshua, C1 ade Boer, Rudolf1 ade Haan, Hugoline, G1 ade Mutsert, Renée1 aDedoussis, George1 aDominiczak, Anna, F1 aDoney, Alex, S F1 aEllinor, Patrick, T1 aEppinga, Ruben, N1 aFelix, Stephan, B1 aGuo, Xiuqing1 aHagemeijer, Yanick1 aHansen, Torben1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHuang, Paul, L1 aHwang, Shih-Jen1 aKähönen, Mika1 aKanters, Jørgen, K1 aKolcic, Ivana1 aLauner, Lenore, J1 aLi, Man1 aYao, Jie1 aLinneberg, Allan1 aLiu, Simin1 aMacfarlane, Peter, W1 aMangino, Massimo1 aMorris, Andrew, D1 aMulas, Antonella1 aMurray, Alison, D1 aNelson, Christopher, P1 aOrrù, Marco1 aPadmanabhan, Sandosh1 aPeters, Annette1 aPorteous, David, J1 aPoulter, Neil1 aPsaty, Bruce, M1 aQi, Lihong1 aRaitakari, Olli, T1 aRivadeneira, Fernando1 aRoselli, Carolina1 aRudan, Igor1 aSattar, Naveed1 aSever, Peter1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStanton, Alice, V1 aStirrups, Kathleen, E1 aTaylor, Kent, D1 aTobin, Martin, D1 aUitterlinden, Andre1 aVaartjes, Ilonca1 aHoes, Arno, W1 avan der Meer, Peter1 aVölker, Uwe1 aWaldenberger, Melanie1 aXie, Zhijun1 aZoledziewska, Magdalena1 aTinker, Andrew1 aPolasek, Ozren1 aRosand, Jonathan1 aJamshidi, Yalda1 aDuijn, Cornelia, M1 aZeggini, Eleftheria1 aJukema, Wouter1 aAsselbergs, Folkert, W1 aSamani, Nilesh, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aWilson, James1 aLubitz, Steven, A1 aKääb, Stefan1 aSotoodehnia, Nona1 aCaulfield, Mark, J1 aPalmer, Colin, N A1 aSanna, Serena1 aMook-Kanamori, Dennis, O1 aDeloukas, Panos1 aPedersen, Oluf1 aRotter, Jerome, I1 aDörr, Marcus1 aO'Donnell, Chris, J1 aHayward, Caroline1 aArking, Dan, E1 aKooperberg, Charles1 aHarst, Pim1 aEijgelsheim, Mark1 aStricker, Bruno, H1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/736304860nas a2201081 4500008004100000022001400041245007600055210006900131260001600200300001200216490000800228520186200236653000902098653001902107653001602126653002802142653002002170653002402190653002202214653003402236653001102270653003702281653001602318653002602334653002802360653001702388100002402405700001902429700002002448700002002468700001702488700002302505700002502528700002202553700001902575700002002594700002202614700001702636700001902653700002202672700002102694700001702715700002202732700001802754700002402772700001602796700002602812700002802838700002402866700002102890700002002911700001202931700002202943700001902965700002002984700002203004700002403026700001403050700002303064700001803087700002303105700001903128700002003147700001603167700001903183700002203202700002303224700002003247700002003267700002003287700002303307700002203330700001903352700001703371700001803388700001903406700002603425700001703451700002003468700002903488700002203517700002303539700002103562700001803583700002603601700002103627700001803648700001903666700001703685700002003702710002003722856003603742 2017 eng d a1537-660500aDNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.0 aDNA Methylation Analysis Identifies Loci for Blood Pressure Regu c2017 Dec 07 a888-9020 v1013 aGenome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
10aAged10aBlood Pressure10aCpG Islands10aCross-Sectional Studies10aDNA Methylation10aEpigenesis, Genetic10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMendelian Randomization Analysis10aMiddle Aged10aNerve Tissue Proteins10aQuantitative Trait Loci10aTetraspanins1 aRichard, Melissa, A1 aHuan, Tianxiao1 aLigthart, Symen1 aGondalia, Rahul1 aJhun, Min, A1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aMarioni, Riccardo1 aShen, Jincheng1 aTsai, Pei-Chien1 aMontasser, May, E1 aJia, Yucheng1 aSyme, Catriona1 aSalfati, Elias, L1 aBoerwinkle, Eric1 aGuan, Weihua1 aMosley, Thomas, H1 aBressler, Jan1 aMorrison, Alanna, C1 aLiu, Chunyu1 aMendelson, Michael, M1 aUitterlinden, André, G1 avan Meurs, Joyce, B1 aFranco, Oscar, H1 aZhang, Guosheng1 aLi, Yun1 aStewart, James, D1 aBis, Joshua, C1 aPsaty, Bruce, M1 aChen, Yii-Der Ida1 aKardia, Sharon, L R1 aZhao, Wei1 aTurner, Stephen, T1 aAbsher, Devin1 aAslibekyan, Stella1 aStarr, John, M1 aMcRae, Allan, F1 aHou, Lifang1 aJust, Allan, C1 aSchwartz, Joel, D1 aVokonas, Pantel, S1 aMenni, Cristina1 aSpector, Tim, D1 aShuldiner, Alan1 aDamcott, Coleen, M1 aRotter, Jerome, I1 aPalmas, Walter1 aLiu, Yongmei1 aPaus, Tomáš1 aHorvath, Steve1 aO'Connell, Jeffrey, R1 aGuo, Xiuqing1 aPausova, Zdenka1 aAssimes, Themistocles, L1 aSotoodehnia, Nona1 aSmith, Jennifer, A1 aArnett, Donna, K1 aDeary, Ian, J1 aBaccarelli, Andrea, A1 aBell, Jordana, T1 aWhitsel, Eric1 aDehghan, Abbas1 aLevy, Daniel1 aFornage, Myriam1 aBIOS Consortium uhttps://chs-nhlbi.org/node/758302652nas a2200265 4500008004100000022001400041245009100055210006900146260001600215490000600231520185100237100002202088700002202110700002302132700002302155700002402178700002202202700002402224700001902248700001702267700002002284700002302304700002302327856003602350 2017 eng d a2047-998000aEctopy on a Single 12-Lead ECG, Incident Cardiac Myopathy, and Death in the Community.0 aEctopy on a Single 12Lead ECG Incident Cardiac Myopathy and Deat c2017 Aug 030 v63 aBACKGROUND: Atrial fibrillation and heart failure are 2 of the most common diseases, yet ready means to identify individuals at risk are lacking. The 12-lead ECG is one of the most accessible tests in medicine. Our objective was to determine whether a premature atrial contraction observed on a standard 12-lead ECG would predict atrial fibrillation and mortality and whether a premature ventricular contraction would predict heart failure and mortality.
METHODS AND RESULTS: We utilized the CHS (Cardiovascular Health) Study, which followed 5577 participants for a median of 12 years, as the primary cohort. The ARIC (Atherosclerosis Risk in Communities Study), the replication cohort, captured data from 15 792 participants over a median of 22 years. In the CHS, multivariable analyses revealed that a baseline 12-lead ECG premature atrial contraction predicted a 60% increased risk of atrial fibrillation (hazard ratio, 1.6; 95% CI, 1.3-2.0; P<0.001) and a premature ventricular contraction predicted a 30% increased risk of heart failure (hazard ratio, 1.3; 95% CI, 1.0-1.6; P=0.021). In the negative control analyses, neither predicted incident myocardial infarction. A premature atrial contraction was associated with a 30% increased risk of death (hazard ratio, 1.3; 95% CI, 1.1-1.5; P=0.008) and a premature ventricular contraction was associated with a 20% increased risk of death (hazard ratio, 1.2; 95% CI, 1.0-1.3; P=0.044). Similarly statistically significant results for each analysis were also observed in ARIC.
CONCLUSIONS: Based on a single standard ECG, a premature atrial contraction predicted incident atrial fibrillation and death and a premature ventricular contraction predicted incident heart failure and death, suggesting that this commonly used test may predict future disease.
1 aNguyen, Kaylin, T1 aVittinghoff, Eric1 aDewland, Thomas, A1 aDukes, Jonathan, W1 aSoliman, Elsayed, Z1 aStein, Phyllis, K1 aGottdiener, John, S1 aAlonso, Alvaro1 aChen, Lin, Y1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/748909668nas a2203061 4500008004100000022001400041245007500055210006900130260001300199300001400212490000700226520116500233653002801398653003001426653001001456653003201466653003801498653002201536653001301558653001101571653001101582653002501593653001401618653001701632100002001649700002001669700001501689700002501704700001501729700002001744700002101764700001801785700001601803700003101819700002201850700003001872700002401902700002901926700001801955700001701973700002801990700001702018700001902035700001902054700002102073700002102094700002302115700002402138700002102162700001802183700002002201700002302221700002202244700002302266700001702289700002202306700001902328700002402347700001902371700002102390700002102411700002502432700002302457700001702480700001802497700002202515700002102537700002102558700002402579700002002603700002402623700001602647700002502663700002102688700002002709700002002729700001402749700002002763700002002783700002502803700002502828700002202853700002302875700002102898700002202919700001302941700002302954700002202977700002302999700002203022700002103044700001803065700001603083700002003099700002403119700001903143700002203162700002203184700002403206700002303230700002203253700001403275700002003289700002003309700002103329700002603350700002703376700002003403700002503423700001903448700002503467700002103492700002203513700001903535700001503554700001903569700001803588700002503606700002203631700002403653700002003677700002203697700001903719700001603738700002403754700001903778700002203797700002303819700002403842700001603866700002103882700002003903700001803923700001803941700001803959700002303977700002104000700002204021700002404043700002004067700002504087700002004112700002004132700001904152700002104171700002204192700002404214700002104238700003004259700002404289700002104313700002204334700002104356700002804377700002104405700001904426700002904445700002504474700002204499700002204521700002504543700002304568700001804591700002304609700001904632700001904651700002004670700002404690700002004714700001904734700001804753700002004771700002104791700001804812700002104830700002204851700002004873700002004893700002104913700002004934700001904954700002304973700001804996700002205014700001605036700002005052700002205072700001805094700001905112700002205131700002105153700001705174700002305191700002605214700001705240700002805257700002105285700002105306700002005327700002605347700002205373700002405395700002805419700001905447700002605466700002105492700002405513700002605537700002305563700001705586700001805603700001405621700002405635700002005659700002005679700002005699700002305719700002605742700002705768700001805795700002005813700001905833700002605852700001405878700002105892700002105913700002005934700002205954700002105976700002105997700002306018700001306041700002306054700001706077700002406094700001406118700001906132700001806151700001506169700001406184700001706198700002806215700002406243700001706267700002206284700001906306700002206325700002006347700002006367700002306387700002206410710003406432710002906466710002406495710002006519710003106539856003606570 2017 eng d a1546-171800aExome-wide association study of plasma lipids in >300,000 individuals.0 aExomewide association study of plasma lipids in 300000 individua c2017 Dec a1758-17660 v493 aWe screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aExome10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aHumans10aLipids10aMacular Degeneration10aPhenotype10aRisk Factors1 aLiu, Dajiang, J1 aPeloso, Gina, M1 aYu, Haojie1 aButterworth, Adam, S1 aWang, Xiao1 aMahajan, Anubha1 aSaleheen, Danish1 aEmdin, Connor1 aAlam, Dewan1 aAlves, Alexessander, Couto1 aAmouyel, Philippe1 aDi Angelantonio, Emanuele1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aAuer, Paul, L1 aBaber, Usman1 aBallantyne, Christie, M1 aBang, Lia, E1 aBenn, Marianne1 aBis, Joshua, C1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrandslund, Ivan1 aBrown, Morris1 aBusonero, Fabio1 aCaulfield, Mark, J1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Eugene1 aChen, Yii-Der Ida1 aChowdhury, Raj1 aChristensen, Cramer1 aChu, Audrey, Y1 aConnell, John, M1 aCucca, Francesco1 aCupples, Adrienne, L1 aDamrauer, Scott, M1 aDavies, Gail1 aDeary, Ian, J1 aDedoussis, George1 aDenny, Joshua, C1 aDominiczak, Anna1 aDubé, Marie-Pierre1 aEbeling, Tapani1 aEiriksdottir, Gudny1 aEsko, Tõnu1 aFarmaki, Aliki-Eleni1 aFeitosa, Mary, F1 aFerrario, Marco1 aFerrieres, Jean1 aFord, Ian1 aFornage, Myriam1 aFranks, Paul, W1 aFrayling, Timothy, M1 aFrikke-Schmidt, Ruth1 aFritsche, Lars, G1 aFrossard, Philippe1 aFuster, Valentin1 aGanesh, Santhi, K1 aGao, Wei1 aGarcia, Melissa, E1 aGieger, Christian1 aGiulianini, Franco1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGrarup, Niels1 aGroop, Leif1 aGrove, Megan, L1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHirschhorn, Joel, N1 aHolmen, Oddgeir, L1 aHuffman, Jennifer1 aHuo, Yong1 aHveem, Kristian1 aJabeen, Sehrish1 aJackson, Anne, U1 aJakobsdottir, Johanna1 aJarvelin, Marjo-Riitta1 aJensen, Gorm, B1 aJørgensen, Marit, E1 aJukema, Wouter1 aJustesen, Johanne, M1 aKamstrup, Pia, R1 aKanoni, Stavroula1 aKarpe, Fredrik1 aKee, Frank1 aKhera, Amit, V1 aKlarin, Derek1 aKoistinen, Heikki, A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo1 aLangenberg, Claudia1 aLangsted, Anne1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLiewald, David, C M1 aLin, Li, An1 aLinneberg, Allan1 aLoos, Ruth, J F1 aLu, Yingchang1 aLu, Xiangfeng1 aMägi, Reedik1 aMälarstig, Anders1 aManichaikul, Ani1 aManning, Alisa, K1 aMäntyselkä, Pekka1 aMarouli, Eirini1 aMasca, Nicholas, G D1 aMaschio, Andrea1 aMeigs, James, B1 aMelander, Olle1 aMetspalu, Andres1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMulas, Antonella1 aMüller-Nurasyid, Martina1 aMunroe, Patricia, B1 aNeville, Matt, J1 aNielsen, Jonas, B1 aNielsen, Sune, F1 aNordestgaard, Børge, G1 aOrdovas, Jose, M1 aMehran, Roxana1 aO'Donnell, Christoper, J1 aOrho-Melander, Marju1 aMolony, Cliona, M1 aMuntendam, Pieter1 aPadmanabhan, Sandosh1 aPalmer, Colin, N A1 aPasko, Dorota1 aPatel, Aniruddh, P1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPisinger, Charlotta1 aPistis, Giorgio1 aPolasek, Ozren1 aPoulter, Neil1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRasheed, Asif1 aRauramaa, Rainer1 aReilly, Dermot, F1 aReiner, Alex, P1 aRenstrom, Frida1 aRich, Stephen, S1 aRidker, Paul, M1 aRioux, John, D1 aRobertson, Neil, R1 aRoden, Dan, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSanna, Serena1 aSattar, Naveed1 aSchmidt, Ellen, M1 aScott, Robert, A1 aSever, Peter1 aSevilla, Raquel, S1 aShaffer, Christian, M1 aSim, Xueling1 aSivapalaratnam, Suthesh1 aSmall, Kerrin, S1 aSmith, Albert, V1 aSmith, Blair, H1 aSomayajula, Sangeetha1 aSoutham, Lorraine1 aSpector, Timothy, D1 aSpeliotes, Elizabeth, K1 aStarr, John, M1 aStirrups, Kathleen, E1 aStitziel, Nathan1 aStrauch, Konstantin1 aStringham, Heather, M1 aSurendran, Praveen1 aTada, Hayato1 aTall, Alan, R1 aTang, Hua1 aTardif, Jean-Claude1 aTaylor, Kent, D1 aTrompet, Stella1 aTsao, Philip, S1 aTuomilehto, Jaakko1 aTybjaerg-Hansen, Anne1 avan Zuydam, Natalie, R1 aVarbo, Anette1 aVarga, Tibor, V1 aVirtamo, Jarmo1 aWaldenberger, Melanie1 aWang, Nan1 aWareham, Nick, J1 aWarren, Helen, R1 aWeeke, Peter, E1 aWeinstock, Joshua1 aWessel, Jennifer1 aWilson, James, G1 aWilson, Peter, W F1 aXu, Ming1 aYaghootkar, Hanieh1 aYoung, Robin1 aZeggini, Eleftheria1 aZhang, He1 aZheng, Neil, S1 aZhang, Weihua1 aZhang, Yan1 aZhou, Wei1 aZhou, Yanhua1 aZoledziewska, Magdalena1 aHowson, Joanna, M M1 aDanesh, John1 aMcCarthy, Mark, I1 aCowan, Chad, A1 aAbecasis, Goncalo1 aDeloukas, Panos1 aMusunuru, Kiran1 aWiller, Cristen, J1 aKathiresan, Sekar1 aCharge Diabetes Working Group1 aEPIC-InterAct Consortium1 aEPIC-CVD Consortium1 aGOLD Consortium1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/757302980nas a2200433 4500008004100000022001400041245009400055210006900149260001600218300001400234490000800248520176800256653001402024653000902038653002202047653002802069653001102097653003002108653003102138653001102169653001102180653000902191653001602200653001302216653003302229653001702262100001802279700002002297700002102317700002202338700002002360700003002380700002002410700001902430700002202449700002102471700001802492856003602510 2017 eng d a1945-719700aFibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function.0 aFibroblast Growth Factor 23 Mineral Metabolism and Adiposity in c2017 Apr 01 a1387-13950 v1023 aContext: Obesity is associated with poor bone mineralization and quality. Fibroblast growth factor 23 (FGF23) plays an important role in skeletal physiology.
Objective: To test hypothesis that greater adiposity results in higher FGF23 levels among individuals with normal estimated glomerular filtration rate (eGFR).
Design, Setting, Participants: Cross-sectional analyses among participants with eGFR ≥60 mL/min/1.73m2. We assessed the association between crude [body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR); n = 5610] and refined (abdominal adipose tissue area by computed tomography; n = 1313) measures of adiposity and FGF23 using multivariable linear regression.
Main Outcome Measure: Serum FGF23.
Results: FGF23 was higher across BMI categories (BMI <25: 37.7; BMI 25 to 29.99: 38.7; BMI 30 to 39.99: 39.8; BMI ≥40: 40.9 pg/mL, unadjusted P trend < 0.0001). The association between BMI and FGF23 was independent of known confounders of FGF23 (adjusted β = +7.2% higher FGF23 per 10 kg/m2; P < 0.0001). Similar results were observed using WC and WHR. Abdominal adipose tissue area was also independently associated with higher FGF23 (P < 0.01). Notably, the positive associations between FGF23 and adiposity were observed despite the fact that eGFR did not decline and serum phosphate levels did not increase with adiposity.
Conclusion: In a large cohort with normal kidney function, adiposity was associated with higher FGF23 levels independent of known confounders, including eGFR and phosphate. Further studies are needed to evaluate the causes of higher FGF23 in settings of greater adiposity and the potential impact on skeletal health.
10aAdiposity10aAged10aAged, 80 and over10aCross-Sectional Studies10aFemale10aFibroblast Growth Factors10aGlomerular Filtration Rate10aHumans10aKidney10aMale10aMiddle Aged10aMinerals10aRenal Insufficiency, Chronic10aRisk Factors1 aZaheer, Sarah1 ade Boer, Ian, H1 aAllison, Matthew1 aBrown, Jenifer, M1 aPsaty, Bruce, M1 aRobinson-Cohen, Cassianne1 aMichos, Erin, D1 aIx, Joachim, H1 aKestenbaum, Bryan1 aSiscovick, David1 aVaidya, Anand uhttps://chs-nhlbi.org/node/760104297nas a2200889 4500008004100000022001400041245007400055210006900129260001300198490000700211520176700218653002501985653001502010653001502025653002402040653001702064653003402081653001302115653001602128653001102144653004002155653004002195653002602235100003002261700002202291700001702313700001802330700001802348700001902366700002602385700002202411700002202433700001502455700002202470700001902492700002202511700001802533700003002551700002302581700001902604700002002623700002202643700001702665700002202682700002302704700002202727700002102749700002302770700002602793700001702819700002602836700002002862700002202882700002402904700002402928700002002952700001902972700002402991700002203015700002003037700002403057700001903081700002003100700002203120700002203142700001803164700001203182700001903194700002403213700001903237700002103256700002303277700002403300700002303324700002403347856003603371 2017 eng d a1942-326800aFifteen Genetic Loci Associated With the Electrocardiographic P Wave.0 aFifteen Genetic Loci Associated With the Electrocardiographic P c2017 Aug0 v103 aBACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.
METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.
CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.
10aArrhythmias, Cardiac10aCaveolin 110aCaveolin 210aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHumans10aNAV1.5 Voltage-Gated Sodium Channel10aNAV1.8 Voltage-Gated Sodium Channel10aT-Box Domain Proteins1 aChristophersen, Ingrid, E1 aMagnani, Jared, W1 aYin, Xiaoyan1 aBarnard, John1 aWeng, Lu-Chen1 aArking, Dan, E1 aNiemeijer, Maartje, N1 aLubitz, Steven, A1 aAvery, Christy, L1 aDuan, Qing1 aFelix, Stephan, B1 aBis, Joshua, C1 aKerr, Kathleen, F1 aIsaacs, Aaron1 aMüller-Nurasyid, Martina1 aMüller, Christian1 aNorth, Kari, E1 aReiner, Alex, P1 aTinker, Lesley, F1 aKors, Jan, A1 aTeumer, Alexander1 aPetersmann, Astrid1 aSinner, Moritz, F1 aBůzková, Petra1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aVölker, Uwe1 aWaldenberger, Melanie1 aPeters, Annette1 aMeitinger, Thomas1 aLimacher, Marian, C1 aWilhelmsen, Kirk, C1 aPsaty, Bruce, M1 aHofman, Albert1 aUitterlinden, Andre1 aKrijthe, Bouwe, P1 aZhang, Zhu-Ming1 aSchnabel, Renate, B1 aKääb, Stefan1 aDuijn, Cornelia1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aDörr, Marcus1 aLi, Yun1 aChung, Mina, K1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aWhitsel, Eric, A1 aStricker, Bruno, H1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/755703442nas a2200469 4500008004100000022001400041245018400055210006900239260001300308300001200321490000700333520199400340100002202334700002502356700002402381700002502405700002002430700001702450700002402467700002002491700002602511700001302537700002302550700002002573700002702593700001902620700002202639700001902661700002102680700002302701700002002724700002102744700002202765700001702787700002102804700001902825700002702844700002202871700002402893700001902917856003602936 2017 eng d a1556-387100aFine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations.0 aFine mapping of QT interval regions in global populations refine c2017 Apr a572-5800 v143 aBACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance.
OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry.
METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis.
RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10(-5)) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs.
CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.
1 aAvery, Christy, L1 aWassel, Christina, L1 aRichard, Melissa, A1 aHighland, Heather, M1 aBien, Stephanie1 aZubair, Niha1 aSoliman, Elsayed, Z1 aFornage, Myriam1 aBielinski, Suzette, J1 aTao, Ran1 aSeyerle, Amanda, A1 aShah, Sanjiv, J1 aLloyd-Jones, Donald, M1 aBuyske, Steven1 aRotter, Jerome, I1 aPost, Wendy, S1 aRich, Stephen, S1 aHindorff, Lucia, A1 aJeff, Janina, M1 aShohet, Ralph, V1 aSotoodehnia, Nona1 aLin, Dan, Yu1 aWhitsel, Eric, A1 aPeters, Ulrike1 aHaiman, Christopher, A1 aCrawford, Dana, C1 aKooperberg, Charles1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/746304137nas a2200733 4500008004100000022001400041245012300055210006900178260001300247300001200260490000700272520230800279100001602587700001102603700001102614700002402625700001102649700001402660700001802674700001802692700001302710700001502723700001402738700001302752700001502765700001202780700001302792700001302805700001602818700001702834700001702851700001902868700001502887700001602902700001502918700001402933700001502947700001602962700001002978700001902988700001703007700001703024700001903041700001703060700001603077700001403093700001803107700001503125700001703140700001603157700001703173700001503190700001603205700002003221700001803241700001503259700001803274700001803292700001403310700001403324700001303338700001603351856003603367 2017 eng d a1476-549700aGeneralization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.0 aGeneralization and fine mapping of European ancestrybased centra c2017 Feb a324-3310 v413 aBACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.
SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.
RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.
CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.
1 aYoneyama, S1 aYao, J1 aGuo, X1 aFernandez-Rhodes, L1 aLim, U1 aBoston, J1 aBůžková, P1 aCarlson, C, S1 aCheng, I1 aCochran, B1 aCooper, R1 aEhret, G1 aFornage, M1 aGong, J1 aGross, M1 aGu, C, C1 aHaessler, J1 aHaiman, C, A1 aHenderson, B1 aHindorff, L, A1 aHouston, D1 aIrvin, M, R1 aJackson, R1 aKuller, L1 aLeppert, M1 aLewis, C, E1 aLi, R1 aLe Marchand, L1 aMatise, T, C1 aNguyen, K-Dh1 aChakravarti, A1 aPankow, J, S1 aPankratz, N1 aPooler, L1 aRitchie, M, D1 aBien, S, A1 aWassel, C, L1 aDI Chen, Y-1 aTaylor, K, D1 aAllison, M1 aRotter, J I1 aSchreiner, P, J1 aSchumacher, F1 aWilkens, L1 aBoerwinkle, E1 aKooperberg, C1 aPeters, U1 aBuyske, S1 aGraff, M1 aNorth, K, E uhttps://chs-nhlbi.org/node/759904213nas a2200973 4500008004100000022001400041245013200055210006900187260001600256300001000272490000600282520142300288100001801711700002401729700003001753700002601783700002701809700002001836700001801856700001901874700002801893700002201921700002401943700001801967700002201985700002002007700002202027700001802049700001802067700002302085700002202108700002602130700002202156700002202178700002402200700001902224700002102243700002302264700002102287700002402308700002602332700002302358700002002381700002202401700002002423700002002443700001702463700002502480700001902505700002202524700001302546700001702559700003002576700002402606700002302630700001802653700002202671700001402693700001802707700002102725700002802746700001702774700002202791700001902813700001902832700002402851700001902875700001702894700001802911700001902929700002302948700002402971700002202995700002003017700001803037700002203055700001503077700001903092700002303111700002203134700002503156700002203181856003603203 2017 eng d a2045-232200aGenetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.0 aGenetic Interactions with Age Sex Body Mass Index and Hypertensi c2017 Sep 12 a113030 v73 aIt is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
1 aWeng, Lu-Chen1 aLunetta, Kathryn, L1 aMüller-Nurasyid, Martina1 aSmith, Albert, Vernon1 aThériault, Sébastien1 aWeeke, Peter, E1 aBarnard, John1 aBis, Joshua, C1 aLyytikäinen, Leo-Pekka1 aKleber, Marcus, E1 aMartinsson, Andreas1 aLin, Henry, J1 aRienstra, Michiel1 aTrompet, Stella1 aKrijthe, Bouwe, P1 aDörr, Marcus1 aKlarin, Derek1 aChasman, Daniel, I1 aSinner, Moritz, F1 aWaldenberger, Melanie1 aLauner, Lenore, J1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aParé, Guillaume1 aTeixeira, Pedro, L1 aDenny, Joshua, C1 aShoemaker, Benjamin1 aVan Wagoner, David, R1 aSmith, Jonathan, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aKähönen, Mika1 aNikus, Kjell1 aDelgado, Graciela, E1 aMelander, Olle1 aEngström, Gunnar1 aYao, Jie1 aGuo, Xiuqing1 aChristophersen, Ingrid, E1 aEllinor, Patrick, T1 aGeelhoed, Bastiaan1 aVerweij, Niek1 aMacfarlane, Peter1 aFord, Ian1 aHeeringa, Jan1 aFranco, Oscar, H1 aUitterlinden, André, G1 aVölker, Uwe1 aTeumer, Alexander1 aRose, Lynda, M1 aKääb, Stefan1 aGudnason, Vilmundur1 aArking, Dan, E1 aConen, David1 aRoden, Dan, M1 aChung, Mina, K1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aLehtimäki, Terho1 aMärz, Winfried1 aSmith, Gustav1 aRotter, Jerome, I1 aHarst, Pim1 aJukema, Wouter1 aStricker, Bruno, H1 aFelix, Stephan, B1 aAlbert, Christine, M1 aLubitz, Steven, A uhttps://chs-nhlbi.org/node/759504391nas a2201129 4500008004100000022001400041245013100055210006900186260001300255300001200268490000700280520110800287100002001395700001701415700002301432700001801455700001701473700002501490700002001515700001701535700002501552700001901577700002501596700001901621700002301640700002301663700002001686700002201706700002001728700002301748700002101771700002001792700002301812700002001835700002001855700001801875700002001893700002201913700001601935700002401951700002101975700002401996700002002020700001602040700002002056700002602076700001902102700002402121700001902145700001802164700002002182700001702202700002002219700002402239700001902263700002402282700002402306700002102330700001802351700002102369700001702390700001902407700002502426700001502451700001902466700001902485700002202504700002302526700002802549700002802577700002402605700002602629700002302655700001602678700002002694700001802714700002102732700002502753700002102778700001802799700002402817700002302841700002202864700002002886700002102906700002402927700001902951700002002970710002702990710002603017710002803043710002903071710005403100710002803154710004303182856003603225 2017 eng d a1546-171800aGenetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.0 aGenetic loci associated with chronic obstructive pulmonary disea c2017 Mar a426-4320 v493 aChronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.
1 aHobbs, Brian, D1 ade Jong, Kim1 aLamontagne, Maxime1 aBossé, Yohan1 aShrine, Nick1 aArtigas, Maria Soler1 aWain, Louise, V1 aHall, Ian, P1 aJackson, Victoria, E1 aWyss, Annah, B1 aLondon, Stephanie, J1 aNorth, Kari, E1 aFranceschini, Nora1 aStrachan, David, P1 aBeaty, Terri, H1 aHokanson, John, E1 aCrapo, James, D1 aCastaldi, Peter, J1 aChase, Robert, P1 aBartz, Traci, M1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aGharib, Sina, A1 aZanen, Pieter1 aLammers, Jan, W1 aOudkerk, Matthijs1 aGroen, H, J1 aLocantore, Nicholas1 aTal-Singer, Ruth1 aRennard, Stephen, I1 aVestbo, Jørgen1 aTimens, Wim1 aParé, Peter, D1 aLatourelle, Jeanne, C1 aDupuis, Josée1 aO'Connor, George, T1 aWilk, Jemma, B1 aKim, Woo, Jin1 aLee, Mi, Kyeong1 aOh, Yeon-Mok1 aVonk, Judith, M1 ade Koning, Harry, J1 aLeng, Shuguang1 aBelinsky, Steven, A1 aTesfaigzi, Yohannes1 aManichaikul, Ani1 aWang, Xin-Qun1 aRich, Stephen, S1 aBarr, Graham1 aSparrow, David1 aLitonjua, Augusto, A1 aBakke, Per1 aGulsvik, Amund1 aLahousse, Lies1 aBrusselle, Guy, G1 aStricker, Bruno, H1 aUitterlinden, André, G1 aAmpleford, Elizabeth, J1 aBleecker, Eugene, R1 aWoodruff, Prescott, G1 aMeyers, Deborah, A1 aQiao, Dandi1 aLomas, David, A1 aYim, Jae-Joon1 aKim, Deog, Kyeom1 aHawrylkiewicz, Iwona1 aSliwinski, Pawel1 aHardin, Megan1 aFingerlin, Tasha, E1 aSchwartz, David, A1 aPostma, Dirkje, S1 aMacNee, William1 aTobin, Martin, D1 aSilverman, Edwin, K1 aBoezen, Marike1 aCho, Michael, H1 aCOPDGene Investigators1 aECLIPSE Investigators1 aLifeLines Investigators1 aSPIROMICS Research Group1 aInternational COPD Genetics Network Investigators1 aUK BiLEVE Investigators1 aInternational COPD Genetics Consortium uhttps://chs-nhlbi.org/node/734506994nas a2202101 4500008004100000022001400041245009900055210006900154260001600223300001000239490000600249520104500255100001901300700001901319700002301338700002201361700001701383700001601400700002801416700002201444700001901466700001801485700002201503700002701525700002201552700002301574700001901597700002001616700001801636700002201654700002301676700002201699700002001721700002801741700002801769700002201797700002001819700002701839700003001866700001901896700001701915700002201932700002201954700001801976700001701994700002102011700002702032700002202059700002302081700002202104700001902126700001702145700001802162700002002180700002202200700002502222700002102247700001802268700002102286700002002307700002302327700002202350700002702372700002102399700002102420700002402441700001902465700002102484700002002505700002102525700001902546700002502565700001902590700002602609700002602635700002102661700001902682700002402701700002002725700002602745700001902771700002102790700002002811700002402831700001702855700001802872700002402890700002102914700002202935700001302957700001202970700001902982700002403001700001803025700002503043700002203068700002003090700002203110700003903132700002103171700001803192700002203210700001903232700001803251700002003269700001703289700001903306700002403325700001703349700002003366700002003386700002003406700002303426700002703449700002203476700002103498700002203519700002303541700002403564700002203588700002103610700002203631700002303653700003203676700002403708700002203732700002003754700002803774700002403802700002003826700002203846700002503868700002203893700002803915700002403943700001803967700002603985700002404011700002304035700001704058700002004075700002304095700001804118700002204136700002304158700001504181700002104196700002004217700002704237700001904264700002004283700001904303700002404322700001504346700002204361700001504383700002804398700002404426700002904450700002004479700002504499700002204524700002204546700001904568700002204587700001704609700002304626700002204649700002604671700002704697700002704724700002304751700002104774700002204795700002004817700001904837856003604856 2017 eng d a2041-172300aGenetic loci associated with heart rate variability and their effects on cardiac disease risk.0 aGenetic loci associated with heart rate variability and their ef c2017 Jun 14 a158050 v83 aReduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.741 aNolte, Ilja, M1 aMunoz, Loretto1 aTragante, Vinicius1 aAmare, Azmeraw, T1 aJansen, Rick1 aVaez, Ahmad1 avon der Heyde, Benedikt1 aAvery, Christy, L1 aBis, Joshua, C1 aDierckx, Bram1 avan Dongen, Jenny1 aGogarten, Stephanie, M1 aGoyette, Philippe1 aHernesniemi, Jussi1 aHuikari, Ville1 aHwang, Shih-Jen1 aJaju, Deepali1 aKerr, Kathleen, F1 aKluttig, Alexander1 aKrijthe, Bouwe, P1 aKumar, Jitender1 avan der Laan, Sander, W1 aLyytikäinen, Leo-Pekka1 aMaihofer, Adam, X1 aMinassian, Arpi1 avan der Most, Peter, J1 aMüller-Nurasyid, Martina1 aNivard, Michel1 aSalvi, Erika1 aStewart, James, D1 aThayer, Julian, F1 aVerweij, Niek1 aWong, Andrew1 aZabaneh, Delilah1 aZafarmand, Mohammad, H1 aAbdellaoui, Abdel1 aAlbarwani, Sulayma1 aAlbert, Christine1 aAlonso, Alvaro1 aAshar, Foram1 aAuvinen, Juha1 aAxelsson, Tomas1 aBaker, Dewleen, G1 ade Bakker, Paul, I W1 aBarcella, Matteo1 aBayoumi, Riad1 aBieringa, Rob, J1 aBoomsma, Dorret1 aBoucher, Gabrielle1 aBritton, Annie, R1 aChristophersen, Ingrid1 aDietrich, Andrea1 aEhret, George, B1 aEllinor, Patrick, T1 aEskola, Markku1 aFelix, Janine, F1 aFloras, John, S1 aFranco, Oscar, H1 aFriberg, Peter1 aGademan, Maaike, G J1 aGeyer, Mark, A1 aGiedraitis, Vilmantas1 aHartman, Catharina, A1 aHemerich, Daiane1 aHofman, Albert1 aHottenga, Jouke-Jan1 aHuikuri, Heikki1 aHutri-Kähönen, Nina1 aJouven, Xavier1 aJunttila, Juhani1 aJuonala, Markus1 aKiviniemi, Antti, M1 aKors, Jan, A1 aKumari, Meena1 aKuznetsova, Tatiana1 aLaurie, Cathy, C1 aLefrandt, Joop, D1 aLi, Yong1 aLi, Yun1 aLiao, Duanping1 aLimacher, Marian, C1 aLin, Henry, J1 aLindgren, Cecilia, M1 aLubitz, Steven, A1 aMahajan, Anubha1 aMcKnight, Barbara1 aSchwabedissen, Henriette, Meyer Zu1 aMilaneschi, Yuri1 aMononen, Nina1 aMorris, Andrew, P1 aNalls, Mike, A1 aNavis, Gerjan1 aNeijts, Melanie1 aNikus, Kjell1 aNorth, Kari, E1 aO'Connor, Daniel, T1 aOrmel, Johan1 aPerz, Siegfried1 aPeters, Annette1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRisbrough, Victoria, B1 aSinner, Moritz, F1 aSiscovick, David1 aSmit, Johannes, H1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStaessen, Jan, A1 aStein, Phyllis, K1 aStilp, Adrienne, M1 aStolarz-Skrzypek, Katarzyna1 aStrauch, Konstantin1 aSundström, Johan1 aSwenne, Cees, A1 aSyvänen, Ann-Christine1 aTardif, Jean-Claude1 aTaylor, Kent, D1 aTeumer, Alexander1 aThornton, Timothy, A1 aTinker, Lesley, E1 aUitterlinden, André, G1 avan Setten, Jessica1 aVoss, Andreas1 aWaldenberger, Melanie1 aWilhelmsen, Kirk, C1 aWillemsen, Gonneke1 aWong, Quenna1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aCusi, Daniele1 aEvans, Michele, K1 aGreiser, Halina, K1 aHarst, Pim1 aHassan, Mohammad1 aIngelsson, Erik1 aJarvelin, Marjo-Riitta1 aKääb, Stefan1 aKähönen, Mika1 aKivimaki, Mika1 aKooperberg, Charles1 aKuh, Diana1 aLehtimäki, Terho1 aLind, Lars1 aNievergelt, Caroline, M1 aO'Donnell, Chris, J1 aOldehinkel, Albertine, J1 aPenninx, Brenda1 aReiner, Alexander, P1 aRiese, Harriëtte1 avan Roon, Arie, M1 aRioux, John, D1 aRotter, Jerome, I1 aSofer, Tamar1 aStricker, Bruno, H1 aTiemeier, Henning1 aVrijkotte, Tanja, G M1 aAsselbergs, Folkert, W1 aBrundel, Bianca, J J M1 aHeckbert, Susan, R1 aWhitsel, Eric, A1 aHoed, Marcel, den1 aSnieder, Harold1 aGeus, Eco, J C uhttps://chs-nhlbi.org/node/757903756nas a2200625 4500008004100000245005200041210005100093260000800144300001600152490000800168520217900176100001902355700001202374700001602386700001402402700001802416700001602434700001702450700001702467700002102484700001602505700002102521700001702542700001702559700001302576700001802589700001202607700001902619700002002638700002302658700001802681700002002699700002002719700001802739700001902757700001702776700001202793700001702805700001602822700001902838700001902857700001602876700001802892700002202910700001502932700001902947700001702966700001502983700001902998700002103017700002003038700001503058700002103073856003603094 2017 eng d00a{Genetic Risk Prediction of Atrial Fibrillation0 aGenetic Risk Prediction of Atrial Fibrillation cApr a1311–13200 v1353 aAtrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.\ To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10-3 to <1×10-8 in a prior independent genetic association study.\ Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13-1.46; P=1.5×10-4) to 1.67 (25 variants; 95% confidence interval, 1.47-1.90; P=9.3×10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39-4.58; P=2.7×10-3). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20-4.40; P=0.01).\ Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.1 aLubitz, S., A.1 aYin, X.1 aLin, H., J.1 aKolek, M.1 aSmith, J., G.1 aTrompet, S.1 aRienstra, M.1 aRost, N., S.1 aTeixeira, P., L.1 aAlmgren, P.1 aAnderson, C., D.1 aChen, L., Y.1 aEngstr?m, G.1 aFord, I.1 aFurie, K., L.1 aGuo, X.1 aLarson, M., G.1 aLunetta, K., L.1 aMacfarlane, P., W.1 aPsaty, B., M.1 aSoliman, E., Z.1 aSotoodehnia, N.1 aStott, D., J.1 aTaylor, K., D.1 aWeng, L., C.1 aYao, J.1 aGeelhoed, B.1 aVerweij, N.1 aSiland, J., E.1 aKathiresan, S.1 aRoselli, C.1 aRoden, D., M.1 avan der Harst, P.1 aDarbar, D.1 aJukema, J., W.1 aMelander, O.1 aRosand, J.1 aRotter, J., I.1 aHeckbert, S., R.1 aEllinor, P., T.1 aAlonso, A.1 aBenjamin, E., J. uhttps://chs-nhlbi.org/node/855703502nas a2200793 4500008004100000022001400041245011400055210006900169260001200238300001400250490000700264520132200271653000901593653002501602653001101627653003401638653001101672653001101683653000901694653003701703653001601740653003601756653000901792100001801801700002001819700001401839700001601853700002201869700002201891700002001913700001501933700001901948700002001967700001801987700001702005700001702022700001402039700001302053700002102066700002102087700001702108700001702125700001902142700001702161700002102178700002402199700001502223700002402238700001402262700001602276700002602292700002002318700001802338700002302356700001802379700002502397700001902422700001702441700001902458700002202477700002202499700001802521700002002539700002302559700002002582700002002602710005002622856003602672 2017 eng d a1939-327X00aGenetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.0 aGenetically Determined Plasma Lipid Levels and Risk of Diabetic c2017 12 a3130-31410 v663 aResults from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
10aAged10aDiabetic Retinopathy10aFemale10aGenome-Wide Association Study10aHumans10aLipids10aMale10aMendelian Randomization Analysis10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk1 aSobrin, Lucia1 aChong, Yong, He1 aFan, Qiao1 aGan, Alfred1 aStanwyck, Lynn, K1 aKaidonis, Georgia1 aCraig, Jamie, E1 aKim, Jihye1 aLiao, Wen-Ling1 aHuang, Yu-Chuen1 aLee, Wen-Jane1 aHung, Yi-Jen1 aGuo, Xiuqing1 aHai, Yang1 aIpp, Eli1 aPollack, Samuela1 aHancock, Heather1 aPrice, Alkes1 aPenman, Alan1 aMitchell, Paul1 aLiew, Gerald1 aSmith, Albert, V1 aGudnason, Vilmundur1 aTan, Gavin1 aKlein, Barbara, E K1 aKuo, Jane1 aLi, Xiaohui1 aChristiansen, Mark, W1 aPsaty, Bruce, M1 aSandow, Kevin1 aJensen, Richard, A1 aKlein, Ronald1 aCotch, Mary, Frances1 aWang, Jie, Jin1 aJia, Yucheng1 aChen, Ching, J1 aChen, Yii-Der Ida1 aRotter, Jerome, I1 aTsai, Fuu-Jen1 aHanis, Craig, L1 aBurdon, Kathryn, P1 aWong, Tien, Yin1 aCheng, Ching-Yu1 aAsian Genetic Epidemiology Network Consortium uhttps://chs-nhlbi.org/node/759005336nas a2201753 4500008004100000245013100041210006900172260000800241300001400249490000700263520094500270100001901215700001801234700002001252700001201272700001201284700001501296700001501311700001801326700001201344700001701356700001801373700001501391700001201406700001601418700001501434700001601449700001701465700002101482700001501503700001601518700001301534700001101547700001601558700001701574700001701591700001401608700001601622700001601638700002301654700002001677700001301697700001601710700001601726700001901742700001701761700002001778700001301798700001401811700001401825700001301839700001601852700002201868700001701890700001801907700002101925700002001946700002001966700002001986700002102006700001302027700001902040700001602059700002002075700001902095700001902114700001802133700001902151700001802170700001702188700001502205700002102220700001302241700001802254700001902272700001202291700001802303700001402321700001302335700001402348700001602362700002602378700001602404700002002420700002202440700001902462700002102481700001702502700001602519700001802535700001602553700001602569700001902585700002102604700001502625700001902640700001902659700001902678700001402697700001802711700001502729700001502744700002002759700001802779700001802797700001802815700001302833700001202846700001602858700002002874700001602894700001602910700001502926700001902941700001602960700001702976700001802993700002203011700001703033700001803050700001503068700001503083700001403098700001903112700002103131700001503152700001703167700001803184700002003202700001903222700001503241700002003256700001903276700001603295700002003311700002003331700001503351700001903366700001303385700001803398700001603416700002203432700001803454700001903472700001703491700002203508700001603530856003603546 2017 eng d00a{Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk0 aGenomewide association analysis identifies novel blood pressure cMar a403–4150 v493 aElevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.1 aWarren, H., R.1 aEvangelou, E.1 aCabrera, C., P.1 aGao, H.1 aRen, M.1 aMifsud, B.1 aNtalla, I.1 aSurendran, P.1 aLiu, C.1 aCook, J., P.1 aKraja, A., T.1 aDrenos, F.1 aLoh, M.1 aVerweij, N.1 aMarten, J.1 aKaraman, I.1 aLepe, M., P.1 aO'Reilly, P., F.1 aKnight, J.1 aSnieder, H.1 aKato, N.1 aHe, J.1 aTai, E., S.1 aSaid, M., A.1 aPorteous, D.1 aAlver, M.1 aPoulter, N.1 aFarrall, M.1 aGansevoort, R., T.1 aPadmanabhan, S.1 aM?gi, R.1 aStanton, A.1 aConnell, J.1 aBakker, S., J.1 aMetspalu, A.1 aShields, D., C.1 aThom, S.1 aBrown, M.1 aSever, P.1 aEsko, T.1 aHayward, C.1 avan der Harst, P.1 aSaleheen, D.1 aChowdhury, R.1 aChambers, J., C.1 aChasman, D., I.1 aChakravarti, A.1 aNewton-Cheh, C.1 aLindgren, C., M.1 aLevy, D.1 aKooner, J., S.1 aKeavney, B.1 aTomaszewski, M.1 aSamani, N., J.1 aHowson, J., M.1 aTobin, M., D.1 aMunroe, P., B.1 aEhret, G., B.1 aWain, L., V.1 aV?lker, U.1 aVollenweider, P.1 aWild, S.1 aWillemsen, G.1 aWright, A., F.1 aYao, J.1 aTh?riault, S.1 aConen, D.1 aJohn, A.1 aSever, P.1 aDebette, S.1 aMook-Kanamori, D., O.1 aZeggini, E.1 aSpector, T., D.1 avan der Harst, P.1 aPalmer, C., N.1 aVergnaud, A., C.1 aLoos, R., J.1 aPolasek, O.1 aStarr, J., M.1 aGirotto, G.1 aHayward, C.1 aKooner, J., S.1 aLindgren, C., M.1 aVitart, V.1 aSamani, N., J.1 aTuomilehto, J.1 aGyllensten, U.1 aKnekt, P.1 aDeary, I., J.1 aCiullo, M.1 aElosua, R.1 aKeavney, B., D.1 aHicks, A., A.1 aScott, R., A.1 aGasparini, P.1 aLaan, M.1 aLiu, Y.1 aWatkins, H.1 aHartman, C., A.1 aSalomaa, V.1 aToniolo, D.1 aPerola, M.1 aWilson, J., F.1 aSchmidt, H.1 aZhao, J., H.1 aLehtim?ki, T.1 avan Duijn, C., M.1 aGudnason, V.1 aPsaty, B., M.1 aPeters, A.1 aRettig, R.1 aJames, A.1 aJukema, J., W.1 aStrachan, D., P.1 aPalmas, W.1 aMetspalu, A.1 aIngelsson, E.1 aBoomsma, D., I.1 aFranco, O., H.1 aBochud, M.1 aNewton-Cheh, C.1 aMunroe, P., B.1 aElliott, P.1 aChasman, D., I.1 aChakravarti, A.1 aKnight, J.1 aMorris, A., P.1 aLevy, D.1 aTobin, M., D.1 aSnieder, H.1 aCaulfield, M., J.1 aEhret, G., B.1 aBarnes, M., R.1 aTzoulaki, I.1 aCaulfield, M., J.1 aElliott, P. uhttps://chs-nhlbi.org/node/856005076nas a2201081 4500008004100000022001400041245010500055210006900160260000900229300001300238490000700251520207300258653001002331653000902341653001902350653002602369653002602395653001102421653004002432653001102472653003402483653001102517653000902528653001602537653001202553653001802565100002502583700002202608700002402630700001902654700002702673700002102700700002302721700001802744700001602762700002302778700002502801700002602826700002102852700002202873700001902895700002002914700002902934700001102963700001702974700001802991700002203009700001903031700001903050700002003069700001603089700002003105700002103125700002103146700002003167700001603187700002103203700002403224700001903248700001703267700001903284700002003303700002003323700002103343700002103364700003203385700001903417700002803436700002403464700002003488700001903508700002103527700002203548700002003570700001903590700002103609700002003630700001603650700002103666700002303687700002503710700002303735700002803758700002503786700002103811700002103832700002003853700002203873700002303895700002003918700002003938856003603958 2017 eng d a1932-620300aGenome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts.0 aGenomewide association metaanalysis of fish and EPADHA consumpti c2017 ae01864560 v123 aBACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.
OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.
DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.
RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.
CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.
10aAdult10aAged10aCohort Studies10aDocosahexaenoic Acids10aEicosapentaenoic Acid10aEurope10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aSeafood10aUnited States1 aMozaffarian, Dariush1 aDashti, Hassan, S1 aWojczynski, Mary, K1 aChu, Audrey, Y1 aNettleton, Jennifer, A1 aMännistö, Satu1 aKristiansson, Kati1 aReedik, Mägi1 aLahti, Jari1 aHouston, Denise, K1 aCornelis, Marilyn, C1 avan Rooij, Frank, J A1 aDimitriou, Maria1 aKanoni, Stavroula1 aMikkilä, Vera1 aSteffen, Lyn, M1 aOtto, Marcia, C de Olive1 aQi, Lu1 aPsaty, Bruce1 aDjoussé, Luc1 aRotter, Jerome, I1 aHarald, Kennet1 aPerola, Markus1 aRissanen, Harri1 aJula, Antti1 aKrista, Fischer1 aMihailov, Evelin1 aFeitosa, Mary, F1 aNgwa, Julius, S1 aXue, Luting1 aJacques, Paul, F1 aPerälä, Mia-Maria1 aPalotie, Aarno1 aLiu, Yongmei1 aNalls, Nike, A1 aFerrucci, Luigi1 aHernandez, Dena1 aManichaikul, Ani1 aTsai, Michael, Y1 ade Jong, Jessica, C Kiefte-1 aHofman, Albert1 aUitterlinden, André, G1 aRallidis, Loukianos1 aRidker, Paul, M1 aRose, Lynda, M1 aBuring, Julie, E1 aLehtimäki, Terho1 aKähönen, Mika1 aViikari, Jorma1 aLemaitre, Rozenn1 aSalomaa, Veikko1 aKnekt, Paul1 aMetspalu, Andres1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aEriksson, Johan, G1 aKritchevsky, Stephen, B1 aBandinelli, Stefania1 aSiscovick, David1 aFranco, Oscar, H1 aDeloukas, Panos1 aDedoussis, George1 aChasman, Daniel, I1 aRaitakari, Olli1 aTanaka, Toshiko uhttps://chs-nhlbi.org/node/757804127nas a2200853 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520188400256653003702140653001902177653001302196653001102209653001702220653003402237653001102271653000902282653001402291653003602305100001702341700002102358700002202379700001702401700001402418700002002432700001402452700002102466700001702487700002202504700001402526700001702540700001702557700001202574700002002586700001802606700001702624700001202641700002002653700001902673700002102692700001502713700001802728700001602746700001502762700002202777700002002799700001602819700001802835700001302853700001702866700001802883700001702901700001502918700001802933700002202951700001902973700001602992700002003008700002203028700001903050700002203069700002303091700001703114700002003131700001803151700001203169700001803181700001703199700002103216856003603237 2017 eng d a1942-326800aGenome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.0 aGenomeWide Association Study MetaAnalysis of LongTerm Average Bl c2017 Apr ae0015270 v103 aBACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.
METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively).
CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.
10aAsian Continental Ancestry Group10aBlood Pressure10aFar East10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aPhenotype10aPolymorphism, Single Nucleotide1 aLi, Changwei1 aKim, Yun, Kyoung1 aDorajoo, Rajkumar1 aLi, Huaixing1 aLee, I-Te1 aCheng, Ching-Yu1 aHe, Meian1 aSheu, Wayne, H-H1 aGuo, Xiuqing1 aGanesh, Santhi, K1 aHe, Jiang1 aLee, Juyoung1 aLiu, Jianjun1 aHu, Yao1 aRao, Dabeeru, C1 aTsai, Fuu-Jen1 aKoh, Jia, Yu1 aHu, Hua1 aLiang, Kae-Woei1 aPalmas, Walter1 aHixson, James, E1 aHan, Sohee1 aTeo, Yik-Ying1 aWang, Yiqin1 aChen, Jing1 aLu, Chieh, Hsiang1 aZheng, Yingfeng1 aGui, Lixuan1 aLee, Wen-Jane1 aYao, Jie1 aGu, Dongfeng1 aHan, Bok-Ghee1 aSim, Xueling1 aSun, Liang1 aZhao, Jinying1 aChen, Chien-Hsiun1 aKumari, Neelam1 aHe, Yunfeng1 aTaylor, Kent, D1 aRaffel, Leslie, J1 aMoon, Sanghoon1 aRotter, Jerome, I1 aChen, Yii-Der, Ida1 aWu, Tangchun1 aWong, Tien, Yin1 aWu, Jer-Yuarn1 aLin, Xu1 aTai, E-Shyong1 aKim, Bong-Jo1 aKelly, Tanika, N uhttps://chs-nhlbi.org/node/757104580nas a2200937 4500008004100000022001400041245022100055210006900276260001300345300001200358490000700370520179400377100002102171700002402192700002202216700002202238700002702260700002202287700002002309700002102329700001602350700002102366700001602387700001202403700002102415700001902436700002302455700001902478700002302497700002102520700002402541700002502565700001502590700002102605700002902626700002202655700002302677700002202700700001902722700002002741700001702761700002202778700001202800700002002812700002102832700001802853700002302871700002302894700002902917700001802946700002502964700002102989700001903010700002503029700002403054700001903078700001703097700002303114700002003137700002403157700002203181700002003203700001803223700002003241700002503261700002803286700002403314700002103338700002403359700001903383700002103402700001703423700002903440700002403469700002203493700002703515700002003542700002303562700002103585856003603606 2017 eng d a1468-624400aA genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.0 agenomewide interaction analysis of tricyclictetracyclic antidepr c2017 May a313-3230 v543 aBACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.
METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.
CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.
1 aNoordam, Raymond1 aSitlani, Colleen, M1 aAvery, Christy, L1 aStewart, James, D1 aGogarten, Stephanie, M1 aWiggins, Kerri, L1 aTrompet, Stella1 aWarren, Helen, R1 aSun, Fangui1 aEvans, Daniel, S1 aLi, Xiaohui1 aLi, Jin1 aSmith, Albert, V1 aBis, Joshua, C1 aBrody, Jennifer, A1 aBusch, Evan, L1 aCaulfield, Mark, J1 aChen, Yii-der, I1 aCummings, Steven, R1 aCupples, Adrienne, L1 aDuan, Qing1 aFranco, Oscar, H1 aMéndez-Giráldez, Rául1 aHarris, Tamara, B1 aHeckbert, Susan, R1 avan Heemst, Diana1 aHofman, Albert1 aFloyd, James, S1 aKors, Jan, A1 aLauner, Lenore, J1 aLi, Yun1 aLi-Gao, Ruifang1 aLange, Leslie, A1 aLin, Henry, J1 ade Mutsert, Renée1 aNapier, Melanie, D1 aNewton-Cheh, Christopher1 aPoulter, Neil1 aReiner, Alexander, P1 aRice, Kenneth, M1 aRoach, Jeffrey1 aRodriguez, Carlos, J1 aRosendaal, Frits, R1 aSattar, Naveed1 aSever, Peter1 aSeyerle, Amanda, A1 aSlagboom, Eline1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStott, David, J1 aStürmer, Til1 aTaylor, Kent, D1 aThornton, Timothy, A1 aUitterlinden, André, G1 aWilhelmsen, Kirk, C1 aWilson, James, G1 aGudnason, Vilmundur1 aJukema, Wouter1 aLaurie, Cathy, C1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aStricker, Bruno, H1 aWhitsel, Eric, A uhttps://chs-nhlbi.org/node/735304016nas a2200865 4500008004100000022001400041245009800055210006900153260001600222520147500238100002001713700002001733700002201753700002001775700002201795700002201817700002801839700002401867700002101891700001901912700003201931700001701963700002801980700002402008700001602032700002202048700001902070700001902089700002002108700001902128700002102147700002002168700002302188700001902211700002002230700001402250700002302264700001902287700002502306700002102331700002102352700002402373700002902397700002502426700002502451700002302476700002502499700002502524700002102549700002402570700002202594700003202616700002002648700002202668700001902690700002302709700002202732700002902754700002502783700002302808700001902831700001702850700002102867700001902888700002202907700002202929700002802951700002602979700002103005700001803026700002403044700002503068700002103093856003603114 2017 eng d a1613-413300aGenome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent.0 aGenomeWide Interactions with Dairy Intake for Body Mass Index in c2017 Sep 213 aSCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.
METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.
CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.
1 aSmith, Caren, E1 aFollis, Jack, L1 aDashti, Hassan, S1 aTanaka, Toshiko1 aGraff, Mariaelisa1 aFretts, Amanda, M1 aKilpeläinen, Tuomas, O1 aWojczynski, Mary, K1 aRichardson, Kris1 aNalls, Mike, A1 aSchulz, Christina-Alexandra1 aLiu, Yongmei1 aFrazier-Wood, Alexis, C1 avan Eekelen, Esther1 aWang, Carol1 ade Vries, Paul, S1 aMikkilä, Vera1 aRohde, Rebecca1 aPsaty, Bruce, M1 aHansen, Torben1 aFeitosa, Mary, F1 aLai, Chao-Qiang1 aHouston, Denise, K1 aFerruci, Luigi1 aEricson, Ulrika1 aWang, Zhe1 ade Mutsert, Renée1 aOddy, Wendy, H1 ade Jonge, Ester, A L1 aSeppälä, Ilkka1 aJustice, Anne, E1 aLemaitre, Rozenn, N1 aSørensen, Thorkild, I A1 aProvince, Michael, A1 aParnell, Laurence, D1 aGarcia, Melissa, E1 aBandinelli, Stefania1 aOrho-Melander, Marju1 aRich, Stephen, S1 aRosendaal, Frits, R1 aPennell, Craig, E1 ade Jong, Jessica, C Kiefte-1 aKähönen, Mika1 aYoung, Kristin, L1 aPedersen, Oluf1 aAslibekyan, Stella1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aZillikens, Carola, M1 aRaitakari, Olli, T1 aNorth, Kari, E1 aOvervad, Kim1 aArnett, Donna, K1 aHofman, Albert1 aLehtimäki, Terho1 aTjønneland, Anne1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aFranco, Oscar, H1 aGerman, Bruce1 aSiscovick, David, S1 aCupples, Adrienne, L1 aOrdovas, Jose, M uhttps://chs-nhlbi.org/node/758805566nas a2201489 4500008004100000022001400041245010700055210006900162260001600231300000800247490000600255520135700261100002001618700002001638700002801658700002001686700001701706700002601723700002001749700001901769700002601788700002501814700001401839700001901853700002101872700002901893700002101922700002301943700002301966700002201989700001402011700002802025700002002053700002002073700002102093700002002114700002502134700002502159700002202184700001902206700002402225700001902249700002102268700002402289700001902313700002402332700002102356700001602377700002102393700002402414700002102438700002302459700001702482700002102499700001402520700002602534700002002560700002202580700002102602700002402623700002302647700002002670700002002690700001802710700001502728700002102743700002302764700002402787700001902811700001802830700002502848700002202873700001702895700001502912700002502927700002402952700002602976700002003002700002603022700002203048700001803070700002203088700002003110700002003130700002003150700002303170700002203193700003503215700002603250700002303276700002303299700002403322700001803346700001803364700002303382700002303405700002203428700002203450700001903472700002703491700001803518700002003536700002403556700001903580700002103599700001703620700002003637700002303657700002103680700001903701700002403720700002803744700002303772700001903795700001903814700002103833700002303854700002203877700002003899700002403919700001903943700002003962700001603982700002103998700002104019856003604040 2017 eng d a2041-172300aGenome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.0 aGenomewide metaanalysis associates HLADQA1DRB1 and LPA and lifes c2017 Oct 13 a9100 v83 aGenomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
1 aJoshi, Peter, K1 aPirastu, Nicola1 aKentistou, Katherine, A1 aFischer, Krista1 aHofer, Edith1 aSchraut, Katharina, E1 aClark, David, W1 aNutile, Teresa1 aBarnes, Catriona, L K1 aTimmers, Paul, R H J1 aShen, Xia1 aGandin, Ilaria1 aMcDaid, Aaron, F1 aHansen, Thomas, Folkmann1 aGordon, Scott, D1 aGiulianini, Franco1 aBoutin, Thibaud, S1 aAbdellaoui, Abdel1 aZhao, Wei1 aMedina-Gómez, Carolina1 aBartz, Traci, M1 aTrompet, Stella1 aLange, Leslie, A1 aRaffield, Laura1 avan der Spek, Ashley1 aGalesloot, Tessel, E1 aProitsi, Petroula1 aYanek, Lisa, R1 aBielak, Lawrence, F1 aPayton, Antony1 aMurgia, Federico1 aConcas, Maria, Pina1 aBiino, Ginevra1 aTajuddin, Salman, M1 aSeppälä, Ilkka1 aAmin, Najaf1 aBoerwinkle, Eric1 aBørglum, Anders, D1 aCampbell, Archie1 aDemerath, Ellen, W1 aDemuth, Ilja1 aFaul, Jessica, D1 aFord, Ian1 aGialluisi, Alessandro1 aGögele, Martin1 aGraff, Mariaelisa1 aHingorani, Aroon1 aHottenga, Jouke-Jan1 aHougaard, David, M1 aHurme, Mikko, A1 aIkram, Arfan, M1 aJylhä, Marja1 aKuh, Diana1 aLigthart, Lannie1 aLill, Christina, M1 aLindenberger, Ulman1 aLumley, Thomas1 aMägi, Reedik1 aMarques-Vidal, Pedro1 aMedland, Sarah, E1 aMilani, Lili1 aNagy, Reka1 aOllier, William, E R1 aPeyser, Patricia, A1 aPramstaller, Peter, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRuggiero, Daniela1 aSaba, Yasaman1 aSchmidt, Reinhold1 aSchmidt, Helena1 aSlagboom, Eline1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aSteinhagen-Thiessen, Elisabeth1 avan Rooij, Frank, J A1 aVerbeek, André, L1 aVermeulen, Sita, H1 aVollenweider, Peter1 aWang, Yunpeng1 aWerge, Thomas1 aWhitfield, John, B1 aZonderman, Alan, B1 aLehtimäki, Terho1 aEvans, Michele, K1 aPirastu, Mario1 aFuchsberger, Christian1 aBertram, Lars1 aPendleton, Neil1 aKardia, Sharon, L R1 aCiullo, Marina1 aBecker, Diane, M1 aWong, Andrew1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWilson, James, G1 aJukema, Wouter1 aKiemeney, Lambertus1 aUitterlinden, André, G1 aFranceschini, Nora1 aNorth, Kari, E1 aWeir, David, R1 aMetspalu, Andres1 aBoomsma, Dorret, I1 aHayward, Caroline1 aChasman, Daniel1 aMartin, Nicholas, G1 aSattar, Naveed1 aCampbell, Harry1 aEsko, Tõnu1 aKutalik, Zoltán1 aWilson, James, F uhttps://chs-nhlbi.org/node/756810949nas a2203925 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2017 eng d00a{Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits0 aGenomewide metaanalysis of 241258 adults accounting for smoking c04 a149770 v83 aFew genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.1 aJustice, A., E.1 aWinkler, T., W.1 aFeitosa, M., F.1 aGraff, M.1 aFisher, V., A.1 aYoung, K.1 aBarata, L.1 aDeng, X.1 aCzajkowski, J.1 aHadley, D.1 aNgwa, J., S.1 aAhluwalia, T., S.1 aChu, A., Y.1 aHeard-Costa, N., L.1 aLim, E.1 aPerez, J.1 aEicher, J., D.1 aKutalik, Z.1 aXue, L.1 aMahajan, A.1 aRenstr?m, F.1 aWu, J.1 aQi, Q.1 aAhmad, S.1 aAlfred, T.1 aAmin, N.1 aBielak, L., F.1 aBonnefond, A.1 aBragg, J.1 aCadby, G.1 aChittani, M.1 aCoggeshall, S.1 aCorre, T.1 aDirek, N.1 aEriksson, J.1 aFischer, K.1 aGorski, M.1 aHarder, Neergaard1 aHorikoshi, M.1 aHuang, T.1 aHuffman, J., E.1 aJackson, A., U.1 aJustesen, J., M.1 aKanoni, S.1 aKinnunen, L.1 aKleber, M., E.1 aKomulainen, P.1 aKumari, M.1 aLim, U.1 aLuan, J.1 aLyytik?inen, L., P.1 aMangino, M.1 aManichaikul, A.1 aMarten, J.1 aMiddelberg, R., P. S.1 aM?ller-Nurasyid, M.1 aNavarro, P.1 aP?russe, L.1 aPervjakova, N.1 aSarti, C.1 aSmith, A., V.1 aSmith, J., A.1 aStan??kov?, A.1 aStrawbridge, R., J.1 aStringham, H., M.1 aSung, Y., J.1 aTanaka, T.1 aTeumer, A.1 aTrompet, S.1 avan der Laan, S., W.1 avan der Most, P., J.1 aVan Vliet-Ostaptchouk, J., V.1 aVedantam, S., L.1 aVerweij, N.1 aVink, J., M.1 aVitart, V.1 aWu, Y.1 aYengo, L.1 aZhang, W.1 aZhao, Hua1 aZimmermann, M., E.1 aZubair, N.1 aAbecasis, G., R.1 aAdair, L., S.1 aAfaq, S.1 aAfzal, U.1 aBakker, S., J. L.1 aBartz, T., M.1 aBeilby, J.1 aBergman, R., N.1 aBergmann, S.1 aBiffar, R.1 aBlangero, J.1 aBoerwinkle, E.1 aBonnycastle, L., L.1 aBottinger, E.1 aBraga, D.1 aBuckley, B., M.1 aBuyske, S.1 aCampbell, H.1 aChambers, J., C.1 aCollins, F., S.1 aCurran, J., E.1 ade Borst, G., J.1 ade Craen, A., J. M.1 ade Geus, E., J. C.1 aDedoussis, G.1 aDelgado, G., E.1 aRuijter, H., M. den1 aEiriksdottir, G.1 aEriksson, A., L.1 aEsko, T.1 aFaul, J., D.1 aFord, I.1 aForrester, T.1 aGertow, K.1 aGigante, B.1 aGlorioso, N.1 aGong, J.1 aGrallert, H.1 aGrammer, T., B.1 aGrarup, N.1 aHaitjema, S.1 aHallmans, G.1 aHamsten, A.1 aHansen, T.1 aHarris, T., B.1 aHartman, C., A.1 aHassinen, M.1 aHastie, N., D.1 aHeath, A., C.1 aHernandez, D.1 aHindorff, L.1 aHocking, L., J.1 aHollensted, M.1 aHolmen, O., L.1 aHomuth, G.1 aHottenga, Jan1 aHuang, J.1 aHung, J.1 aHutri-K?h?nen, N.1 aIngelsson, E.1 aJames, A., L.1 aJansson, J., O.1 aJarvelin, M., R.1 aJhun, M., A.1 aJ?rgensen, M., E.1 aJuonala, M.1 aK?h?nen, M.1 aKarlsson, M.1 aKoistinen, H., A.1 aKolcic, I.1 aKolovou, G.1 aKooperberg, C.1 aKr?mer, B., K.1 aKuusisto, J.1 aKval?y, K.1 aLakka, T., A.1 aLangenberg, C.1 aLauner, L., J.1 aLeander, K.1 aLee, N., R.1 aLind, L.1 aLindgren, C., M.1 aLinneberg, A.1 aLobbens, S.1 aLoh, M.1 aLorentzon, M.1 aLuben, R.1 aLubke, G.1 aLudolph-Donislawski, A.1 aLupoli, S.1 aMadden, P., A. F.1 aM?nnikk?, R.1 aMarques-Vidal, P.1 aMartin, N., G.1 aMcKenzie, C., A.1 aMcKnight, B.1 aMellstr?m, D.1 aMenni, C.1 aMontgomery, G., W.1 aMusk, A., B.1 aNarisu, N.1 aNauck, M.1 aNolte, I., M.1 aOldehinkel, A., J.1 aOlden, M.1 aOng, K., K.1 aPadmanabhan, S.1 aPeyser, P., A.1 aPisinger, C.1 aPorteous, D., J.1 aRaitakari, O., T.1 aRankinen, T.1 aRao, D., C.1 aRasmussen-Torvik, L., J.1 aRawal, R.1 aRice, T.1 aRidker, P., M.1 aRose, L., M.1 aBien, S., A.1 aRudan, I.1 aSanna, S.1 aSarzynski, M., A.1 aSattar, N.1 aSavonen, K.1 aSchlessinger, D.1 aScholtens, S.1 aSchurmann, C.1 aScott, R., A.1 aSennblad, B.1 aSiemelink, M., A.1 aSilbernagel, G.1 aSlagboom, P., E.1 aSnieder, H.1 aStaessen, J., A.1 aStott, D., J.1 aSwertz, M., A.1 aSwift, A., J.1 aTaylor, K., D.1 aTayo, B., O.1 aThorand, B.1 aThuillier, D.1 aTuomilehto, J.1 aUitterlinden, A., G.1 aVandenput, L.1 aVohl, M., C.1 aV?lzke, H.1 aVonk, J., M.1 aWaeber, G.1 aWaldenberger, M.1 aWestendorp, R., G. J.1 aWild, S.1 aWillemsen, G.1 aWolffenbuttel, B., H. R.1 aWong, A.1 aWright, A., F.1 aZhao, W.1 aZillikens, M., C.1 aBaldassarre, D.1 aBalkau, B.1 aBandinelli, S.1 aB?ger, C., A.1 aBoomsma, D., I.1 aBouchard, C.1 aBruinenberg, M.1 aChasman, D., I.1 aChen, Y., D.1 aChines, P., S.1 aCooper, R., S.1 aCucca, F.1 aCusi, D.1 aFaire, U.1 aFerrucci, L.1 aFranks, P., W.1 aFroguel, P.1 aGordon-Larsen, P.1 aGrabe, H., J.1 aGudnason, V.1 aHaiman, C., A.1 aHayward, C.1 aHveem, K.1 aJohnson, A., D.1 aJukema, Wouter1 aKardia, S., L. R.1 aKivimaki, M.1 aKooner, J., S.1 aKuh, D.1 aLaakso, M.1 aLehtim?ki, T.1 aMarchand, L., L.1 aM?rz, W.1 aMcCarthy, M., I.1 aMetspalu, A.1 aMorris, A., P.1 aOhlsson, C.1 aPalmer, L., J.1 aPasterkamp, G.1 aPedersen, O.1 aPeters, A.1 aPeters, U.1 aPolasek, O.1 aPsaty, B., M.1 aQi, L.1 aRauramaa, R.1 aSmith, B., H.1 aS?rensen, T., I. A.1 aStrauch, K.1 aTiemeier, H.1 aTremoli, E.1 avan der Harst, P.1 aVestergaard, H.1 aVollenweider, P.1 aWareham, N., J.1 aWeir, D., R.1 aWhitfield, J., B.1 aWilson, J., F.1 aTyrrell, J.1 aFrayling, T., M.1 aBarroso, I.1 aBoehnke, M.1 aDeloukas, P.1 aFox, C., S.1 aHirschhorn, J., N.1 aHunter, D., J.1 aSpector, T., D.1 aStrachan, D., P.1 avan Duijn, C., M.1 aHeid, I., M.1 aMohlke, K., L.1 aMarchini, J.1 aLoos, R., J. F.1 aKilpel?inen, T., O.1 aLiu, C., T.1 aBorecki, I., B.1 aNorth, K., E.1 aCupples, L., A. uhttps://chs-nhlbi.org/node/855404812nas a2201345 4500008004100000022001400041245014400055210006900199260001600268300001000284490000800294520106400302100002601366700001801392700002101410700001301431700002001444700002001464700002301484700002001507700002001527700001801547700002001565700001701585700002301602700001901625700002301644700001801667700002001685700002101705700002301726700001901749700001901768700002301787700001901810700001801829700001801847700002401865700001801889700002201907700002001929700002101949700002101970700002001991700002202011700002102033700002002054700001402074700002002088700001602108700001902124700002002143700002802163700002102191700001702212700002002229700001402249700002102263700002202284700002302306700001502329700001502344700001802359700002202377700002302399700002202422700001902444700002102463700001202484700002402496700002202520700001702542700002002559700002202579700002202601700002002623700001402643700002202657700002102679700002002700700002002720700002302740700002002763700002202783700002202805700001502827700002302842700002302865700002402888700002202912700001702934700001802951700001802969700001802987700002103005700002103026700001603047700002003063700002103083700002103104700002903125700002103154700002403175700003003199700001903229700002503248700002203273700002203295700002003317700002503337700002003362700002203382710002603404856003603430 2017 eng d a1537-660500aGenome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.0 aGenomewide Transethnic Metaanalysis Identifies Seven Genetic Loc c2017 Jan 05 a51-630 v1003 aGenome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.
1 avan Rooij, Frank, J A1 aQayyum, Rehan1 aSmith, Albert, V1 aZhou, Yi1 aTrompet, Stella1 aTanaka, Toshiko1 aKeller, Margaux, F1 aChang, Li-Ching1 aSchmidt, Helena1 aYang, Min-Lee1 aChen, Ming-Huei1 aHayes, James1 aJohnson, Andrew, D1 aYanek, Lisa, R1 aMueller, Christian1 aLange, Leslie1 aFloyd, James, S1 aGhanbari, Mohsen1 aZonderman, Alan, B1 aJukema, Wouter1 aHofman, Albert1 aDuijn, Cornelia, M1 aDesch, Karl, C1 aSaba, Yasaman1 aOzel, Ayse, B1 aSnively, Beverly, M1 aWu, Jer-Yuarn1 aSchmidt, Reinhold1 aFornage, Myriam1 aKlein, Robert, J1 aFox, Caroline, S1 aMatsuda, Koichi1 aKamatani, Naoyuki1 aWild, Philipp, S1 aStott, David, J1 aFord, Ian1 aSlagboom, Eline1 aYang, Jaden1 aChu, Audrey, Y1 aLambert, Amy, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aHofer, Edith1 aGinsburg, David1 aHu, Bella1 aKeating, Brendan1 aSchick, Ursula, M1 aBrody, Jennifer, A1 aLi, Jun, Z1 aChen, Zhao1 aZeller, Tanja1 aGuralnik, Jack, M1 aChasman, Daniel, I1 aPeters, Luanne, L1 aKubo, Michiaki1 aBecker, Diane, M1 aLi, Jin1 aEiriksdottir, Gudny1 aRotter, Jerome, I1 aLevy, Daniel1 aGrossmann, Vera1 aPatel, Kushang, V1 aChen, Chien-Hsiun1 aRidker, Paul, M1 aTang, Hua1 aLauner, Lenore, J1 aRice, Kenneth, M1 aLi-Gao, Ruifang1 aFerrucci, Luigi1 aEvans, Michelle, K1 aChoudhuri, Avik1 aTrompouki, Eirini1 aAbraham, Brian, J1 aYang, Song1 aTakahashi, Atsushi1 aKamatani, Yoichiro1 aKooperberg, Charles1 aHarris, Tamara, B1 aJee, Sun, Ha1 aCoresh, Josef1 aTsai, Fuu-Jen1 aLongo, Dan, L1 aChen, Yuan-Tsong1 aFelix, Janine, F1 aYang, Qiong1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aBecker, Lewis, C1 aMook-Kanamori, Dennis, O1 aWilson, James, G1 aGudnason, Vilmundur1 aO'Donnell, Christopher, J1 aDehghan, Abbas1 aCupples, Adrienne, L1 aNalls, Michael, A1 aMorris, Andrew, P1 aOkada, Yukinori1 aReiner, Alexander, P1 aZon, Leonard, I1 aGanesh, Santhi, K1 aBioBank Japan Project uhttps://chs-nhlbi.org/node/736400567nas a2200181 4500008004100000022001400041245007900055210006900134260001600203300001200219490000800231100002300239700002600262700002100288700002000309700002000329856003600349 2017 eng d a2168-611400aHealth and Functional Status of Adults Aged 90 Years in the United States.0 aHealth and Functional Status of Adults Aged 90 Years in the Unit c2017 May 01 a732-7340 v1771 aOdden, Michelle, C1 aKoh, William, Jen Hoe1 aArnold, Alice, M1 aPsaty, Bruce, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/735511080nas a2202833 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2017 eng d a1549-167600aImpact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.0 aImpact of common genetic determinants of Hemoglobin A1c on type c2017 Sep ae10023830 v143 aBACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.
METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.
CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
10aDiabetes Mellitus, Type 210aGenetic Variation10aGenome-Wide Association Study10aGlycated Hemoglobin A10aHumans10aPhenotype10aRisk1 aWheeler, Eleanor1 aLeong, Aaron1 aLiu, Ching-Ti1 aHivert, Marie-France1 aStrawbridge, Rona, J1 aPodmore, Clara1 aLi, Man1 aYao, Jie1 aSim, Xueling1 aHong, Jaeyoung1 aChu, Audrey, Y1 aZhang, Weihua1 aWang, Xu1 aChen, Peng1 aMaruthur, Nisa, M1 aPorneala, Bianca, C1 aSharp, Stephen, J1 aJia, Yucheng1 aKabagambe, Edmond, K1 aChang, Li-Ching1 aChen, Wei-Min1 aElks, Cathy, E1 aEvans, Daniel, S1 aFan, Qiao1 aGiulianini, Franco1 aGo, Min Jin1 aHottenga, Jouke-Jan1 aHu, Yao1 aJackson, Anne, U1 aKanoni, Stavroula1 aKim, Young, Jin1 aKleber, Marcus, E1 aLadenvall, Claes1 aLecoeur, Cécile1 aLim, Sing-Hui1 aLu, Yingchang1 aMahajan, Anubha1 aMarzi, Carola1 aNalls, Mike, A1 aNavarro, Pau1 aNolte, Ilja, M1 aRose, Lynda, M1 aRybin, Denis, V1 aSanna, Serena1 aShi, Yuan1 aStram, Daniel, O1 aTakeuchi, Fumihiko1 aTan, Shu, Pei1 avan der Most, Peter, J1 avan Vliet-Ostaptchouk, Jana, V1 aWong, Andrew1 aYengo, Loic1 aZhao, Wanting1 aGoel, Anuj1 aLarrad, Maria, Teresa Mar1 aRadke, Dörte1 aSalo, Perttu1 aTanaka, Toshiko1 avan Iperen, Erik, P A1 aAbecasis, Goncalo1 aAfaq, Saima1 aAlizadeh, Behrooz, Z1 aBertoni, Alain, G1 aBonnefond, Amélie1 aBöttcher, Yvonne1 aBottinger, Erwin, P1 aCampbell, Harry1 aCarlson, Olga, D1 aChen, Chien-Hsiun1 aCho, Yoon Shin1 aGarvey, Timothy1 aGieger, Christian1 aGoodarzi, Mark, O1 aGrallert, Harald1 aHamsten, Anders1 aHartman, Catharina, A1 aHerder, Christian1 aHsiung, Chao, Agnes1 aHuang, Jie1 aIgase, Michiya1 aIsono, Masato1 aKatsuya, Tomohiro1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKohara, Katsuhiko1 aKovacs, Peter1 aLee, Juyoung1 aLee, Wen-Jane1 aLehne, Benjamin1 aLi, Huaixing1 aLiu, Jianjun1 aLobbens, Stephane1 aLuan, Jian'an1 aLyssenko, Valeriya1 aMeitinger, Thomas1 aMiki, Tetsuro1 aMiljkovic, Iva1 aMoon, Sanghoon1 aMulas, Antonella1 aMüller, Gabriele1 aMüller-Nurasyid, Martina1 aNagaraja, Ramaiah1 aNauck, Matthias1 aPankow, James, S1 aPolasek, Ozren1 aProkopenko, Inga1 aRamos, Paula, S1 aRasmussen-Torvik, Laura1 aRathmann, Wolfgang1 aRich, Stephen, S1 aRobertson, Neil, R1 aRoden, Michael1 aRoussel, Ronan1 aRudan, Igor1 aScott, Robert, A1 aScott, William, R1 aSennblad, Bengt1 aSiscovick, David, S1 aStrauch, Konstantin1 aSun, Liang1 aSwertz, Morris1 aTajuddin, Salman, M1 aTaylor, Kent, D1 aTeo, Yik-Ying1 aTham, Yih, Chung1 aTönjes, Anke1 aWareham, Nicholas, J1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aHingorani, Aroon, D1 aEgan, Josephine1 aFerrucci, Luigi1 aHovingh, Kees1 aJula, Antti1 aKivimaki, Mika1 aKumari, Meena1 aNjølstad, Inger1 aPalmer, Colin, N A1 aRíos, Manuel, Serrano1 aStumvoll, Michael1 aWatkins, Hugh1 aAung, Tin1 aBlüher, Matthias1 aBoehnke, Michael1 aBoomsma, Dorret, I1 aBornstein, Stefan, R1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aChen, Yduan-Tsong1 aCheng, Ching-Yu1 aCucca, Francesco1 aGeus, Eco, J C1 aDeloukas, Panos1 aEvans, Michele, K1 aFornage, Myriam1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGroop, Leif1 aGross, Myron, D1 aHarris, Tamara, B1 aHayward, Caroline1 aHeng, Chew-Kiat1 aIngelsson, Erik1 aKato, Norihiro1 aKim, Bong-Jo1 aKoh, Woon-Puay1 aKooner, Jaspal, S1 aKörner, Antje1 aKuh, Diana1 aKuusisto, Johanna1 aLaakso, Markku1 aLin, Xu1 aLiu, Yongmei1 aLoos, Ruth, J F1 aMagnusson, Patrik, K E1 aMärz, Winfried1 aMcCarthy, Mark, I1 aOldehinkel, Albertine, J1 aOng, Ken, K1 aPedersen, Nancy, L1 aPereira, Mark, A1 aPeters, Annette1 aRidker, Paul, M1 aSabanayagam, Charumathi1 aSale, Michele1 aSaleheen, Danish1 aSaltevo, Juha1 aSchwarz, Peter, Eh1 aSheu, Wayne, H H1 aSnieder, Harold1 aSpector, Timothy, D1 aTabara, Yasuharu1 aTuomilehto, Jaakko1 avan Dam, Rob, M1 aWilson, James, G1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWong, Tien, Yin1 aWu, Jer-Yuarn1 aYuan, Jian-Min1 aZonderman, Alan, B1 aSoranzo, Nicole1 aGuo, Xiuqing1 aRoberts, David, J1 aFlorez, Jose, C1 aSladek, Robert1 aDupuis, Josée1 aMorris, Andrew, P1 aTai, E-Shyong1 aSelvin, Elizabeth1 aRotter, Jerome, I1 aLangenberg, Claudia1 aBarroso, Inês1 aMeigs, James, B1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/759608180nas a2202449 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2017 eng d a2041-172300aLarge meta-analysis of genome-wide association studies identifies five loci for lean body mass.0 aLarge metaanalysis of genomewide association studies identifies c2017 Jul 19 a800 v83 aLean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
1 aZillikens, Carola, M1 aDemissie, Serkalem1 aHsu, Yi-Hsiang1 aYerges-Armstrong, Laura, M1 aChou, Wen-Chi1 aStolk, Lisette1 aLivshits, Gregory1 aBroer, Linda1 aJohnson, Toby1 aKoller, Daniel, L1 aKutalik, Zoltán1 aLuan, Jian'an1 aMalkin, Ida1 aRied, Janina, S1 aSmith, Albert, V1 aThorleifsson, Gudmar1 aVandenput, Liesbeth1 aZhao, Jing, Hua1 aZhang, Weihua1 aAghdassi, Ali1 aÅkesson, Kristina1 aAmin, Najaf1 aBaier, Leslie, J1 aBarroso, Inês1 aBennett, David, A1 aBertram, Lars1 aBiffar, Rainer1 aBochud, Murielle1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aBuchman, Aron, S1 aByberg, Liisa1 aCampbell, Harry1 aObanda, Natalia, Campos1 aCauley, Jane, A1 aCawthon, Peggy, M1 aCederberg, Henna1 aChen, Zhao1 aCho, Nam, H1 aChoi, Hyung, Jin1 aClaussnitzer, Melina1 aCollins, Francis1 aCummings, Steven, R1 aDe Jager, Philip, L1 aDemuth, Ilja1 aDhonukshe-Rutten, Rosalie, A M1 aDiatchenko, Luda1 aEiriksdottir, Gudny1 aEnneman, Anke, W1 aErdos, Mike1 aEriksson, Johan, G1 aEriksson, Joel1 aEstrada, Karol1 aEvans, Daniel, S1 aFeitosa, Mary, F1 aFu, Mao1 aGarcia, Melissa1 aGieger, Christian1 aGirke, Thomas1 aGlazer, Nicole, L1 aGrallert, Harald1 aGrewal, Jagvir1 aHan, Bok-Ghee1 aHanson, Robert, L1 aHayward, Caroline1 aHofman, Albert1 aHoffman, Eric, P1 aHomuth, Georg1 aHsueh, Wen-Chi1 aHubal, Monica, J1 aHubbard, Alan1 aHuffman, Kim, M1 aHusted, Lise, B1 aIllig, Thomas1 aIngelsson, Erik1 aIttermann, Till1 aJansson, John-Olov1 aJordan, Joanne, M1 aJula, Antti1 aKarlsson, Magnus1 aKhaw, Kay-Tee1 aKilpeläinen, Tuomas, O1 aKlopp, Norman1 aKloth, Jacqueline, S L1 aKoistinen, Heikki, A1 aKraus, William, E1 aKritchevsky, Stephen1 aKuulasmaa, Teemu1 aKuusisto, Johanna1 aLaakso, Markku1 aLahti, Jari1 aLang, Thomas1 aLangdahl, Bente, L1 aLauner, Lenore, J1 aLee, Jong-Young1 aLerch, Markus, M1 aLewis, Joshua, R1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLiu, Tian1 aLiu, Youfang1 aLjunggren, Osten1 aLorentzon, Mattias1 aLuben, Robert, N1 aMaixner, William1 aMcGuigan, Fiona, E1 aMedina-Gómez, Carolina1 aMeitinger, Thomas1 aMelhus, Håkan1 aMellström, Dan1 aMelov, Simon1 aMichaëlsson, Karl1 aMitchell, Braxton, D1 aMorris, Andrew, P1 aMosekilde, Leif1 aNewman, Anne1 aNielson, Carrie, M1 aO'Connell, Jeffrey, R1 aOostra, Ben, A1 aOrwoll, Eric, S1 aPalotie, Aarno1 aParker, Stephen, C J1 aPeacock, Munro1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPrince, Richard, L1 aRäikkönen, Katri1 aRalston, Stuart, H1 aRipatti, Samuli1 aRobbins, John, A1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSatterfield, Suzanne1 aSchadt, Eric, E1 aSchipf, Sabine1 aScott, Laura1 aSehmi, Joban1 aShen, Jian1 aShin, Chan, Soo1 aSigurdsson, Gunnar1 aSmith, Shad1 aSoranzo, Nicole1 aStančáková, Alena1 aSteinhagen-Thiessen, Elisabeth1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aSwart, Karin, M A1 aTan, Sian-Tsung1 aTarnopolsky, Mark, A1 aThompson, Patricia1 aThomson, Cynthia, A1 aThorsteinsdottir, Unnur1 aTikkanen, Emmi1 aTranah, Gregory, J1 aTuomilehto, Jaakko1 avan Schoor, Natasja, M1 aVerma, Arjun1 aVollenweider, Peter1 aVölzke, Henry1 aWactawski-Wende, Jean1 aWalker, Mark1 aWeedon, Michael, N1 aWelch, Ryan1 aWichmann, H-Erich1 aWiden, Elisabeth1 aWilliams, Frances, M K1 aWilson, James, F1 aWright, Nicole, C1 aXie, Weijia1 aYu, Lei1 aZhou, Yanhua1 aChambers, John, C1 aDöring, Angela1 aDuijn, Cornelia, M1 aEcons, Michael, J1 aGudnason, Vilmundur1 aKooner, Jaspal, S1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aStefansson, Kari1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aOssowski, Vicky1 aWaterworth, Dawn1 aLoos, Ruth, J F1 aKarasik, David1 aHarris, Tamara, B1 aOhlsson, Claes1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/760006999nas a2202113 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2017 eng d a1546-171800aLarge-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.0 aLargescale analyses of common and rare variants identify 12 new c2017 Jun a946-9520 v493 aAtrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.
1 aChristophersen, Ingrid, E1 aRienstra, Michiel1 aRoselli, Carolina1 aYin, Xiaoyan1 aGeelhoed, Bastiaan1 aBarnard, John1 aLin, Honghuang1 aArking, Dan, E1 aSmith, Albert, V1 aAlbert, Christine, M1 aChaffin, Mark1 aTucker, Nathan, R1 aLi, Molong1 aKlarin, Derek1 aBihlmeyer, Nathan, A1 aLow, Siew-Kee1 aWeeke, Peter, E1 aMüller-Nurasyid, Martina1 aSmith, Gustav1 aBrody, Jennifer, A1 aNiemeijer, Maartje, N1 aDörr, Marcus1 aTrompet, Stella1 aHuffman, Jennifer1 aGustafsson, Stefan1 aSchurmann, Claudia1 aKleber, Marcus, E1 aLyytikäinen, Leo-Pekka1 aSeppälä, Ilkka1 aMalik, Rainer1 aHorimoto, Andrea, R V R1 aPerez, Marco1 aSinisalo, Juha1 aAeschbacher, Stefanie1 aThériault, Sébastien1 aYao, Jie1 aRadmanesh, Farid1 aWeiss, Stefan1 aTeumer, Alexander1 aChoi, Seung, Hoan1 aWeng, Lu-Chen1 aClauss, Sebastian1 aDeo, Rajat1 aRader, Daniel, J1 aShah, Svati, H1 aSun, Albert1 aHopewell, Jemma, C1 aDebette, Stephanie1 aChauhan, Ganesh1 aYang, Qiong1 aWorrall, Bradford, B1 aParé, Guillaume1 aKamatani, Yoichiro1 aHagemeijer, Yanick, P1 aVerweij, Niek1 aSiland, Joylene, E1 aKubo, Michiaki1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aBis, Joshua, C1 aPerz, Siegfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aMagnani, Jared, W1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShoemaker, Benjamin1 aPadmanabhan, Sandosh1 aHaessler, Jeffrey1 aBartz, Traci, M1 aWaldenberger, Melanie1 aLichtner, Peter1 aArendt, Marina1 aKrieger, Jose, E1 aKähönen, Mika1 aRisch, Lorenz1 aMansur, Alfredo, J1 aPeters, Annette1 aSmith, Blair, H1 aLind, Lars1 aScott, Stuart, A1 aLu, Yingchang1 aBottinger, Erwin, B1 aHernesniemi, Jussi1 aLindgren, Cecilia, M1 aWong, Jorge, A1 aHuang, Jie1 aEskola, Markku1 aMorris, Andrew, P1 aFord, Ian1 aReiner, Alex, P1 aDelgado, Graciela1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aSandhu, Roopinder, K1 aLi, Man1 aBoerwinkle, Eric1 aEisele, Lewin1 aLannfelt, Lars1 aRost, Natalia1 aAnderson, Christopher, D1 aTaylor, Kent, D1 aCampbell, Archie1 aMagnusson, Patrik, K1 aPorteous, David1 aHocking, Lynne, J1 aVlachopoulou, Efthymia1 aPedersen, Nancy, L1 aNikus, Kjell1 aOrho-Melander, Marju1 aHamsten, Anders1 aHeeringa, Jan1 aDenny, Joshua, C1 aKriebel, Jennifer1 aDarbar, Dawood1 aNewton-Cheh, Christopher1 aShaffer, Christian1 aMacfarlane, Peter, W1 aHeilmann-Heimbach, Stefanie1 aAlmgren, Peter1 aHuang, Paul, L1 aSotoodehnia, Nona1 aSoliman, Elsayed, Z1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aVölker, Uwe1 aJöckel, Karl-Heinz1 aSinner, Moritz, F1 aLin, Henry, J1 aGuo, Xiuqing1 aDichgans, Martin1 aIngelsson, Erik1 aKooperberg, Charles1 aMelander, Olle1 aLoos, Ruth, J F1 aLaurikka, Jari1 aConen, David1 aRosand, Jonathan1 aHarst, Pim1 aLokki, Marja-Liisa1 aKathiresan, Sekar1 aPereira, Alexandre1 aJukema, Wouter1 aHayward, Caroline1 aRotter, Jerome, I1 aMärz, Winfried1 aLehtimäki, Terho1 aStricker, Bruno, H1 aChung, Mina, K1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aRoden, Dan, M1 aKääb, Stefan1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aTanaka, Toshihiro1 aLunetta, Kathryn, L1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aMETASTROKE Consortium of the ISGC1 aNeurology Working Group of the CHARGE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/739603729nas a2200913 4500008004100000022001400041245012500055210006900180260001600249300001400265490000700279520113900286100001301425700002201438700001201460700001801472700001701490700002201507700001901529700002101548700001801569700001901587700002501606700001901631700002001650700002501670700002001695700002101715700002301736700002101759700001901780700002301799700001801822700001901840700001901859700002301878700002601901700001901927700002001946700002301966700002201989700001802011700002602029700002802055700002302083700002802106700002302134700001902157700002202176700002202198700002302220700002202243700001902265700002502284700001802309700001902327700002702346700002202373700002202395700002302417700001802440700001802458700001802476700001802494700002102512700002602533700002002559700001902579700001702598700001602615700002602631700002302657700002302680700001802703700002002721700002202741700001602763856003602779 2017 eng d a2211-124700aLarge-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.0 aLargeScale Cognitive GWAS MetaAnalysis Reveals TissueSpecific Ne c2017 Nov 28 a2597-26130 v213 aHere, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
1 aLam, Max1 aTrampush, Joey, W1 aYu, Jin1 aKnowles, Emma1 aDavies, Gail1 aLiewald, David, C1 aStarr, John, M1 aDjurovic, Srdjan1 aMelle, Ingrid1 aSundet, Kjetil1 aChristoforou, Andrea1 aReinvang, Ivar1 aDeRosse, Pamela1 aLundervold, Astri, J1 aSteen, Vidar, M1 aEspeseth, Thomas1 aRäikkönen, Katri1 aWiden, Elisabeth1 aPalotie, Aarno1 aEriksson, Johan, G1 aGiegling, Ina1 aKonte, Bettina1 aRoussos, Panos1 aGiakoumaki, Stella1 aBurdick, Katherine, E1 aPayton, Antony1 aOllier, William1 aChiba-Falek, Ornit1 aAttix, Deborah, K1 aNeed, Anna, C1 aCirulli, Elizabeth, T1 aVoineskos, Aristotle, N1 aStefanis, Nikos, C1 aAvramopoulos, Dimitrios1 aHatzimanolis, Alex1 aArking, Dan, E1 aSmyrnis, Nikolaos1 aBilder, Robert, M1 aFreimer, Nelson, A1 aCannon, Tyrone, D1 aLondon, Edythe1 aPoldrack, Russell, A1 aSabb, Fred, W1 aCongdon, Eliza1 aConley, Emily, Drabant1 aScult, Matthew, A1 aDickinson, Dwight1 aStraub, Richard, E1 aDonohoe, Gary1 aMorris, Derek1 aCorvin, Aiden1 aGill, Michael1 aHariri, Ahmad, R1 aWeinberger, Daniel, R1 aPendleton, Neil1 aBitsios, Panos1 aRujescu, Dan1 aLahti, Jari1 aLe Hellard, Stephanie1 aKeller, Matthew, C1 aAndreassen, Ole, A1 aDeary, Ian, J1 aGlahn, David, C1 aMalhotra, Anil, K1 aLencz, Todd uhttps://chs-nhlbi.org/node/768706419nas a2201621 4500008004100000022001400041245011300055210006900168260001600237300001400253490000800267520184900275100002102124700002102145700002002166700002202186700002002208700002602228700001702254700002002271700002302291700002502314700002002339700001902359700001902378700002202397700002202419700002102441700002602462700002202488700002102510700002202531700002802553700001902581700001802600700002202618700002402640700002302664700002402687700001802711700002002729700002202749700002102771700002402792700001902816700002002835700002102855700001702876700002102893700002602914700002002940700002002960700001702980700002002997700002203017700001703039700001903056700001503075700002003090700002003110700002403130700001903154700002103173700001903194700002203213700002203235700002503257700001903282700002503301700002103326700002103347700002403368700001703392700002203409700002203431700002303453700003003476700002003506700002203526700002203548700001903570700002003589700001803609700002003627700002603647700002303673700002103696700002603717700002203743700002203765700002003787700002503807700002003832700002303852700002203875700002103897700002203918700002303940700002303963700001603986700002404002700002804026700001804054700001904072700002104091700002004112700002004132700002304152700002404175700002204199700002304221700001804244700002204262700002504284700001904309700001704328700002204345700001904367700002104386700001504407700002404422700002004446700002304466700002004489700002404509700002004533700001504553700002104568700002004589700002404609700002204633700002204655700002104677700001804698700002704716700001804743856003604761 2017 eng d a1558-823800aLarge-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.0 aLargescale genomewide analysis identifies genetic variants assoc c2017 May 01 a1798-18120 v1273 aBACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.
METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.
RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.
CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
FUNDING: For detailed information per study, see Acknowledgments.
1 aWild, Philipp, S1 aFelix, Janine, F1 aSchillert, Arne1 aTeumer, Alexander1 aChen, Ming-Huei1 aLeening, Maarten, J G1 aVölker, Uwe1 aGroßmann, Vera1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aShah, Sanjiv, J1 aPramana, Setia1 aLieb, Wolfgang1 aSchmidt, Reinhold1 aStanton, Alice, V1 aMalzahn, Dörthe1 aSmith, Albert, Vernon1 aSundström, Johan1 aMinelli, Cosetta1 aRuggiero, Daniela1 aLyytikäinen, Leo-Pekka1 aTiller, Daniel1 aSmith, Gustav1 aMonnereau, Claire1 aDi Tullio, Marco, R1 aMusani, Solomon, K1 aMorrison, Alanna, C1 aPers, Tune, H1 aMorley, Michael1 aKleber, Marcus, E1 aAragam, Jayashri1 aBenjamin, Emelia, J1 aBis, Joshua, C1 aBisping, Egbert1 aBroeckel, Ulrich1 aCheng, Susan1 aDeckers, Jaap, W1 aM, Fabiola, del Greco1 aEdelmann, Frank1 aFornage, Myriam1 aFranke, Lude1 aFriedrich, Nele1 aHarris, Tamara, B1 aHofer, Edith1 aHofman, Albert1 aHuang, Jie1 aHughes, Alun, D1 aKähönen, Mika1 aInvestigators, Knhi1 aKruppa, Jochen1 aLackner, Karl, J1 aLannfelt, Lars1 aLaskowski, Rafael1 aLauner, Lenore, J1 aLeosdottir, Margrét1 aLin, Honghuang1 aLindgren, Cecilia, M1 aLoley, Christina1 aMacRae, Calum, A1 aMascalzoni, Deborah1 aMayet, Jamil1 aMedenwald, Daniel1 aMorris, Andrew, P1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNappo, Stefania1 aNilsson, Peter, M1 aNuding, Sebastian1 aNutile, Teresa1 aPeters, Annette1 aPfeufer, Arne1 aPietzner, Diana1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aRuohonen, Saku, T1 aSacco, Ralph, L1 aSamdarshi, Tandaw, E1 aSchmidt, Helena1 aSharp, Andrew, S P1 aShields, Denis, C1 aSorice, Rossella1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSurendran, Praveen1 aThom, Simon1 aTöglhofer, Anna, M1 aUitterlinden, André, G1 aWachter, Rolf1 aVölzke, Henry1 aZiegler, Andreas1 aMünzel, Thomas1 aMärz, Winfried1 aCappola, Thomas, P1 aHirschhorn, Joel, N1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aFox, Ervin, R1 aDueker, Nicole, D1 aJaddoe, Vincent, W V1 aMelander, Olle1 aRuss, Martin1 aLehtimäki, Terho1 aCiullo, Marina1 aHicks, Andrew, A1 aLind, Lars1 aGudnason, Vilmundur1 aPieske, Burkert1 aBarron, Anthony, J1 aZweiker, Robert1 aSchunkert, Heribert1 aIngelsson, Erik1 aLiu, Kiang1 aArnett, Donna, K1 aPsaty, Bruce, M1 aBlankenberg, Stefan1 aLarson, Martin, G1 aFelix, Stephan, B1 aFranco, Oscar, H1 aZeller, Tanja1 aVasan, Ramachandran, S1 aDörr, Marcus uhttps://chs-nhlbi.org/node/737303989nas a2201057 4500008004100000022001400041245012200055210006900177260001600246300001000262490000600272520101400278100002101292700002201313700001801335700002501353700002001378700002001398700002101418700002101439700001801460700002201478700002601500700002101526700001301547700001901560700001601579700001401595700001501609700002701624700002101651700001901672700002501691700002101716700001501737700001501752700001801767700001601785700001901801700001901820700002001839700001801859700002001877700002301897700001601920700002701936700001501963700002101978700002101999700002302020700002502043700002202068700002102090700002502111700002102136700002702157700002202184700001602206700002502222700002102247700001702268700002102285700001602306700002002322700001902342700002502361700002502386700002402411700002202435700001902457700001802476700002102494700002302515700001902538700002002557700002202577700002302599700002102622700001902643700001702662700001702679700002402696700002002720700002602740700002402766700002102790700002102811700002102832710004202853856003602895 2017 eng d a2041-172300aLarge-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.0 aLargescale GWAS identifies multiple loci for hand grip strength c2017 Jul 12 a160150 v83 aHand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.
1 aWillems, Sara, M1 aWright, Daniel, J1 aDay, Felix, R1 aTrajanoska, Katerina1 aJoshi, Peter, K1 aMorris, John, A1 aMatteini, Amy, M1 aGarton, Fleur, C1 aGrarup, Niels1 aOskolkov, Nikolay1 aThalamuthu, Anbupalam1 aMangino, Massimo1 aLiu, Jun1 aDemirkan, Ayse1 aLek, Monkol1 aXu, Liwen1 aWang, Guan1 aOldmeadow, Christopher1 aGaulton, Kyle, J1 aLotta, Luca, A1 aMiyamoto-Mikami, Eri1 aRivas, Manuel, A1 aWhite, Tom1 aLoh, Po-Ru1 aAadahl, Mette1 aAmin, Najaf1 aAttia, John, R1 aAustin, Krista1 aBenyamin, Beben1 aBrage, Søren1 aCheng, Yu-Ching1 aCięszczyk, Paweł1 aDerave, Wim1 aEriksson, Karl-Fredrik1 aEynon, Nir1 aLinneberg, Allan1 aLucia, Alejandro1 aMassidda, Myosotis1 aMitchell, Braxton, D1 aMiyachi, Motohiko1 aMurakami, Haruka1 aPadmanabhan, Sandosh1 aPandey, Ashutosh1 aPapadimitriou, Ioannis1 aRajpal, Deepak, K1 aSale, Craig1 aSchnurr, Theresia, M1 aSessa, Francesco1 aShrine, Nick1 aTobin, Martin, D1 aVarley, Ian1 aWain, Louise, V1 aWray, Naomi, R1 aLindgren, Cecilia, M1 aMacArthur, Daniel, G1 aWaterworth, Dawn, M1 aMcCarthy, Mark, I1 aPedersen, Oluf1 aKhaw, Kay-Tee1 aKiel, Douglas, P1 aPitsiladis, Yannis1 aFuku, Noriyuki1 aFranks, Paul, W1 aNorth, Kathryn, N1 aDuijn, Cornelia, M1 aMather, Karen, A1 aHansen, Torben1 aHansson, Ola1 aSpector, Tim1 aMurabito, Joanne, M1 aRichards, Brent1 aRivadeneira, Fernando1 aLangenberg, Claudia1 aPerry, John, R B1 aWareham, Nick, J1 aScott, Robert, A1 aGEFOS Any-Type of Fracture Consortium uhttps://chs-nhlbi.org/node/768804416nas a2200913 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520169200286653003701978653002902015653001902044653003802063653001802101653003402119653001102153653002302164653003602187653001702223653001402240653002502254100002402279700001702303700001902320700001902339700001802358700002802376700002002404700002802424700001902452700003002471700002402501700002102525700002402546700002102570700002302591700002602614700001902640700002002659700002202679700002202701700002602723700001802749700002302767700002102790700002502811700002202836700002702858700002102885700002602906700001702932700002702949700002102976700002002997700001903017700002303036700002403059700002403083700002003107700001503127700002003142700002903162700002303191700002203214700001903236700002003255700003103275700002303306700002103329700002503350700002603375700002003401700002503421700002003446856003603466 2017 eng d a1537-660500aLow-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.0 aLowFrequency Synonymous Coding Variation in CYP2R1 Has Large Eff c2017 Aug 03 a227-2380 v1013 aVitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
10aCholestanetriol 26-Monooxygenase10aCytochrome P450 Family 210aGene Frequency10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMultiple Sclerosis10aPolymorphism, Single Nucleotide10aRisk Factors10aVitamin D10aVitamin D Deficiency1 aManousaki, Despoina1 aDudding, Tom1 aHaworth, Simon1 aHsu, Yi-Hsiang1 aLiu, Ching-Ti1 aMedina-Gómez, Carolina1 aVoortman, Trudy1 avan der Velde, Nathalie1 aMelhus, Håkan1 aRobinson-Cohen, Cassianne1 aCousminer, Diana, L1 aNethander, Maria1 aVandenput, Liesbeth1 aNoordam, Raymond1 aForgetta, Vincenzo1 aGreenwood, Celia, M T1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aZemel, Babette, S1 aMitchell, Jonathan, A1 aTaylor, Bruce1 aLorentzon, Mattias1 aKarlsson, Magnus1 aJaddoe, Vincent, V W1 aTiemeier, Henning1 aCampos-Obando, Natalia1 aFranco, Oscar, H1 aUtterlinden, Andre, G1 aBroer, Linda1 avan Schoor, Natasja, M1 aHam, Annelies, C1 aIkram, Arfan, M1 aKarasik, David1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aHeijer, Martin, den1 aWang, Thomas, J1 aLind, Lars1 aOrwoll, Eric, S1 aMook-Kanamori, Dennis, O1 aMichaëlsson, Karl1 aKestenbaum, Bryan1 aOhlsson, Claes1 aMellström, Dan1 ade Groot, Lisette, C P G M1 aGrant, Struan, F A1 aKiel, Douglas, P1 aZillikens, Carola, M1 aRivadeneira, Fernando1 aSawcer, Stephen1 aTimpson, Nicholas, J1 aRichards, Brent uhttps://chs-nhlbi.org/node/748702661nas a2200253 4500008004100000022001400041245014400055210006900199260001300268490000700281520182600288100001402114700001702128700002302145700002102168700002002189700002502209700002102234700001802255700002402273700002002297710005402317856003602371 2017 eng d a1942-326800aMultiancestry Study of Gene-Lifestyle Interactions for Cardiovascular Traits in 610 475 Individuals From 124 Cohorts: Design and Rationale.0 aMultiancestry Study of GeneLifestyle Interactions for Cardiovasc c2017 Jun0 v103 aBACKGROUND: Several consortia have pursued genome-wide association studies for identifying novel genetic loci for blood pressure, lipids, hypertension, etc. They demonstrated the power of collaborative research through meta-analysis of study-specific results.
METHODS AND RESULTS: The Gene-Lifestyle Interactions Working Group was formed to facilitate the first large, concerted, multiancestry study to systematically evaluate gene-lifestyle interactions. In stage 1, genome-wide interaction analysis is performed in 53 cohorts with a total of 149 684 individuals from multiple ancestries. In stage 2 involving an additional 71 cohorts with 460 791 individuals from multiple ancestries, focused analysis is performed for a subset of the most promising variants from stage 1. In all, the study involves up to 610 475 individuals. Current focus is on cardiovascular traits including blood pressure and lipids, and lifestyle factors including smoking, alcohol, education (as a surrogate for socioeconomic status), physical activity, psychosocial variables, and sleep. The total sample sizes vary among projects because of missing data. Large-scale gene-lifestyle or more generally gene-environment interaction (G×E) meta-analysis studies can be cumbersome and challenging. This article describes the design and some of the approaches pursued in the interaction projects.
CONCLUSIONS: The Gene-Lifestyle Interactions Working Group provides an excellent framework for understanding the lifestyle context of genetic effects and to identify novel trait loci through analysis of interactions. An important and novel feature of our study is that the gene-lifestyle interaction (G×E) results may improve our knowledge about the underlying mechanisms for novel and already known trait loci.
1 aRao, D, C1 aSung, Yun, J1 aWinkler, Thomas, W1 aSchwander, Karen1 aBorecki, Ingrid1 aCupples, Adrienne, L1 aGauderman, James1 aRice, Kenneth1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aCHARGE Gene-Lifestyle Interactions Working Group* uhttps://chs-nhlbi.org/node/745007019nas a2201849 4500008004100000022001400041245009300055210006900148260001300217490000700230520169900237100001901936700001901955700002101974700002301995700001602018700002502034700002202059700001802081700001902099700001702118700002602135700001602161700003002177700002302207700002102230700002502251700002002276700002102296700002302317700001602340700002302356700002002379700001702399700002102416700002302437700002202460700001402482700002502496700002902521700002402550700002102574700001802595700001702613700002502630700001802655700001802673700002002691700002202711700002502733700001302758700002002771700002402791700002502815700001902840700001902859700002102878700002702899700001902926700001402945700002402959700002302983700002203006700002503028700002603053700002303079700002203102700002103124700002003145700001803165700002603183700001703209700001803226700002303244700002403267700001203291700002103303700002103324700002203345700002103367700002703388700002303415700001803438700002203456700002003478700002403498700001803522700001903540700002103559700001603580700002003596700002303616700002003639700002203659700001603681700002103697700001903718700002203737700001703759700002003776700002303796700002703819700002403846700001903870700002203889700001903911700002403930700001503954700002003969700001903989700002204008700001904030700002104049700002204070700002304092700001904115700001904134700002104153700002504174700002004199700002004219700002204239700001604261700002004277700002204297700002004319700001604339700002604355700001904381700001504400700002404415700002304439700002604462700002404488700002504512700002104537700002304558700002104581700002404602700002104626700002504647700001704672700002704689700002004716700002004736700002304756700002304779700001804802700002504820700001704845700002904862700002404891700002404915710004304939710015104982856003605133 2017 eng d a1942-326800aNew Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.0 aNew Blood PressureAssociated Loci Identified in MetaAnalyses of c2017 Oct0 v103 aBACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.
METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.
CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
1 aKraja, Aldi, T1 aCook, James, P1 aWarren, Helen, R1 aSurendran, Praveen1 aLiu, Chunyu1 aEvangelou, Evangelos1 aManning, Alisa, K1 aGrarup, Niels1 aDrenos, Fotios1 aSim, Xueling1 aSmith, Albert, Vernon1 aAmin, Najaf1 aBlakemore, Alexandra, I F1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aFarmaki, Aliki-Eleni1 aFava, Cristiano1 aFerreira, Teresa1 aHerzig, Karl-Heinz1 aGiri, Ayush1 aGiulianini, Franco1 aGrove, Megan, L1 aGuo, Xiuqing1 aHarris, Sarah, E1 aHave, Christian, T1 aHavulinna, Aki, S1 aZhang, He1 aJørgensen, Marit, E1 aKäräjämäki, AnneMari1 aKooperberg, Charles1 aLinneberg, Allan1 aLittle, Louis1 aLiu, Yongmei1 aBonnycastle, Lori, L1 aLu, Yingchang1 aMägi, Reedik1 aMahajan, Anubha1 aMalerba, Giovanni1 aMarioni, Riccardo, E1 aMei, Hao1 aMenni, Cristina1 aMorrison, Alanna, C1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRayner, Nigel, William1 aRiaz, Muhammad1 aRice, Ken1 aRichard, Melissa, A1 aSmith, Jennifer, A1 aSoutham, Lorraine1 aStančáková, Alena1 aStirrups, Kathleen, E1 aTragante, Vinicius1 aTuomi, Tiinamaija1 aTzoulaki, Ioanna1 aVarga, Tibor, V1 aWeiss, Stefan1 aYiorkas, Andrianos, M1 aYoung, Robin1 aZhang, Weihua1 aBarnes, Michael, R1 aCabrera, Claudia, P1 aGao, He1 aBoehnke, Michael1 aBoerwinkle, Eric1 aChambers, John, C1 aConnell, John, M1 aChristensen, Cramer, K1 ade Boer, Rudolf, A1 aDeary, Ian, J1 aDedoussis, George1 aDeloukas, Panos1 aDominiczak, Anna, F1 aDörr, Marcus1 aJoehanes, Roby1 aEdwards, Todd, L1 aEsko, Tõnu1 aFornage, Myriam1 aFranceschini, Nora1 aFranks, Paul, W1 aGambaro, Giovanni1 aGroop, Leif1 aHallmans, Göran1 aHansen, Torben1 aHayward, Caroline1 aHeikki, Oksa1 aIngelsson, Erik1 aTuomilehto, Jaakko1 aJarvelin, Marjo-Riitta1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKooner, Jaspal, S1 aLakka, Timo, A1 aLangenberg, Claudia1 aLind, Lars1 aLoos, Ruth, J F1 aLaakso, Markku1 aMcCarthy, Mark, I1 aMelander, Olle1 aMohlke, Karen, L1 aMorris, Andrew, P1 aPalmer, Colin, N A1 aPedersen, Oluf1 aPolasek, Ozren1 aPoulter, Neil, R1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSever, Peter, J1 aSkaaby, Tea1 aStafford, Jeanette, M1 aStarr, John, M1 aHarst, Pim1 avan der Meer, Peter1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aGudnason, Vilmundur1 aWareham, Nicholas, J1 aWilson, James, G1 aWiller, Cristen, J1 aWitte, Daniel, R1 aZeggini, Eleftheria1 aSaleheen, Danish1 aButterworth, Adam, S1 aDanesh, John1 aAsselbergs, Folkert, W1 aWain, Louise, V1 aEhret, Georg, B1 aChasman, Daniel, I1 aCaulfield, Mark, J1 aElliott, Paul1 aLindgren, Cecilia, M1 aLevy, Daniel1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aHowson, Joanna, M M1 aUnderstanding Society Scientific Group1 aCHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group† uhttps://chs-nhlbi.org/node/756909467nas a2203025 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2017 eng d a1524-456300aNovel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.0 aNovel Blood Pressure Locus and Gene Discovery Using GenomeWide A c2017 Jul 243 aElevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
1 aWain, Louise, V1 aVaez, Ahmad1 aJansen, Rick1 aJoehanes, Roby1 avan der Most, Peter, J1 aErzurumluoglu, Mesut1 aO'Reilly, Paul, F1 aCabrera, Claudia, P1 aWarren, Helen, R1 aRose, Lynda, M1 aVerwoert, Germaine, C1 aHottenga, Jouke-Jan1 aStrawbridge, Rona, J1 aEsko, Tõnu1 aArking, Dan, E1 aHwang, Shih-Jen1 aGuo, Xiuqing1 aKutalik, Zoltán1 aTrompet, Stella1 aShrine, Nick1 aTeumer, Alexander1 aRied, Janina, S1 aBis, Joshua, C1 aSmith, Albert, V1 aAmin, Najaf1 aNolte, Ilja, M1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aWareham, Nicholas, J1 aHofer, Edith1 aJoshi, Peter, K1 aKristiansson, Kati1 aTraglia, Michela1 aHavulinna, Aki, S1 aGoel, Anuj1 aNalls, Mike, A1 aSõber, Siim1 aVuckovic, Dragana1 aLuan, Jian'an1 aM, Fabiola, del Greco1 aAyers, Kristin, L1 aMarrugat, Jaume1 aRuggiero, Daniela1 aLopez, Lorna, M1 aNiiranen, Teemu1 aEnroth, Stefan1 aJackson, Anne, U1 aNelson, Christopher, P1 aHuffman, Jennifer, E1 aZhang, Weihua1 aMarten, Jonathan1 aGandin, Ilaria1 aHarris, Sarah, E1 aZemunik, Tatijana1 aLu, Yingchang1 aEvangelou, Evangelos1 aShah, Nabi1 ade Borst, Martin, H1 aMangino, Massimo1 aPrins, Bram, P1 aCampbell, Archie1 aLi-Gao, Ruifang1 aChauhan, Ganesh1 aOldmeadow, Christopher1 aAbecasis, Goncalo1 aAbedi, Maryam1 aBarbieri, Caterina, M1 aBarnes, Michael, R1 aBatini, Chiara1 aBeilby, John1 aBlake, Tineka1 aBoehnke, Michael1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrown, Morris1 aBrumat, Marco1 aCampbell, Harry1 aChambers, John, C1 aCocca, Massimiliano1 aCollins, Francis1 aConnell, John1 aCordell, Heather, J1 aDamman, Jeffrey, J1 aDavies, Gail1 ade Geus, Eco, J1 ade Mutsert, Renée1 aDeelen, Joris1 aDemirkale, Yusuf1 aDoney, Alex, S F1 aDörr, Marcus1 aFarrall, Martin1 aFerreira, Teresa1 aFrånberg, Mattias1 aGao, He1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGiulianini, Franco1 aGow, Alan, J1 aHamsten, Anders1 aHarris, Tamara, B1 aHofman, Albert1 aHolliday, Elizabeth, G1 aHui, Jennie1 aJarvelin, Marjo-Riitta1 aJohansson, Asa1 aJohnson, Andrew, D1 aJousilahti, Pekka1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKhaw, Kay-Tee1 aKolcic, Ivana1 aKoskinen, Seppo1 aLangenberg, Claudia1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aMach, François1 aMamasoula, Chrysovalanto1 aMenni, Cristina1 aMifsud, Borbala1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNandakumar, Priyanka1 aNguyen, Quang, Tri1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalotie, Aarno1 aParé, Guillaume1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPoulter, Neil1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRen, Meixia1 aRice, Kenneth1 aRidker, Paul, M1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRotter, Jerome, I1 aRudan, Igor1 aSaba, Yasaman1 aPierre, Aude, Saint1 aSala, Cinzia, F1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aScott, Rodney1 aSeelen, Marc, A1 aShields, Denis, C1 aSiscovick, David1 aSorice, Rossella1 aStanton, Alice1 aStott, David, J1 aSundström, Johan1 aSwertz, Morris1 aTaylor, Kent, D1 aThom, Simon1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, André, G1 aVölker, Uwe1 aVollenweider, Peter1 aWild, Sarah1 aWillemsen, Gonneke1 aWright, Alan, F1 aYao, Jie1 aThériault, Sébastien1 aConen, David1 aAttia, John1 aSever, Peter1 aDebette, Stephanie1 aMook-Kanamori, Dennis, O1 aZeggini, Eleftheria1 aSpector, Tim, D1 aHarst, Pim1 aPalmer, Colin, N A1 aVergnaud, Anne-Claire1 aLoos, Ruth, J F1 aPolasek, Ozren1 aStarr, John, M1 aGirotto, Giorgia1 aHayward, Caroline1 aKooner, Jaspal, S1 aLindgren, Cecila, M1 aVitart, Veronique1 aSamani, Nilesh, J1 aTuomilehto, Jaakko1 aGyllensten, Ulf1 aKnekt, Paul1 aDeary, Ian, J1 aCiullo, Marina1 aElosua, Roberto1 aKeavney, Bernard, D1 aHicks, Andrew, A1 aScott, Robert, A1 aGasparini, Paolo1 aLaan, Maris1 aLiu, Yongmei1 aWatkins, Hugh1 aHartman, Catharina, A1 aSalomaa, Veikko1 aToniolo, Daniela1 aPerola, Markus1 aWilson, James, F1 aSchmidt, Helena1 aZhao, Jing Hua1 aLehtimäki, Terho1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aPeters, Annette1 aRettig, Rainer1 aJames, Alan1 aJukema, Wouter1 aStrachan, David, P1 aPalmas, Walter1 aMetspalu, Andres1 aIngelsson, Erik1 aBoomsma, Dorret, I1 aFranco, Oscar, H1 aBochud, Murielle1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aElliott, Paul1 aChasman, Daniel, I1 aChakravarti, Aravinda1 aKnight, Joanne1 aMorris, Andrew, P1 aLevy, Daniel1 aTobin, Martin, D1 aSnieder, Harold1 aCaulfield, Mark, J1 aEhret, Georg, B uhttps://chs-nhlbi.org/node/749211478nas a2204105 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2017 eng d00a{Novel genetic loci associated with hippocampal volume0 aNovel genetic loci associated with hippocampal volume c01 a136240 v83 aThe hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.1 aHibar, D., P.1 aAdams, H., H. H.1 aJahanshad, N.1 aChauhan, G.1 aStein, J., L.1 aHofer, E.1 aRenteria, M., E.1 aBis, J., C.1 aArias-Vasquez, A.1 aIkram, M., K.1 aDesrivi?res, S.1 aVernooij, M., W.1 aAbramovic, L.1 aAlhusaini, S.1 aAmin, N.1 aAndersson, M.1 aArfanakis, K.1 aAribisala, B., S.1 aArmstrong, N., J.1 aAthanasiu, L.1 aAxelsson, T.1 aBeecham, A., H.1 aBeiser, A.1 aBernard, M.1 aBlanton, S., H.1 aBohlken, M., M.1 aBoks, M., P.1 aBralten, J.1 aBrickman, A., M.1 aCarmichael, O.1 aChakravarty, M., M.1 aChen, Q.1 aChing, C., R. K.1 aChouraki, V.1 aCuellar-Partida, G.1 aCrivello, F.1 aBraber, den1 aDoan, N., T.1 aEhrlich, S.1 aGiddaluru, S.1 aGoldman, A., L.1 aGottesman, R., F.1 aGrimm, O.1 aGriswold, M., E.1 aGuadalupe, T.1 aGutman, B., A.1 aHass, J.1 aHaukvik, U., K.1 aHoehn, D.1 aHolmes, A., J.1 aHoogman, M.1 aJanowitz, D.1 aJia, T.1 aJ?rgensen, K., N.1 aKarbalai, N.1 aKasperaviciute, D.1 aKim, S.1 aKlein, M.1 aKraemer, B.1 aLee, P., H.1 aLiewald, D., C. M.1 aLopez, L., M.1 aLuciano, M.1 aMacare, C.1 aMarquand, A., F.1 aMatarin, M.1 aMather, K., A.1 aMattheisen, M.1 aMcKay, D., R.1 aMilaneschi, Y.1 aManiega, Mu?oz1 aNho, K.1 aNugent, A., C.1 aNyquist, P.1 aLoohuis, L., M. O.1 aOosterlaan, J.1 aPapmeyer, M.1 aPirpamer, L.1 aP?tz, B.1 aRamasamy, A.1 aRichards, J., S.1 aRisacher, S., L.1 aRoiz-Santia?ez, R.1 aRommelse, N.1 aRopele, S.1 aRose, E., J.1 aRoyle, N., A.1 aRundek, T.1 aS?mann, P., G.1 aSaremi, A.1 aSatizabal, C., L.1 aSchmaal, L.1 aSchork, A., J.1 aShen, L.1 aShin, J.1 aShumskaya, E.1 aSmith, A., V.1 aSprooten, E.1 aStrike, L., T.1 aTeumer, A.1 aTordesillas-Gutierrez, D.1 aToro, R.1 aTrabzuni, D.1 aTrompet, S.1 aVaidya, D.1 avan der Grond, J.1 avan der Lee, S., J.1 avan der Meer, D.1 avan Donkelaar, M., M. J.1 aVan Eijk, K., R.1 avan Erp, T., G. M.1 avan Rooij, D.1 aWalton, E.1 aWestlye, L., T.1 aWhelan, C., D.1 aWindham, B., G.1 aWinkler, A., M.1 aWittfeld, K.1 aWoldehawariat, G.1 aWolf, C.1 aWolfers, T.1 aYanek, L., R.1 aYang, J.1 aZijdenbos, A.1 aZwiers, M., P.1 aAgartz, I.1 aAlmasy, L.1 aAmes, D.1 aAmouyel, P.1 aAndreassen, O., A.1 aArepalli, S.1 aAssareh, A., A.1 aBarral, S.1 aBastin, M., E.1 aBecker, D., M.1 aBecker, J., T.1 aBennett, D., A.1 aBlangero, J.1 avan Bokhoven, H.1 aBoomsma, D., I.1 aBrodaty, H.1 aBrouwer, R., M.1 aBrunner, H., G.1 aBuckner, R., L.1 aBuitelaar, J., K.1 aBulayeva, K., B.1 aCahn, W.1 aCalhoun, V., D.1 aCannon, D., M.1 aCavalleri, G., L.1 aCheng, C., Y.1 aCichon, S.1 aCookson, M., R.1 aCorvin, A.1 aCrespo-Facorro, B.1 aCurran, J., E.1 aCzisch, M.1 aDale, A., M.1 aDavies, G., E.1 ade Craen, A., J. M.1 ade Geus, E., J. C.1 aDe Jager, P., L.1 ade Zubicaray, G., I.1 aDeary, I., J.1 aDebette, S.1 aDeCarli, C.1 aDelanty, N.1 aDepondt, C.1 aDeStefano, A.1 aDillman, A.1 aDjurovic, S.1 aDonohoe, G.1 aDrevets, W., C.1 aDuggirala, R.1 aDyer, T., D.1 aEnzinger, C.1 aErk, S.1 aEspeseth, T.1 aFedko, I., O.1 aFern?ndez, G.1 aFerrucci, L.1 aFisher, S., E.1 aFleischman, D., A.1 aFord, I.1 aFornage, M.1 aForoud, T., M.1 aFox, P., T.1 aFrancks, C.1 aFukunaga, M.1 aGibbs, J., R.1 aGlahn, D., C.1 aGollub, R., L.1 aG?ring, H., H. H.1 aGreen, R., C.1 aGruber, O.1 aGudnason, V.1 aGuelfi, S.1 aH?berg, A., K.1 aHansell, N., K.1 aHardy, J.1 aHartman, C., A.1 aHashimoto, R.1 aHegenscheid, K.1 aHeinz, A.1 aLe Hellard, S.1 aHernandez, D., G.1 aHeslenfeld, D., J.1 aHo, B., C.1 aHoekstra, P., J.1 aHoffmann, W.1 aHofman, A.1 aHolsboer, F.1 aHomuth, G.1 aHosten, N.1 aHottenga, J., J.1 aHuentelman, M.1 aPol, H., E. Hulshof1 aIkeda, M.1 aJack, C., R.1 aJenkinson, M.1 aJohnson, R.1 aJ?nsson, E., G.1 aJukema, J., W.1 aKahn, R., S.1 aKanai, R.1 aKloszewska, I.1 aKnopman, D., S.1 aKochunov, P.1 aKwok, J., B.1 aLawrie, S., M.1 aLema?tre, H.1 aLiu, X.1 aLongo, D., L.1 aLopez, O., L.1 aLovestone, S.1 aMartinez, O.1 aMartinot, J., L.1 aMattay, V., S.1 aMcDonald, C.1 aMcIntosh, A., M.1 aMcMahon, F., J.1 aMcMahon, K., L.1 aMecocci, P.1 aMelle, I.1 aMeyer-Lindenberg, A.1 aMohnke, S.1 aMontgomery, G., W.1 aMorris, D., W.1 aMosley, T., H.1 aM?hleisen, T., W.1 aM?ller-Myhsok, B.1 aNalls, M., A.1 aNauck, M.1 aNichols, T., E.1 aNiessen, W., J.1 aN?then, M., M.1 aNyberg, L.1 aOhi, K.1 aOlvera, R., L.1 aOphoff, R., A.1 aPandolfo, M.1 aPaus, T.1 aPausova, Z.1 aPenninx, B., W. J. H.1 aPike, G., B.1 aPotkin, S., G.1 aPsaty, B., M.1 aReppermund, S.1 aRietschel, M.1 aRoffman, J., L.1 aRomanczuk-Seiferth, N.1 aRotter, J., I.1 aRyten, M.1 aSacco, R., L.1 aSachdev, P., S.1 aSaykin, A., J.1 aSchmidt, R.1 aSchmidt, H.1 aSchofield, P., R.1 aSigursson, S.1 aSimmons, A.1 aSingleton, A.1 aSisodiya, S., M.1 aSmith, C.1 aSmoller, J., W.1 aSoininen, H.1 aSteen, V., M.1 aStott, D., J.1 aSussmann, J., E.1 aThalamuthu, A.1 aToga, A., W.1 aTraynor, B., J.1 aTroncoso, J.1 aTsolaki, M.1 aTzourio, C.1 aUitterlinden, A., G.1 aHern?ndez, M., C. V.1 aVan der Brug, M.1 avan der Lugt, A.1 aVan der Wee, N., J. A.1 avan Haren, N., E. M.1 aEnt, van, 't1 avan Tol, M., J.1 aVardarajan, B., N.1 aVellas, B.1 aVeltman, D., J.1 aV?lzke, H.1 aWalter, H.1 aWardlaw, J., M.1 aWassink, T., H.1 aWeale, M., E.1 aWeinberger, D., R.1 aWeiner, M., W.1 aWen, W.1 aWestman, E.1 aWhite, T.1 aWong, T., Y.1 aWright, C., B.1 aZielke, R., H.1 aZonderman, A., B.1 aMartin, N., G.1 avan Duijn, C., M.1 aWright, M., J.1 aLongstreth, W., T.1 aSchumann, G.1 aGrabe, H., J.1 aFranke, B.1 aLauner, L., J.1 aMedland, S., E.1 aSeshadri, S.1 aThompson, P., M.1 aIkram, M., A. uhttps://chs-nhlbi.org/node/855203304nas a2200553 4500008004100000022001400041245016300055210006900218260001300287300001200300490000700312520166500319100001801984700002402002700002202026700002102048700001902069700002402088700002502112700001802137700002102155700002402176700002202200700001902222700002502241700002102266700001902287700001802306700002202324700001602346700001702362700001902379700001802398700002002416700002202436700002302458700002402481700002102505700002202526700002002548700001602568700002702584700002102611700002102632700002202653700002102675700001802696856003602714 2017 eng d a1942-326800aPCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.0 aPCSK9 LossofFunction Variants LowDensity Lipoprotein Cholesterol c2017 Aug ae0016320 v103 aBACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.
METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).
CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.
1 aKent, Shia, T1 aRosenson, Robert, S1 aAvery, Christy, L1 aChen, Yii-der, I1 aCorrea, Adolfo1 aCummings, Steven, R1 aCupples, Adrienne, L1 aCushman, Mary1 aEvans, Daniel, S1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHoward, George1 aIrvin, Marguerite, R1 aJudd, Suzanne, E1 aJukema, Wouter1 aLange, Leslie1 aLevitan, Emily, B1 aLi, Xiaohui1 aLiu, Yongmei1 aPost, Wendy, S1 aPostmus, Iris1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aSafford, Monika, M1 aSitlani, Colleen, M1 aSmith, Albert, V1 aStewart, James, D1 aTrompet, Stella1 aSun, Fangui1 aVasan, Ramachandran, S1 aWoolley, Michael1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aWilson, James, G1 aMuntner, Paul uhttps://chs-nhlbi.org/node/744803872nas a2200997 4500008004100000022001400041245016000055210006900215260001600284520133100300100001801631700001801649700001501667700001901682700001001701700001001711700001601721700001101737700002001748700001401768700002001782700001901802700001801821700001601839700001501855700001301870700001701883700001601900700001301916700001601929700001201945700001601957700001901973700002101992700001602013700001502029700001402044700001402058700001302072700002502085700001902110700001802129700001402147700001202161700001002173700001602183700001502199700001902214700001702233700001502250700001702265700001502282700001302297700001802310700001802328700001802346700001902364700002202383700001602405700001402421700001602435700001602451700002002467700001702487700001802504700001702522700001602539700001702555700001802572700001802590700001502608700001702623700001702640700001102657700002402668700001602692700001502708700001502723700001802738700001702756700001602773700001802789700001502807700001602822856003602838 2017 eng d a1473-115000aPharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.0 aPharmacogenomics study of thiazide diuretics and QT interval in c2017 Jul 183 aThiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10(-8)), we found suggestive evidence (P<5 × 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.The Pharmacogenomics Journal advance online publication, 18 July 2017; doi:10.1038/tpj.2017.10.
1 aSeyerle, A, A1 aSitlani, C, M1 aNoordam, R1 aGogarten, S, M1 aLi, J1 aLi, X1 aEvans, D, S1 aSun, F1 aLaaksonen, M, A1 aIsaacs, A1 aKristiansson, K1 aHighland, H, M1 aStewart, J, D1 aHarris, T B1 aTrompet, S1 aBis, J C1 aPeloso, G, M1 aBrody, J, A1 aBroer, L1 aBusch, E, L1 aDuan, Q1 aStilp, A, M1 aO'Donnell, C J1 aMacfarlane, P, W1 aFloyd, J, S1 aKors, J, A1 aLin, H, J1 aLi-Gao, R1 aSofer, T1 aMéndez-Giráldez, R1 aCummings, S, R1 aHeckbert, S R1 aHofman, A1 aFord, I1 aLi, Y1 aLauner, L J1 aPorthan, K1 aNewton-Cheh, C1 aNapier, M, D1 aKerr, K, F1 aReiner, A, P1 aRice, K, M1 aRoach, J1 aBuckley, B, M1 aSoliman, E, Z1 ade Mutsert, R1 aSotoodehnia, N1 aUitterlinden, A G1 aNorth, K, E1 aLee, C, R1 aGudnason, V1 aStürmer, T1 aRosendaal, F, R1 aTaylor, K, D1 aWiggins, K, L1 aWilson, J, G1 aDI Chen, Y-1 aKaplan, R, C1 aWilhelmsen, K1 aCupples, L, A1 aSalomaa, V1 avan Duijn, C1 aJukema, J, W1 aLiu, Y1 aMook-Kanamori, D, O1 aLange, L, A1 aVasan, R S1 aSmith, A V1 aStricker, B H1 aLaurie, C, C1 aRotter, J I1 aWhitsel, E, A1 aPsaty, B M1 aAvery, C, L uhttps://chs-nhlbi.org/node/749103411nas a2200541 4500008004100000022001400041245007900055210006900134260001600203520185300219100002202072700002002094700002102114700001502135700002102150700001902171700003102190700002202221700002202243700001802265700002002283700002302303700002102326700002102347700001902368700001502387700002702402700002002429700002002449700002302469700002102492700002002513700002402533700001902557700002102576700002202597700002202619700001702641700002502658700001902683700002202702700002202724700002302746700002402769700002002793700002002813856003602833 2017 eng d a1879-084400aPredictors and outcomes of heart failure with mid-range ejection fraction.0 aPredictors and outcomes of heart failure with midrange ejection c2017 Dec 113 aAIMS: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.
METHODS AND RESULTS: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78).
CONCLUSIONS: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.
1 aBhambhani, Vijeta1 aKizer, Jorge, R1 aLima, João, A C1 aHarst, Pim1 aBahrami, Hossein1 aNayor, Matthew1 ade Filippi, Christopher, R1 aEnserro, Danielle1 aBlaha, Michael, J1 aCushman, Mary1 aWang, Thomas, J1 aGansevoort, Ron, T1 aFox, Caroline, S1 aGaggin, Hanna, K1 aKop, Willem, J1 aLiu, Kiang1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aLee, Douglas, S1 aBrouwers, Frank, P1 aHillege, Hans, L1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aChan, Cheeling1 aAllison, Matthew1 aGardin, Julius, M1 aJanuzzi, James, L1 aLevy, Daniel1 aHerrington, David, M1 aGilst, Wiek, H1 aBertoni, Alain, G1 aLarson, Martin, G1 ade Boer, Rudolf, A1 aGottdiener, John, S1 aShah, Sanjiv, J1 aHo, Jennifer, E uhttps://chs-nhlbi.org/node/754902283nas a2200205 4500008004100000022001400041245008600055210006900141260001600210300001200226490000700238520167300245100001701918700001701935700002601952700002001978700002001998700002302018856003602041 2017 eng d a1526-632X00aPredictors of incident epilepsy in older adults: The Cardiovascular Health Study.0 aPredictors of incident epilepsy in older adults The Cardiovascul c2017 Feb 28 a870-8770 v883 aOBJECTIVE: To determine the prevalence, incidence, and predictors of epilepsy among older adults in the Cardiovascular Health Study (CHS).
METHODS: We analyzed data prospectively collected in CHS and merged with data from outpatient Medicare administrative claims. We identified cases with epilepsy using self-report, antiepileptic medication, hospitalization discharge ICD-9 codes, and outpatient Medicare ICD-9 codes. We used Cox proportional hazards regression to identify factors independently associated with incident epilepsy.
RESULTS: At baseline, 42% of the 5,888 participants were men and 84% were white. At enrollment, 3.7% (215 of 5,888) met the criteria for prevalent epilepsy. During 14 years of follow-up totaling 48,651 person-years, 120 participants met the criteria for incident epilepsy, yielding an incidence rate of 2.47 per 1,000 person-years. The period prevalence of epilepsy by the end of follow-up was 5.7% (335 of 5,888). Epilepsy incidence rates were significantly higher among blacks than nonblacks: 4.44 vs 2.17 per 1,000 person-years (p < 0.001). In multivariable analyses, risk of incident epilepsy was significantly higher among blacks compared to nonblacks (hazard ratio [HR] 4.04, 95% confidence interval [CI] 1.99-8.17), those 75 to 79 compared to those 65 to 69 years of age (HR 2.07, 95% CI 1.21-3.55), and those with history of stroke (HR 3.49, 95% CI 1.37-8.88).
CONCLUSIONS: Epilepsy in older adults in the United States was common. Blacks, the very old, and those with history of stroke have a higher risk of incident epilepsy. The association with race remains unexplained.
1 aChoi, Hyunmi1 aPack, Alison1 aElkind, Mitchell, S V1 aLongstreth, W T1 aTon, Thanh, G N1 aOnchiri, Frankline uhttps://chs-nhlbi.org/node/734217687nas a2205785 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02010465700002210485700002510507700001910532700001610551700001910567700002010586700002110606700002110627700002610648700002110674700002410695700001610719700002110735700002810756700001810784700002110802700002210823700002210845700001710867700001910884700002010903700002410923700001810947700002710965700002210992700002011014700002011034700002311054700001911077700002411096700001711120700002311137700003011160700002411190700002411214700002211238700002311260700001711283700002311300700002311323700003111346700002011377700001811397700002411415700002411439700002211463700002811485700002011513700002711533700001611560700002211576700003111598700002211629700002311651700002111674700001811695700002611713700002011739700002011759700002811779710002011807710003811827856003611865 2017 eng d a1546-171800aRare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.0 aRare coding variants in PLCG2 ABI3 and TREM2 implicate microglia c2017 Sep a1373-13840 v493 aWe identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
10aAdaptor Proteins, Signal Transducing10aAlzheimer Disease10aAmino Acid Sequence10aCase-Control Studies10aExome10aGene Expression Profiling10aGene Frequency10aGenetic Predisposition to Disease10aGenotype10aHumans10aImmunity, Innate10aLinkage Disequilibrium10aMembrane Glycoproteins10aMicroglia10aOdds Ratio10aPhospholipase C gamma10aPolymorphism, Single Nucleotide10aProtein Interaction Maps10aReceptors, Immunologic10aSequence Homology, Amino Acid1 aSims, Rebecca1 avan der Lee, Sven, J1 aNaj, Adam, C1 aBellenguez, Céline1 aBadarinarayan, Nandini1 aJakobsdottir, Johanna1 aKunkle, Brian, W1 aBoland, Anne1 aRaybould, Rachel1 aBis, Joshua, C1 aMartin, Eden, R1 aGrenier-Boley, Benjamin1 aHeilmann-Heimbach, Stefanie1 aChouraki, Vincent1 aKuzma, Amanda, B1 aSleegers, Kristel1 aVronskaya, Maria1 aRuiz, Agustin1 aGraham, Robert, R1 aOlaso, Robert1 aHoffmann, Per1 aGrove, Megan, L1 aVardarajan, Badri, N1 aHiltunen, Mikko1 aNöthen, Markus, M1 aWhite, Charles, C1 aHamilton-Nelson, Kara, L1 aEpelbaum, Jacques1 aMaier, Wolfgang1 aChoi, Seung-Hoan1 aBeecham, Gary, W1 aDulary, Cécile1 aHerms, Stefan1 aSmith, Albert, V1 aFunk, Cory, C1 aDerbois, Céline1 aForstner, Andreas, J1 aAhmad, Shahzad1 aLi, Hongdong1 aBacq, Delphine1 aHarold, Denise1 aSatizabal, Claudia, L1 aValladares, Otto1 aSquassina, Alessio1 aThomas, Rhodri1 aBrody, Jennifer, A1 aQu, Liming1 aSánchez-Juan, Pascual1 aMorgan, Taniesha1 aWolters, Frank, J1 aZhao, Yi1 aGarcia, Florentino, Sanchez1 aDenning, Nicola1 aFornage, Myriam1 aMalamon, John1 aNaranjo, Maria, Candida De1 aMajounie, Elisa1 aMosley, Thomas, H1 aDombroski, Beth1 aWallon, David1 aLupton, Michelle, K1 aDupuis, Josée1 aWhitehead, Patrice1 aFratiglioni, Laura1 aMedway, Christopher1 aJian, Xueqiu1 aMukherjee, Shubhabrata1 aKeller, Lina1 aBrown, Kristelle1 aLin, Honghuang1 aCantwell, Laura, B1 aPanza, Francesco1 aMcGuinness, Bernadette1 aMoreno-Grau, Sonia1 aBurgess, Jeremy, D1 aSolfrizzi, Vincenzo1 aProitsi, Petra1 aAdams, Hieab, H1 aAllen, Mariet1 aSeripa, Davide1 aPastor, Pau1 aCupples, Adrienne, L1 aPrice, Nathan, D1 aHannequin, Didier1 aFrank-García, Ana1 aLevy, Daniel1 aChakrabarty, Paramita1 aCaffarra, Paolo1 aGiegling, Ina1 aBeiser, Alexa, S1 aGiedraitis, Vilmantas1 aHampel, Harald1 aGarcia, Melissa, E1 aWang, Xue1 aLannfelt, Lars1 aMecocci, Patrizia1 aEiriksdottir, Gudny1 aCrane, Paul, K1 aPasquier, Florence1 aBoccardi, Virginia1 aHenández, Isabel1 aBarber, Robert, C1 aScherer, Martin1 aTarraga, Lluis1 aAdams, Perrie, M1 aLeber, Markus1 aChen, Yuning1 aAlbert, Marilyn, S1 aRiedel-Heller, Steffi1 aEmilsson, Valur1 aBeekly, Duane1 aBraae, Anne1 aSchmidt, Reinhold1 aBlacker, Deborah1 aMasullo, Carlo1 aSchmidt, Helena1 aDoody, Rachelle, S1 aSpalletta, Gianfranco1 aJr, W, T Longstre1 aFairchild, Thomas, J1 aBossù, Paola1 aLopez, Oscar, L1 aFrosch, Matthew, P1 aSacchinelli, Eleonora1 aGhetti, Bernardino1 aYang, Qiong1 aHuebinger, Ryan, M1 aJessen, Frank1 aLi, Shuo1 aKamboh, Ilyas1 aMorris, John1 aSotolongo-Grau, Oscar1 aKatz, Mindy, J1 aCorcoran, Chris1 aDunstan, Melanie1 aBraddel, Amy1 aThomas, Charlene1 aMeggy, Alun1 aMarshall, Rachel1 aGerrish, Amy1 aChapman, Jade1 aAguilar, Miquel1 aTaylor, Sarah1 aHill, Matt1 aFairén, Mònica, Díez1 aHodges, Angela1 aVellas, Bruno1 aSoininen, Hilkka1 aKloszewska, Iwona1 aDaniilidou, Makrina1 aUphill, James1 aPatel, Yogen1 aHughes, Joseph, T1 aLord, Jenny1 aTurton, James1 aHartmann, Annette, M1 aCecchetti, Roberta1 aFenoglio, Chiara1 aSerpente, Maria1 aArcaro, Marina1 aCaltagirone, Carlo1 aOrfei, Maria, Donata1 aCiaramella, Antonio1 aPichler, Sabrina1 aMayhaus, Manuel1 aGu, Wei1 aLleo, Alberto1 aFortea, Juan1 aBlesa, Rafael1 aBarber, Imelda, S1 aBrookes, Keeley1 aCupidi, Chiara1 aMaletta, Raffaele, Giovanni1 aCarrell, David1 aSorbi, Sandro1 aMoebus, Susanne1 aUrbano, Maria1 aPilotto, Alberto1 aKornhuber, Johannes1 aBosco, Paolo1 aTodd, Stephen1 aCraig, David1 aJohnston, Janet1 aGill, Michael1 aLawlor, Brian1 aLynch, Aoibhinn1 aFox, Nick, C1 aHardy, John1 aAlbin, Roger, L1 aApostolova, Liana, G1 aArnold, Steven, E1 aAsthana, Sanjay1 aAtwood, Craig, S1 aBaldwin, Clinton, T1 aBarnes, Lisa, L1 aBarral, Sandra1 aBeach, Thomas, G1 aBecker, James, T1 aBigio, Eileen, H1 aBird, Thomas, D1 aBoeve, Bradley, F1 aBowen, James, D1 aBoxer, Adam1 aBurke, James, R1 aBurns, Jeffrey, M1 aBuxbaum, Joseph, D1 aCairns, Nigel, J1 aCao, Chuanhai1 aCarlson, Chris, S1 aCarlsson, Cynthia, M1 aCarney, Regina, M1 aCarrasquillo, Minerva, M1 aCarroll, Steven, L1 aDiaz, Carolina, Ceballos1 aChui, Helena, C1 aClark, David, G1 aCribbs, David, H1 aCrocco, Elizabeth, A1 aDeCarli, Charles1 aDick, Malcolm1 aDuara, Ranjan1 aEvans, Denis, A1 aFaber, Kelley, M1 aFallon, Kenneth, B1 aFardo, David, W1 aFarlow, Martin, R1 aFerris, Steven1 aForoud, Tatiana, M1 aGalasko, Douglas, R1 aGearing, Marla1 aGeschwind, Daniel, H1 aGilbert, John, R1 aGraff-Radford, Neill, R1 aGreen, Robert, C1 aGrowdon, John, H1 aHamilton, Ronald, L1 aHarrell, Lindy, E1 aHonig, Lawrence, S1 aHuentelman, Matthew, J1 aHulette, Christine, M1 aHyman, Bradley, T1 aJarvik, Gail, P1 aAbner, Erin1 aJin, Lee-Way1 aJun, Gyungah1 aKarydas, Anna1 aKaye, Jeffrey, A1 aKim, Ronald1 aKowall, Neil, W1 aKramer, Joel, H1 aLaFerla, Frank, M1 aLah, James, J1 aLeverenz, James, B1 aLevey, Allan, I1 aLi, Ge1 aLieberman, Andrew, P1 aLunetta, Kathryn, L1 aLyketsos, Constantine, G1 aMarson, Daniel, C1 aMartiniuk, Frank1 aMash, Deborah, C1 aMasliah, Eliezer1 aMcCormick, Wayne, C1 aMcCurry, Susan, M1 aMcDavid, Andrew, N1 aMcKee, Ann, C1 aMesulam, Marsel1 aMiller, Bruce, L1 aMiller, Carol, A1 aMiller, Joshua, W1 aMorris, John, C1 aMurrell, Jill, R1 aMyers, Amanda, J1 aO'Bryant, Sid1 aOlichney, John, M1 aPankratz, Vernon, S1 aParisi, Joseph, E1 aPaulson, Henry, L1 aPerry, William1 aPeskind, Elaine1 aPierce, Aimee1 aPoon, Wayne, W1 aPotter, Huntington1 aQuinn, Joseph, F1 aRaj, Ashok1 aRaskind, Murray1 aReisberg, Barry1 aReitz, Christiane1 aRingman, John, M1 aRoberson, Erik, D1 aRogaeva, Ekaterina1 aRosen, Howard, J1 aRosenberg, Roger, N1 aSager, Mark, A1 aSaykin, Andrew, J1 aSchneider, Julie, A1 aSchneider, Lon, S1 aSeeley, William, W1 aSmith, Amanda, G1 aSonnen, Joshua, A1 aSpina, Salvatore1 aStern, Robert, A1 aSwerdlow, Russell, H1 aTanzi, Rudolph, E1 aThornton-Wells, Tricia, A1 aTrojanowski, John, Q1 aTroncoso, Juan, C1 aVan Deerlin, Vivianna, M1 aVan Eldik, Linda, J1 aVinters, Harry, V1 aVonsattel, Jean, Paul1 aWeintraub, Sandra1 aWelsh-Bohmer, Kathleen, A1 aWilhelmsen, Kirk, C1 aWilliamson, Jennifer1 aWingo, Thomas, S1 aWoltjer, Randall, L1 aWright, Clinton, B1 aYu, Chang-En1 aYu, Lei1 aGarzia, Fabienne1 aGolamaully, Feroze1 aSeptier, Gislain1 aEngelborghs, Sebastien1 aVandenberghe, Rik1 aDe Deyn, Peter, P1 aFernadez, Carmen, Muñoz1 aBenito, Yoland, Aladro1 aThonberg, Håkan1 aForsell, Charlotte1 aLilius, Lena1 aKinhult-Ståhlbom, Anne1 aKilander, Lena1 aBrundin, RoseMarie1 aConcari, Letizia1 aHelisalmi, Seppo1 aKoivisto, Anne, Maria1 aHaapasalo, Annakaisa1 aDermecourt, Vincent1 aFiévet, Nathalie1 aHanon, Olivier1 aDufouil, Carole1 aBrice, Alexis1 aRitchie, Karen1 aDubois, Bruno1 aHimali, Jayanadra, J1 aKeene, Dirk1 aTschanz, JoAnn1 aFitzpatrick, Annette, L1 aKukull, Walter, A1 aNorton, Maria1 aAspelund, Thor1 aLarson, Eric, B1 aMunger, Ron1 aRotter, Jerome, I1 aLipton, Richard, B1 aBullido, María, J1 aHofman, Albert1 aMontine, Thomas, J1 aCoto, Eliecer1 aBoerwinkle, Eric1 aPetersen, Ronald, C1 aAlvarez, Victoria1 aRivadeneira, Fernando1 aReiman, Eric, M1 aGallo, Maura1 aO'Donnell, Christopher, J1 aReisch, Joan, S1 aBruni, Amalia, Cecilia1 aRoyall, Donald, R1 aDichgans, Martin1 aSano, Mary1 aGalimberti, Daniela1 aSt George-Hyslop, Peter1 aScarpini, Elio1 aTsuang, Debby, W1 aMancuso, Michelangelo1 aBonuccelli, Ubaldo1 aWinslow, Ashley, R1 aDaniele, Antonio1 aWu, Chuang-Kuo1 aPeters, Oliver1 aNacmias, Benedetta1 aRiemenschneider, Matthias1 aHeun, Reinhard1 aBrayne, Carol1 aRubinsztein, David, C1 aBras, Jose1 aGuerreiro, Rita1 aAl-Chalabi, Ammar1 aShaw, Christopher, E1 aCollinge, John1 aMann, David1 aTsolaki, Magda1 aClarimon, Jordi1 aSussams, Rebecca1 aLovestone, Simon1 aO'Donovan, Michael, C1 aOwen, Michael, J1 aBehrens, Timothy, W1 aMead, Simon1 aGoate, Alison, M1 aUitterlinden, André, G1 aHolmes, Clive1 aCruchaga, Carlos1 aIngelsson, Martin1 aBennett, David, A1 aPowell, John1 aGolde, Todd, E1 aGraff, Caroline1 aDe Jager, Philip, L1 aMorgan, Kevin1 aErtekin-Taner, Nilufer1 aCombarros, Onofre1 aPsaty, Bruce, M1 aPassmore, Peter1 aYounkin, Steven, G1 aBerr, Claudine1 aGudnason, Vilmundur1 aRujescu, Dan1 aDickson, Dennis, W1 aDartigues, Jean-François1 aDeStefano, Anita, L1 aOrtega-Cubero, Sara1 aHakonarson, Hakon1 aCampion, Dominique1 aBoada, Merce1 aKauwe, John, Keoni1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aIkram, Arfan, M1 aJones, Lesley1 aHaines, Jonathan, L1 aTzourio, Christophe1 aLauner, Lenore, J1 aEscott-Price, Valentina1 aMayeux, Richard1 aDeleuze, Jean-Francois1 aAmin, Najaf1 aHolmans, Peter, A1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aDuijn, Cornelia, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aLambert, Jean-Charles1 aSeshadri, Sudha1 aWilliams, Julie1 aSchellenberg, Gerard, D1 aARUK Consortium1 aGERAD/PERADES, CHARGE, ADGC, EADI uhttps://chs-nhlbi.org/node/758703066nas a2200577 4500008004100000022001400041245008100055210006900136260001300205300001300218490000700231520143400238653001101672653002301683653001801706653001101724653004301735653001901778653001701797653001801814653003401832653001101866653001901877653001801896653002001914653000901934653002301943653001401966653001601980653001901996653003602015653003302051653002102084653002302105653002702128100001802155700002302173700002002196700001302216700002502229700002102254700001802275700002002293700001802313700002302331700002502354700002202379700002502401710002602426856003602452 2017 eng d a1553-740400aRare coding variants pinpoint genes that control human hematological traits.0 aRare coding variants pinpoint genes that control human hematolog c2017 Aug ae10069250 v133 aThe identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.
10aAsthma10aDatabases, Genetic10aEndometriosis10aFemale10aFibrin Fibrinogen Degradation Products10aGene Frequency10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aInterleukin-3310aLinear Models10aLogistic Models10aMale10aMutation, Missense10aPhenotype10aPlasminogen10aPlatelet Count10aPolymorphism, Single Nucleotide10aPrincipal Component Analysis10aProtein Splicing10aRhinitis, Allergic10aSequence Analysis, DNA1 aMousas, Abdou1 aNtritsos, Georgios1 aChen, Ming-Huei1 aSong, Ci1 aHuffman, Jennifer, E1 aTzoulaki, Ioanna1 aElliott, Paul1 aPsaty, Bruce, M1 aAuer, Paul, L1 aJohnson, Andrew, D1 aEvangelou, Evangelos1 aLettre, Guillaume1 aReiner, Alexander, P1 aBlood-Cell Consortium uhttps://chs-nhlbi.org/node/757703136nas a2200313 4500008004100000022001400041245012400055210006900179260001600248300001200264490000700276520219200283100002602475700002002501700001802521700001602539700002002555700001502575700002502590700002002615700002402635700002202659700002002681700002002701700002202721700002402743700001902767856003602786 2017 eng d a1555-905X00aThe Relation of Serum Potassium Concentration with Cardiovascular Events and Mortality in Community-Living Individuals.0 aRelation of Serum Potassium Concentration with Cardiovascular Ev c2017 Feb 07 a245-2520 v123 aBACKGROUND AND OBJECTIVES: Hyperkalemia is associated with adverse outcomes in patients with CKD and in hospitalized patients with acute medical conditions. Little is known regarding hyperkalemia, cardiovascular disease (CVD), and mortality in community-living populations. In a pooled analysis of two large observational cohorts, we investigated associations between serum potassium concentrations and CVD events and mortality, and whether potassium-altering medications and eGFR<60 ml/min per 1.73 m(2) modified these associations.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 9651 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), who were free of CVD at baseline (2000-2002 in the MESA and 1989-1993 in the CHS), we investigated associations between serum potassium categories (<3.5, 3.5-3.9, 4.0-4.4, 4.5-4.9, and ≥5.0 mEq/L) and CVD events, mortality, and mortality subtypes (CVD versus non-CVD) using Cox proportional hazards models, adjusting for demographics, time-varying eGFR, traditional CVD risk factors, and use of potassium-altering medications.
RESULTS: Compared with serum potassium concentrations between 4.0 and 4.4 mEq/L, those with concentrations ≥5.0 mEq/L were at higher risk for all-cause mortality (hazard ratio, 1.41; 95% confidence interval, 1.12 to 1.76), CVD death (hazard ratio, 1.50; 95% confidence interval, 1.00 to 2.26), and non-CVD death (hazard ratio, 1.40; 95% confidence interval, 1.07 to 1.83) in fully adjusted models. Associations of serum potassium with these end points differed among diuretic users (Pinteraction<0.02 for all), such that participants who had serum potassium ≥5.0 mEq/L and were concurrently using diuretics were at higher risk of each end point compared with those not using diuretics.
CONCLUSIONS: Serum potassium concentration ≥5.0 mEq/L was associated with all-cause mortality, CVD death, and non-CVD death in community-living individuals; associations were stronger in diuretic users. Whether maintenance of potassium within the normal range may improve clinical outcomes requires future study.
1 aHughes-Austin, Jan, M1 aRifkin, Dena, E1 aBeben, Tomasz1 aKatz, Ronit1 aSarnak, Mark, J1 aDeo, Rajat1 aHoofnagle, Andrew, N1 aHomma, Shunichi1 aSiscovick, David, S1 aSotoodehnia, Nona1 aPsaty, Bruce, M1 ade Boer, Ian, H1 aKestenbaum, Bryan1 aShlipak, Michael, G1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/734702701nas a2200241 4500008004100000022001400041245022700055210006900282260001600351300001200367490000800379520184500387100002202232700002202254700002002276700002302296700001802319700002202337700002402359700002002383700002002403856003602423 2017 eng d a1879-191300aRelation of the Myocardial Contraction Fraction, as Calculated from M-Mode Echocardiography, With Incident Heart Failure, Atherosclerotic Cardiovascular Disease and Mortality (Results from the Cardiovascular Health Study).0 aRelation of the Myocardial Contraction Fraction as Calculated fr c2017 Mar 15 a923-9280 v1193 aWe evaluated the association between 2-dimensional (2D) echocardiography (echo)-determined myocardial contraction fraction (MCF) and adverse cardiovascular outcomes including incident heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and mortality. The MCF, the ratio of left ventricular (LV) stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening that can distinguish pathologic from physiological hypertrophy. Using 2D echo-guided M-mode data from the Cardiovascular Health Study, we calculated MCF in subjects with LV ejection fraction (EF) ≥55% and used Cox models to evaluate its association with incident HF, ASCVD, and all-cause mortality after adjusting for clinical and echo parameters. We assessed whether log2(SV) and log2(MV) were consistent with the expected 1:-1 ratio used in the definition of MCF. Among 2,147 participants (age 72 ± 5 years), average MCF was 59 ± 13%. After controlling for clinical and echo variables, each 10% absolute increment in MCF was associated with lower risk of HF (hazard ratio [HR] 0.88; 95% confidence interval [CI] 0.82, 0.94), ASCVD (HR 0.90; 95% CI 0.85, 0.95), and death (HR 0.93; 95% CI 0.89, 0.97). Moreover, the MCF was still significantly associated with ASCVD and mortality, but not HF, after adjustment for percent-predicted LV mass. Significant departure from the 1:-1 ratio was not observed for ASCVD or death, but did occur for HF, driven by a stronger association for MV than SV. In conclusion, among older adults without CVD or low LV ejection fraction, 2D echo-guided M-mode-derived MCF was independently associated with lower risk of adverse cardiovascular outcomes, but this ratiometric index may not capture the full relation that is apparent when its components are modeled separately in the case of HF.
1 aMaurer, Mathew, S1 aKoh, William, J H1 aBartz, Traci, M1 aVullaganti, Sirish1 aBarasch, Eddy1 aGardin, Julius, M1 aGottdiener, John, S1 aPsaty, Bruce, M1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/735003009nas a2200265 4500008004100000022001400041245008800055210006900143260001600212300001400228490000700242520222800249100002102477700002102498700001702519700001702536700002002553700002202573700002202595700002302617700002402640700002202664700002102686856003602707 2017 eng d a1558-359700aRelationship Between Physical Activity, Body Mass Index, and Risk of Heart Failure.0 aRelationship Between Physical Activity Body Mass Index and Risk c2017 Mar 07 a1129-11420 v693 aBACKGROUND: Lower leisure-time physical activity (LTPA) and higher body mass index (BMI) are independently associated with risk of heart failure (HF). However, it is unclear if this relationship is consistent for both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).
OBJECTIVES: This study sought to quantify dose-response associations between LTPA, BMI, and the risk of different HF subtypes.
METHODS: Individual-level data from 3 cohort studies (WHI [Women's Health Initiative], MESA [Multi-Ethnic Study of Atherosclerosis], and CHS [Cardiovascular Health Study]) were pooled and participants were stratified into guideline-recommended categories of LTPA and BMI. Associations between LTPA, BMI, and risk of overall HF, HFpEF (ejection fraction ≥45%), and HFrEF (ejection fraction <45%) were assessed by using multivariable adjusted Cox models and restricted cubic splines.
RESULTS: The study included 51,451 participants with 3,180 HF events (1,252 HFpEF, 914 HFrEF, and 1,014 unclassified HF). In the adjusted analysis, there was a dose-dependent association between higher LTPA levels, lower BMI, and overall HF risk. Among HF subtypes, LTPA in any dose range was not associated with HFrEF risk. In contrast, lower levels of LTPA (<500 MET-min/week) were not associated with HFpEF risk, and dose-dependent associations with lower HFpEF risk were observed at higher levels. Compared with no LTPA, higher than twice the guideline-recommended minimum LTPA levels (>1,000 MET-min/week) were associated with an 19% lower risk of HFpEF (hazard ratio: 0.81; 95% confidence interval: 0.68 to 0.97). The dose-response relationship for BMI with HFpEF risk was also more consistent than with HFrEF risk, such that increasing BMI above the normal range (≥25 kg/m(2)) was associated with a greater increase in risk of HFpEF than HFrEF.
CONCLUSIONS: Our study findings show strong, dose-dependent associations between LTPA levels, BMI, and risk of overall HF. Among HF subtypes, higher LTPA levels and lower BMI were more consistently associated with lower risk of HFpEF compared with HFrEF.
1 aPandey, Ambarish1 aLaMonte, Michael1 aKlein, Liviu1 aAyers, Colby1 aPsaty, Bruce, M1 aEaton, Charles, B1 aAllen, Norrina, B1 ade Lemos, James, A1 aCarnethon, Mercedes1 aGreenland, Philip1 aBerry, Jarett, D uhttps://chs-nhlbi.org/node/735603467nas a2200673 4500008004100000022001400041245015500055210006900210260001600279520146600295100001701761700002101778700001901799700002201818700001901840700003001859700002401889700002801913700002001941700001901961700001801980700001801998700002202016700002102038700002802059700002102087700002402108700002002132700002402152700002402176700001902200700002402219700002002243700001602263700003502279700001902314700001902333700002002352700002302372700001802395700002502413700002102438700002002459700002002479700001902499700001802518700002102536700002202557700002002579700002002599700002202619700002002641700002102661700001802682700001702700700002302717700001702740856003602757 2017 eng d a1476-625600aREPEATED MEASUREMENTS OF BLOOD PRESSURE AND CHOLESTEROL IMPROVES CARDIOVASCULAR DISEASE RISK PREDICTION: AN INDIVIDUAL-PARTICIPANT-DATA META-ANALYSIS.0 aREPEATED MEASUREMENTS OF BLOOD PRESSURE AND CHOLESTEROL IMPROVES c2017 May 263 aThe added value of incorporating information from repeated measurements of blood pressure and cholesterol for cardiovascular disease (CVD) risk prediction has not been rigorously assessed. We used data from the Emerging Risk Factors Collaboration on 191,445 adults (38 cohorts from across 17 countries with data from 1962-2014) with > 1 million measurements of systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol; over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative means of repeated measurements and summary measures from longitudinal modelling of the repeated measurements were compared to models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analysed across studies. Compared to the single time point model, the cumulative means and the longitudinal models increased the C-index by 0.0040 (95% CI: 0.0023, 0.0057) and 0.0023 (0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared to the single time point model, overall net reclassification improvements were 0.0369 (0.0303, 0.0436) for the cumulative means model and 0.0177 (0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.
1 aPaige, Ellie1 aBarrett, Jessica1 aPennells, Lisa1 aSweeting, Michael1 aWilleit, Peter1 aDi Angelantonio, Emanuele1 aGudnason, Vilmundur1 aNordestgaard, Børge, G1 aPsaty, Bruce, M1 aGoldbourt, Uri1 aBest, Lyle, G1 aAssmann, Gerd1 aSalonen, Jukka, T1 aNietert, Paul, J1 aVerschuren, Wm, Monique1 aBrunner, Eric, J1 aKronmal, Richard, A1 aSalomaa, Veikko1 aBakker, Stephan, Jl1 aDagenais, Gilles, R1 aSato, Shinichi1 aJansson, Jan-Håkan1 aWilleit, Johann1 aOnat, Altan1 ade la Cámara, Agustin, Gómez1 aRoussel, Ronan1 aVölzke, Henry1 aDankner, Rachel1 aTipping, Robert, W1 aMeade, Tom, W1 aDonfrancesco, Chiara1 aKuller, Lewis, H1 aPeters, Annette1 aGallacher, John1 aKromhout, Daan1 aIso, Hiroyasu1 aKnuiman, Matthew1 aCasiglia, Edoardo1 aKavousi, Maryam1 aPalmieri, Luigi1 aSundström, Johan1 aDavis, Barry, R1 aNjølstad, Inger1 aCouper, David1 aDanesh, John1 aThompson, Simon, G1 aWood, Angela uhttps://chs-nhlbi.org/node/745104138nas a2200889 4500008004100000022001400041245010600055210006900161260001500230300001000245490000600255520183000261653001002091653000902101653002202110653002602132653001902158653004002177653001102217653003002228653001302258653001102271653000902282653003702291653001602328653002902344653001802373653002402391653001302415100001302428700001202441700001602453700001702469700001402486700002202500700001302522700001402535700001802549700001202567700001702579700001102596700001802607700001902625700001602644700001502660700001502675700002102690700001602711700001702727700001302744700002202757700002102779700002002800700001902820700001602839700002102855700001602876700002102892700001702913700001802930700001802948700001602966700001702982700001702999700001703016700001403033700001703047700001103064700001603075700001603091700001903107700001503126700001203141700001903153710004003172856003603212 2017 eng d a2158-318800aShort telomere length is associated with impaired cognitive performance in European ancestry cohorts.0 aShort telomere length is associated with impaired cognitive perf c2017 04 18 ae11000 v73 aThe association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (β=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (β=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (β=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.
10aAdult10aAged10aApolipoprotein E410aCognitive Dysfunction10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Carrier Screening10aGenotype10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aNeuropsychological Tests10aPsychometrics10aStatistics as Topic10aTelomere1 aHägg, S1 aZhan, Y1 aKarlsson, R1 aGerritsen, L1 aPloner, A1 avan der Lee, S, J1 aBroer, L1 aDeelen, J1 aMarioni, R, E1 aWong, A1 aLundquist, A1 aZhu, G1 aHansell, N, K1 aSillanpää, E1 aFedko, I, O1 aAmin, N, A1 aBeekman, M1 ade Craen, A, J M1 aDegerman, S1 aHarris, S, E1 aKan, K-J1 aMartin-Ruiz, C, M1 aMontgomery, G, W1 aAdolfsson, A, N1 aReynolds, C, A1 aSamani, N J1 aSuchiman, H, E D1 aViljanen, A1 avon Zglinicki, T1 aWright, M, J1 aHottenga, J-J1 aBoomsma, D, I1 aRantanen, T1 aKaprio, J, A1 aNyholt, D, R1 aMartin, N, G1 aNyberg, L1 aAdolfsson, R1 aKuh, D1 aStarr, J, M1 aDeary, I, J1 aSlagboom, P, E1 aDuijn, C M1 aCodd, V1 aPedersen, N, L1 aNeuroCHARGE Cognitive Working Group uhttps://chs-nhlbi.org/node/756405167nas a2201273 4500008004100000022001400041245013800055210006900193260001300262300001300275490000700288520164300295653002201938653001201960653004901972653001902021653001402040653002502054653001102079653001702090653003402107653001102141653001702152653000902169653002202178653000902200653003102209653003602240100002002276700001502296700002802311700002202339700002102361700002302382700001802405700002302423700001802446700001902464700002102483700002402504700001702528700001502545700001802560700002302578700001502601700002202616700002102638700001602659700002402675700002002699700001402719700001402733700002002747700002302767700001702790700001702807700002302824700002502847700002402872700001702896700001802913700002202931700002402953700002002977700002202997700001303019700001403032700002403046700001803070700002103088700002003109700001803129700002103147700002203168700001903190700001703209700002803226700002003254700002103274700001803295700001903313700002103332700002403353700001503377700001603392700002003408700002403428700002303452700002103475700002103496700001703517700002003534700002003554700001903574700002403593700002103617700001603638700002103654700001903675700002303694700001403717700002203731700002003753700001703773700002603790700001803816700002303834856003603857 2017 eng d a1553-740400aSingle-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.0 aSingletrait and multitrait genomewide association analyses ident c2017 May ae10067280 v133 aHypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
10aAfrican Americans10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aBlood Pressure10aCadherins10aCase-Control Studies10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMembrane Proteins10aMice10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide1 aLiang, Jingjing1 aLe, Thu, H1 aEdwards, Digna, R Velez1 aTayo, Bamidele, O1 aGaulton, Kyle, J1 aSmith, Jennifer, A1 aLu, Yingchang1 aJensen, Richard, A1 aChen, Guanjie1 aYanek, Lisa, R1 aSchwander, Karen1 aTajuddin, Salman, M1 aSofer, Tamar1 aKim, Wonji1 aKayima, James1 aMcKenzie, Colin, A1 aFox, Ervin1 aNalls, Michael, A1 aYoung, Hunter, J1 aSun, Yan, V1 aLane, Jacqueline, M1 aCechova, Sylvia1 aZhou, Jie1 aTang, Hua1 aFornage, Myriam1 aMusani, Solomon, K1 aWang, Heming1 aLee, Juyoung1 aAdeyemo, Adebowale1 aDreisbach, Albert, W1 aForrester, Terrence1 aChu, Pei-Lun1 aCappola, Anne1 aEvans, Michele, K1 aMorrison, Alanna, C1 aMartin, Lisa, W1 aWiggins, Kerri, L1 aHui, Qin1 aZhao, Wei1 aJackson, Rebecca, D1 aWare, Erin, B1 aFaul, Jessica, D1 aReiner, Alex, P1 aBray, Michael1 aDenny, Joshua, C1 aMosley, Thomas, H1 aPalmas, Walter1 aGuo, Xiuqing1 aPapanicolaou, George, J1 aPenman, Alan, D1 aPolak, Joseph, F1 aRice, Kenneth1 aTaylor, Ken, D1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aLiu, Kiang1 aRisch, Neil1 aHunt, Steven, C1 aKooperberg, Charles1 aZonderman, Alan, B1 aLaurie, Cathy, C1 aBecker, Diane, M1 aCai, Jianwen1 aLoos, Ruth, J F1 aPsaty, Bruce, M1 aWeir, David, R1 aKardia, Sharon, L R1 aArnett, Donna, K1 aWon, Sungho1 aEdwards, Todd, L1 aRedline, Susan1 aCooper, Richard, S1 aRao, D, C1 aRotter, Jerome, I1 aRotimi, Charles1 aLevy, Daniel1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/757202586nas a2200289 4500008004100000022001400041245011400055210006900169260001600238520170000254100002601954700002101980700002402001700002302025700002002048700002002068700002002088700001802108700002202126700001902148700002002167700001302187700001902200700001702219700002402236856003602260 2017 eng d a1523-468100aSoluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study.0 aSoluble Inflammatory Markers and Risk of Incident Fractures in O c2017 Oct 043 aSeveral in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up. We assessed the association of four inflammatory markers with the risk of incident hip fractures among 5265 participants of the Cardiovascular Health Study (CHS) and a composite endpoint of incident fractures of the hip, pelvis, humerus, or proximal forearm in 4477 participants. Among CHS participants followed between 1992 and 2009, we observed 480 incident hip fractures during a median follow-up of 11 years. In the composite fracture analysis cohort of 4477 participants, we observed 711 fractures during a median follow-up of 7 years. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for hip fracture associated with doubling of IL-6 were HR 1.15 (95% CI, 1.02 to 1.30) overall and HR 1.17 (95% CI, 1.01 to 1.35) in women. We also observed a positive association between each unit increase in white blood cell (WBC) count and risk of hip fracture: HR 1.04 (95% CI, 1.01 to 1.06) overall and HR 1.06 (95% CI, 0.95 to 1.20) in women. We observed no significant associations between any of the four inflammatory markers and a composite fracture endpoint. Our findings suggest that chronic inflammatory and immune processes may be related to higher rates of incident hip fractures. © 2017 American Society for Bone and Mineral Research.
1 aStojanović, Danijela1 aBůzková, Petra1 aMukamal, Kenneth, J1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aFink, Howard, A1 aCauley, Jane, A1 aWallace, Erin1 aCurtis, Lesley, H1 aHirsch, Calvin1 aBudoff, Matthew1 aLi, Dong1 aYoung, Rebekah1 aJalal, Diana1 aDelaney, Joseph, Ac uhttps://chs-nhlbi.org/node/759202476nas a2200253 4500008004100000022001400041245010400055210006900159260001600228520173900244100001801983700001702001700001702018700001702035700001202052700002002064700001702084700002002101700001802121700001502139700001502154700001702169856003602186 2017 eng d a1538-783600aTaller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis.0 aTaller height as a risk factor for venous thromboembolism a Mend c2017 Apr 263 aBACKGROUND: Taller height is associated with greater risk of venous thromboembolism (VTE).
OBJECTIVES: We used instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationship METHODS: Participants of European ancestry were included from two cohort studies [Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS)] and one case-control study [Mayo Clinic VTE Study (Mayo)]. We created two weighted genetic risk scores (GRS) for height; the full GRS included 668 single nucleotide polymorphisms (SNPs) from a previously published meta-analysis and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10 cm increment in height. ORs were pooled across the three studies using inverse variance weighted random effects meta-analysis RESULTS: Among 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95% CI: 1.11, 1.46), 1.34 (95% CI: 1.04, 1.73), and 1.45 (95% CI: 1.04, 2.01) per 10 cm greater height, respectively CONCLUSIONS: Taller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including that taller people may have greater venous surface area, greater number of venous valves, or greater hydrostatic pressure, need to be explored further. This article is protected by copyright. All rights reserved.
1 aRoetker, N, S1 aArmasu, S, M1 aPankow, J, S1 aLutsey, P, L1 aTang, W1 aRosenberg, M, A1 aPalmer, T, M1 aMacLehose, R, F1 aHeckbert, S R1 aCushman, M1 aAndrade, M1 aFolsom, A, R uhttps://chs-nhlbi.org/node/735902054nas a2200481 4500008004100000022001400041245005600055210005500111260001300166300001400179490000600193520069800199100002300897700002000920700002000940700002300960700002600983700002401009700002301033700002301056700002101079700002401100700001901124700002101143700002201164700001801186700002101204700002001225700001701245700002001262700002801282700001401310700002401324700002701348700002301375700002501398700002201423700002301445700002401468700002601492700001801518856003601536 2017 eng d a1945-458900aTelomeres and the natural lifespan limit in humans.0 aTelomeres and the natural lifespan limit in humans c2017 Apr a1130-11420 v93 aAn ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.
1 aSteenstrup, Troels1 aKark, Jeremy, D1 aVerhulst, Simon1 aThinggaard, Mikael1 aHjelmborg, Jacob, V B1 aDalgård, Christine1 aKyvik, Kirsten Ohm1 aChristiansen, Lene1 aMangino, Massimo1 aSpector, Timothy, D1 aPetersen, Inge1 aKimura, Masayuki1 aBenetos, Athanase1 aLabat, Carlos1 aSinnreich, Ronit1 aHwang, Shih-Jen1 aLevy, Daniel1 aHunt, Steven, C1 aFitzpatrick, Annette, L1 aChen, Wei1 aBerenson, Gerald, S1 aBarbieri, Michelangela1 aPaolisso, Giuseppe1 aGadalla, Shahinaz, M1 aSavage, Sharon, A1 aChristensen, Kaare1 aYashin, Anatoliy, I1 aArbeev, Konstantin, G1 aAviv, Abraham uhttps://chs-nhlbi.org/node/759104137nas a2200745 4500008004100000022001400041245011100055210006900166260001600235300001400251490000800265520205100273653001002324653000902334653002202343653002602365653002402391653001502415653002802430653001102458653001102469653001902480653001402499653000902513653001602522653003002538653001402568653003202582653002002614653001702634653002702651653001802678653001602696653001402712653001702726653001602743100002702759700002302786700002102809700001902830700002102849700002202870700002102892700002302913700002302936700002402959700002602983700002203009700001803031700001903049700001803068700001903086700002303105700002403128700002203152700001803174700002003192700002603212700001803238700002203256700002203278700002103300710003403321856003603355 2017 eng d a1524-453900aThyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation.0 aThyroid Function Within the Normal Range Subclinical Hypothyroid c2017 Nov 28 a2100-21160 v1363 aBACKGROUND: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF.
METHODS: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF.
RESULTS: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease.
CONCLUSIONS: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.
10aAdult10aAged10aAged, 80 and over10aAsymptomatic Diseases10aAtrial Fibrillation10aBiomarkers10aChi-Square Distribution10aFemale10aHumans10aHypothyroidism10aIncidence10aMale10aMiddle Aged10aPredictive Value of Tests10aPrognosis10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aThyroid Function Tests10aThyroid Gland10aThyrotropin10aThyroxine10aTime Factors10aYoung Adult1 aBaumgartner, Christine1 ada Costa, Bruno, R1 aCollet, Tinh-Hai1 aFeller, Martin1 aFloriani, Carmen1 aBauer, Douglas, C1 aCappola, Anne, R1 aHeckbert, Susan, R1 aCeresini, Graziano1 aGussekloo, Jacobijn1 aElzen, Wendy, P J den1 aPeeters, Robin, P1 aLuben, Robert1 aVölzke, Henry1 aDörr, Marcus1 aWalsh, John, P1 aBremner, Alexandra1 aIacoviello, Massimo1 aMacfarlane, Peter1 aHeeringa, Jan1 aStott, David, J1 aWestendorp, Rudi, G J1 aKhaw, Kay-Tee1 aMagnani, Jared, W1 aAujesky, Drahomir1 aRodondi, Nicolas1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/755002424nas a2200217 4500008004100000022001400041245009400055210006900149260001600218520174800234100002201982700001802004700002202022700002202044700002302066700002002089700002002109700002002129700002102149856003602170 2017 eng d a1758-535X00aTrajectories of IGF-I Predict Mortality in Older Adults: The Cardiovascular Health Study.0 aTrajectories of IGFI Predict Mortality in Older Adults The Cardi c2017 Jul 233 aBackground: Disruption of insulin-like growth factor-I (IGF-I) increases health and life span in animal models, though this is unconfirmed in humans. If IGF-I stability indicates homeostasis, the absolute level of IGF-I may be less clinically relevant than maintaining an IGF-I setpoint.
Methods: Participants were 945 U.S. community-dwelling individuals aged ≥65 years enrolled in the Cardiovascular Health Study with IGF-I levels at 3-6 timepoints. We examined the association of baseline IGF-I level, trajectory slope, and variability around the trajectory with mortality.
Results: There were 633 deaths over median 11.3 years of follow-up. Lower IGF-I levels, declining or increasing slope, and increasing variability were each individually associated with higher mortality (all p < .001). In an adjusted model including all three trajectory parameters, baseline IGF-I levels <70 ng/mL (hazard ratio [HR] 1.58, 95% CI 1.28-1.96 relative to IGF-I levels of 170 ng/mL), steep declines and steep increases in trajectory slope (HR 2.22, 1.30-3.80 for a 15% decline; HR 1.40, 1.07-1.84 for a 10% decline; HR 1.80, 1.12-2.89 for a 15% increase; HR 1.31, 1.00-1.72 for a 10% increase, each vs no change), and variability ≥10% (HR 1.59, 1.09-2.32 for ≥ 30%; HR 1.36, 1.06-1.75 for 20%; and HR 1.17, 1.03-1.32 for 10% variability, each vs 0%) in IGF-I levels were independently associated with mortality.
Conclusions: In contrast to data from animal models, low IGF-I levels are associated with higher mortality in older humans. Irrespective of the actual IGF-I level, older individuals with stability of IGF-I levels have lower mortality than those whose IGF-I levels fluctuate over time.
1 aSanders, Jason, L1 aGuo, Wensheng1 aO'Meara, Ellen, S1 aKaplan, Robert, C1 aPollak, Michael, N1 aBartz, Traci, M1 aNewman, Anne, B1 aFried, Linda, P1 aCappola, Anne, R uhttps://chs-nhlbi.org/node/758404643nas a2200985 4500008004100000022001400041245023800055210006900293260001300362300001200375490000800387520178500395653002002180653001802200653002502218653001102243653001202254100003002266700001502296700002202311700002302333700002202356700002802378700001602406700002502422700002202447700002102469700002002490700002402510700001902534700001702553700002002570700002102590700001302611700001802624700002702642700002102669700002202690700002002712700001602732700001702748700002602765700001902791700001802810700002502828700001502853700002702868700002302895700002502918700001902943700001802962700002402980700002003004700002103024700001703045700001803062700001403080700001703094700001803111700001603129700002003145700001403165700001603179700002003195700002403215700002303239700002203262700002603284700002003310700002203330700001903352700002103371700002103392700002403413700002003437700002503457700002503482700001703507700002003524700001903544700002003563700001903583700001903602856003603621 2017 eng d a1432-120300aTrans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.0 aTransethnic finemapping of genetic loci for body mass index in t c2017 Jun a771-8000 v1363 aMost body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.
10aBody Mass Index10aEthnic Groups10aGenetics, Population10aHumans10aObesity1 aFernandez-Rhodes, Lindsay1 aGong, Jian1 aHaessler, Jeffrey1 aFranceschini, Nora1 aGraff, Mariaelisa1 aNishimura, Katherine, K1 aWang, Yujie1 aHighland, Heather, M1 aYoneyama, Sachiko1 aBush, William, S1 aGoodloe, Robert1 aRitchie, Marylyn, D1 aCrawford, Dana1 aGross, Myron1 aFornage, Myriam1 aBůzková, Petra1 aTao, Ran1 aIsasi, Carmen1 aAvilés-Santa, Larissa1 aDaviglus, Martha1 aMackey, Rachel, H1 aHouston, Denise1 aGu, Charles1 aEhret, Georg1 aNguyen, Khanh-Dung, H1 aLewis, Cora, E1 aLeppert, Mark1 aIrvin, Marguerite, R1 aLim, Unhee1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aSchumacher, Fredrick1 aWilkens, Lynne1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J L1 aSheu, Wayne, H-H1 aGuo, Xiuqing1 aLee, Wen-Jane1 aHai, Yang1 aHung, Yi-Jen1 aAbsher, Devin1 aWu, I-Chien1 aTaylor, Kent, D1 aLee, I-Te1 aLiu, Yeheng1 aWang, Tzung-Dau1 aQuertermous, Thomas1 aJuang, Jyh-Ming, J1 aRotter, Jerome, I1 aAssimes, Themistocles1 aHsiung, Chao, A1 aChen, Yii-Der Ida1 aPrentice, Ross1 aKuller, Lewis, H1 aManson, JoAnn, E1 aKooperberg, Charles1 aSmokowski, Paul1 aRobinson, Whitney, R1 aGordon-Larsen, Penny1 aLi, Rongling1 aHindorff, Lucia1 aBuyske, Steven1 aMatise, Tara, C1 aPeters, Ulrike1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/746503062nas a2200601 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520134100253100002101594700002201615700002501637700001801662700001901680700001901699700002101718700001601739700001801755700003001773700002601803700002301829700002901852700002001881700002001901700002001921700002401941700003501965700002202000700002002022700001802042700001602060700002102076700001902097700002002116700002002136700002202156700001902178700001702197700002002214700002602234700002002260700001802280700002602298700002402324700001702348700001902365700002102384700001902405856003602424 2017 eng d a1573-728400aTrends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium.0 aTrends in the incidence of dementia design and methods in the Al c2017 Oct a931-9380 v323 aSeveral studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
1 aChibnik, Lori, B1 aWolters, Frank, J1 aBäckman, Kristoffer1 aBeiser, Alexa1 aBerr, Claudine1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBos, Daniel1 aBrayne, Carol1 aDartigues, Jean-François1 aDarweesh, Sirwan, K L1 aDebette, Stephanie1 aDavis-Plourde, Kendra, L1 aDufouil, Carole1 aFornage, Myriam1 aGrasset, Leslie1 aGudnason, Vilmundur1 aHadjichrysanthou, Christoforos1 aHelmer, Catherine1 aIkram, Arfan, M1 aIkram, Kamran1 aKern, Silke1 aKuller, Lewis, H1 aLauner, Lenore1 aLopez, Oscar, L1 aMatthews, Fiona1 aMeirelles, Osorio1 aMosley, Thomas1 aOwer, Alison1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aSeshadri, Sudha1 aSkoog, Ingmar1 aStephan, Blossom, C M1 aTzourio, Christophe1 aWaziry, Reem1 aWong, Mei, Mei1 aZettergren, Anna1 aHofman, Albert uhttps://chs-nhlbi.org/node/755403343nas a2200517 4500008004100000022001400041245015500055210006900210260001300279300001200292490000700304520187900311653000902190653001002199653001902209653003302228653002102261653001502282653001902297653001102316653001802327653001102345653001702356653001402373653002502387653000902412653002602421653001802447653001402465653002602479653001702505653001102522653001802533100001602551700002402567700002302591700002302614700002002637700002202657700002502679700002102704700002002725700002302745710002102768856003602789 2017 eng d a1941-722500aVisit-to-Visit Blood Pressure Variability and Mortality and Cardiovascular Outcomes Among Older Adults: The Health, Aging, and Body Composition Study.0 aVisittoVisit Blood Pressure Variability and Mortality and Cardio c2017 Feb a151-1580 v303 aBACKGROUND: Level of blood pressure (BP) is strongly associated with cardiovascular (CV) events and mortality. However, it is questionable whether mean BP can fully capture BP-related vascular risk. Increasing attention has been given to the value of visit-to-visit BP variability.
METHODS: We examined the association of visit-to-visit BP variability with mortality, incident myocardial infarction (MI), and incident stroke among 1,877 well-functioning elders in the Health, Aging, and Body Composition Study. We defined visit-to-visit diastolic BP (DBP) and systolic BP (SBP) variability as the root-mean-square error of person-specific linear regression of BP as a function of time. Alternatively, we counted the number of considerable BP increases and decreases (separately; 10mm Hg for DBP and 20mm Hg for SBP) between consecutive visits for each individual.
RESULTS: Over an average follow-up of 8.5 years, 623 deaths (207 from CV disease), 153 MIs, and 156 strokes occurred. The median visit-to-visit DBP and SBP variability was 4.96 mmHg and 8.53 mmHg, respectively. After multivariable adjustment, visit-to-visit DBP variability was related to higher all-cause (hazard ratio (HR) = 1.18 per 1 SD, 95% confidence interval (CI) = 1.01-1.37) and CV mortality (HR = 1.35, 95% CI = 1.05-1.73). Additionally, individuals having more considerable decreases of DBP (≥10mm Hg between 2 consecutive visits) had higher risk of all-cause (HR = 1.13, 95% CI = 0.99-1.28) and CV mortality (HR = 1.30, 95% CI = 1.05-1.61); considerable increases of SBP (≥20mm Hg) were associated with higher risk of all-cause (HR = 1.18, 95% CI = 1.03-1.36) and CV mortality (HR = 1.37, 95% CI = 1.08-1.74).
CONCLUSIONS: Visit-to-visit DBP variability and considerable changes in DBP and SBP were risk factors for mortality in the elderly.
10aAged10aAging10aBlood Pressure10aBlood Pressure Determination10aBody Composition10aCalifornia10aCohort Studies10aFemale10aHealth Status10aHumans10aHypertension10aIncidence10aLongitudinal Studies10aMale10aMyocardial Infarction10aOffice Visits10aPrognosis10aRetrospective Studies10aRisk Factors10aStroke10aSurvival Rate1 aWu, Chenkai1 aShlipak, Michael, G1 aStawski, Robert, S1 aPeralta, Carmen, A1 aPsaty, Bruce, M1 aHarris, Tamara, B1 aSatterfield, Suzanne1 aShiroma, Eric, J1 aNewman, Anne, B1 aOdden, Michelle, C1 aHealth ABC Study uhttps://chs-nhlbi.org/node/857203528nas a2200577 4500008004100000022001400041245011500055210006900170260001300239300001000252490000800262520200100270653000902271653002602280653001702306653001102323653002002334653001102354653002002365653001902385653000902404653001702413100001302430700001602443700001402459700001702473700001502490700001702505700001602522700001902538700001502557700001802572700001802590700001502608700002202623700001502645700001402660700001502674700002202689700002502711700001502736700001702751700001902768700001602787700001702803700001802820700002702838700001502865710003402880856003602914 2018 eng d a1365-279600aAssociation between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts.0 aAssociation between subclinical thyroid dysfunction and change i c2018 Jan a56-720 v2833 aBACKGROUND: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear.
OBJECTIVE: To investigate the association between subclinical thyroid dysfunction and bone loss.
METHODS: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach.
RESULTS: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site.
CONCLUSION: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.
10aAged10aAsymptomatic Diseases10aBone Density10aFemale10aFractures, Bone10aHumans10aHyperthyroidism10aHypothyroidism10aMale10aRisk Factors1 aSegna, D1 aBauer, D, C1 aFeller, M1 aSchneider, C1 aFink, H, A1 aAubert, C, E1 aCollet, T-H1 ada Costa, B, R1 aFischer, K1 aPeeters, R, P1 aCappola, A, R1 aBlum, M, R1 avan Dorland, H, A1 aRobbins, J1 aNaylor, K1 aEastell, R1 aUitterlinden, A G1 aRamirez, Rivadeneira1 aGogakos, A1 aGussekloo, J1 aWilliams, G, R1 aSchwartz, A1 aCauley, J, A1 aAujesky, D, A1 aBischoff-Ferrari, H, A1 aRodondi, N1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/758504477nas a2200217 4500008004100000022001400041245014300055210006900198260001600267300001200283490000600295520377900301100002104080700001604101700002404117700002004141700002004161700002204181700002004203856003604223 2018 eng d a2574-380500aAssociation of Alcohol Consumption After Development of Heart Failure With Survival Among Older Adults in the Cardiovascular Health Study.0 aAssociation of Alcohol Consumption After Development of Heart Fa c2018 Dec 07 ae1863830 v13 aImportance: More than 1 million older adults develop heart failure annually. The association of alcohol consumption with survival among these individuals after diagnosis is unknown.
Objective: To determine whether alcohol use is associated with increased survival among older adults with incident heart failure.
Design, Setting, and Participants: This prospective cohort study included 5888 community-dwelling adults aged 65 years or older who were recruited to participate in the Cardiovascular Health Study between June 12, 1989, and June 1993, from 4 US sites. Of the total participants, 393 individuals had a new diagnosis of heart failure within the first 9 years of follow-up through June 2013. The study analysis was performed between January 19, 2016, and September 22, 2016.
Exposures: Alcohol consumption was divided into 4 categories: abstainers (never drinkers), former drinkers, 7 or fewer alcoholic drinks per week, and more than 7 drinks per week.
Primary Outcomes and Measures: Participant survival after the diagnosis of incident heart failure.
Results: Among the 393 adults diagnosed with incident heart failure, 213 (54.2%) were female, 339 (86.3%) were white, and the mean (SD) age was 78.7 (6.0) years. Alcohol consumption after diagnosis was reported in 129 (32.8%) of the participants. Across alcohol consumption categories of long-term abstainers, former drinkers, consumers of 1-7 drinks weekly and consumers of more than 7 drinks weekly, the percentage of men (32.1%, 49.0%, 58.0%, and 82.4%, respectively; P < .001 for trend), white individuals (78.0%, 92.7%, 92.0%, and 94.1%, respectively, P <. 001 for trend), and high-income participants (22.0%, 43.8%, 47.3%, and 64.7%, respectively; P < .001 for trend) increased with increasing alcohol consumption. Across the 4 categories, participants who consumed more alcohol had more years of education (mean, 12 years [interquartile range (IQR), 8.0-10.0 years], 12 years [IQR, 11.0-14.0 years], 13 years [IQR, 12.0-15.0 years], and 13 years [IQR, 12.0-14.0 years]; P < .001 for trend). Diabetes was less common across the alcohol consumption categories (32.1%, 26.0%, 22.3%, and 5.9%, respectively; P = .01 for trend). Across alcohol consumption categories, there were fewer never smokers (58.3%, 44.8%, 35.7%, and 29.4%, respectively; P < .001 for trend) and more former smokers (34.5%, 38.5%, 50.0%, and 52.9%, respectively; P = .006 for trend). After controlling for other factors, consumption of 7 or fewer alcoholic drinks per week was associated with additional mean survival of 383 days (95% CI, 17-748 days; P = .04) compared with abstinence from alcohol. Although the robustness was limited by the small number of individuals who consumed more than 7 drinks per week, a significant inverted U-shaped association between alcohol consumption and survival was observed. Multivariable model estimates of mean time from heart failure diagnosis to death were 2640 days (95% CI, 1967-3313 days) for never drinkers, 3046 days (95% CI, 2372-3719 days) for consumers of 0 to 7 drinks per week, and 2806 (95% CI, 1879-3734 days) for consumers of more than 7 drinks per week (P = .02). Consumption of 10 drinks per week was associated with the longest survival, a mean of 3381 days (95% CI, 2806-3956 days) after heart failure diagnosis.
Conclusions and Relevance: These findings suggest that limited alcohol consumption among older adults with incident heart failure is associated with survival benefit compared with long-term abstinence. These findings suggest that older adults who develop heart failure may not need to abstain from moderate levels of alcohol consumption.
1 aSadhu, Justin, S1 aNovak, Eric1 aMukamal, Kenneth, J1 aKizer, Jorge, R1 aPsaty, Bruce, M1 aStein, Phyllis, K1 aBrown, David, L uhttps://chs-nhlbi.org/node/798304686nas a2200541 4500008004100000022001400041245011900055210006900174260001600243520308900259100002303348700001903371700003003390700002203420700002203442700002003464700002203484700002303506700001803529700002103547700002103568700001503589700002003604700002303624700002103647700002103668700001903689700001503708700002703723700002003750700002003770700002103790700002003811700002403831700001903855700002103874700002203895700002203917700002003939700001703959700002503976700002204001700001904023700002404042700002204066700002004088856003604108 2018 eng d a2380-659100aAssociation of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction.0 aAssociation of Cardiovascular Biomarkers With Incident Heart Fai c2018 Jan 103 aImportance: Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood.
Objective: To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population.
Design, Setting, and Participants: This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017.
Exposures: The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6.
Main Outcomes and Measures: Development of incident HFpEF and incident HFrEF.
Results: Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF.
Conclusions and Relevance: Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.
1 ade Boer, Rudolf, A1 aNayor, Matthew1 adeFilippi, Christopher, R1 aEnserro, Danielle1 aBhambhani, Vijeta1 aKizer, Jorge, R1 aBlaha, Michael, J1 aBrouwers, Frank, P1 aCushman, Mary1 aLima, João, A C1 aBahrami, Hossein1 aHarst, Pim1 aWang, Thomas, J1 aGansevoort, Ron, T1 aFox, Caroline, S1 aGaggin, Hanna, K1 aKop, Willem, J1 aLiu, Kiang1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aLee, Douglas, S1 aHillege, Hans, L1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aChan, Cheeling1 aAllison, Matthew1 aGardin, Julius, M1 aJanuzzi, James, L1 aShah, Sanjiv, J1 aLevy, Daniel1 aHerrington, David, M1 aLarson, Martin, G1 aGilst, Wiek, H1 aGottdiener, John, S1 aBertoni, Alain, G1 aHo, Jennifer, E uhttps://chs-nhlbi.org/node/760303200nas a2200493 4500008004100000022001400041245009000055210006900145260001300214300001200227490000600239520182400245100001702069700002302086700002002109700002202129700001802151700001902169700002002188700001502208700002202223700002302245700002202268700002102290700001202311700001902323700001802342700002002360700002102380700001902401700002002420700002302440700002702463700002202490700002002512700001502532700001702547700001902564700002002583700002302603700002402626700002002650856003602670 2018 eng d a2213-178700aThe Association of Obesity and Cardiometabolic Traits With Incident HFpEF and HFrEF.0 aAssociation of Obesity and Cardiometabolic Traits With Incident c2018 Aug a701-7090 v63 aOBJECTIVES: This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences in HF subtype, we examined men and women separately.
BACKGROUND: Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear.
METHODS: We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction ≥50% vs. <50%). We evaluated the association of body mass index (BMI) and cardiometabolic traits with incident HF subtype using Cox models.
RESULTS: The mean age was 60 ± 13 years, and 53% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio [HR]: 1.34 per 1-SD increase in BMI; 95% confidence interval [CI]: 1.24 to 1.45 vs. HR: 1.18; 95% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95% CI: 0.88 to 1.11; p < 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF = 0.01) when compared with men (p = 0.34).
CONCLUSIONS: Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among women and may underlie sex differences in HF subtypes.
1 aSavji, Nazir1 aMeijers, Wouter, C1 aBartz, Traci, M1 aBhambhani, Vijeta1 aCushman, Mary1 aNayor, Matthew1 aKizer, Jorge, R1 aSarma, Amy1 aBlaha, Michael, J1 aGansevoort, Ron, T1 aGardin, Julius, M1 aHillege, Hans, L1 aJi, Fei1 aKop, Willem, J1 aLau, Emily, S1 aLee, Douglas, S1 aSadreyev, Ruslan1 aGilst, Wiek, H1 aWang, Thomas, J1 aZanni, Markella, V1 aVasan, Ramachandran, S1 aAllen, Norrina, B1 aPsaty, Bruce, M1 aHarst, Pim1 aLevy, Daniel1 aLarson, Martin1 aShah, Sanjiv, J1 ade Boer, Rudolf, A1 aGottdiener, John, S1 aHo, Jennifer, E uhttps://chs-nhlbi.org/node/781203103nas a2200289 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520222800253100001802481700002002499700002602519700001902545700002102564700002302585700002202608700003002630700002602660700002302686700002402709700002402733700002002757856003602777 2018 eng d a1524-462800aAtrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study).0 aAtrial Cardiopathy and the Risk of Ischemic Stroke in the CHS Ca c2018 Apr a980-9860 v493 aBACKGROUND AND PURPOSE: Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke.
METHODS: The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V, left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors.
RESULTS: Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V (hazard ratio per 1000 μV*ms 1.04; 95% confidence interval, 1.001-1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT-proBNP, 1.09; 95% confidence interval, 1.03-1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67-2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84-1.10).
CONCLUSIONS: In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease.
1 aKamel, Hooman1 aBartz, Traci, M1 aElkind, Mitchell, S V1 aOkin, Peter, M1 aThacker, Evan, L1 aPatton, Kristen, K1 aStein, Phyllis, K1 adeFilippi, Christopher, R1 aGottesman, Rebecca, F1 aHeckbert, Susan, R1 aKronmal, Richard, A1 aSoliman, Elsayed, Z1 aLongstreth, W T uhttps://chs-nhlbi.org/node/768202652nas a2200265 4500008004100000022001400041245010600055210006900161260001600230300001200246490000600258520184300264100002402107700002202131700002202153700002202175700002202197700001902219700001902238700002402257700002402281700002002305700002502325856003602350 2018 eng d a2047-998000aCirculating Very Long-Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study.0 aCirculating Very LongChain Saturated Fatty Acids and Heart Failu c2018 Nov 06 ae0100190 v73 aBackground Circulating very-long-chain saturated fatty acids ( VLSFAs ) are integrated biomarkers of diet and metabolism that may point to new risk pathways and potential targets for heart failure ( HF ) prevention. The associations of VLSFA to HF in humans are not known. Methods and Results Using a cohort study design, we studied the associations of serially measured plasma phospholipid VLSFA with incident HF in the Cardiovascular Health Study. We investigated the associations of time-varying levels of the 3 major circulating VLSFAs , lignoceric acid (24:0), behenic acid (22:0), and arachidic acid (20:0), with the risk of incident HF using Cox regression. During 45030 person-years among 4249 participants, we identified 1304 cases of incident HF , including 489 with preserved and 310 with reduced ejection fraction. Adjusting for major HF risk factors and other circulating fatty acids, higher levels of each VLSFAs were associated with lower risk of incident HF ( P trend≤0.0007 each). The hazard ratio comparing the highest quintile to the lowest quintile was 0.67 (95% confidence interval, 0.55-0.81) for 24:0, 0.72 (95% confidence interval, 0.60-0.87) for 22:0 and 0.72 (95% confidence interval, 0.59-0.88) for 20:0. The associations were similar in subgroups defined by sex, age, body mass index, coronary heart disease, and diabetes mellitus. Among those with ejection fraction data, the associations appeared similar for those with preserved and with reduced ejection fraction. Conclusions Higher levels of circulating VLSFAs are associated with lower risk of incident HF in older adults. These novel associations should prompt further research on the role of VLSFA in HF , including relevant new risk pathways. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00005133.
1 aLemaitre, Rozenn, N1 aMcKnight, Barbara1 aSotoodehnia, Nona1 aFretts, Amanda, M1 aQureshi, Waqas, T1 aSong, Xiaoling1 aKing, Irena, B1 aSitlani, Colleen, M1 aSiscovick, David, S1 aPsaty, Bruce, M1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/791905196nas a2201345 4500008004100000022001400041245009400055210006900149260001300218300001200231490000700243520143500250100001901685700002401704700002101728700002501749700002101774700002301795700002101818700001701839700001801856700003001874700002001904700001801924700001801942700002001960700002801980700002102008700001802029700001902047700002202066700002802088700001302116700002202129700002202151700001202173700001902185700002402204700002102228700001902249700001802268700002402286700002002310700001702330700002202347700002202369700001902391700002102410700002402431700001702455700001602472700001902488700002202507700002702529700002402556700002202580700002402602700002002626700002602646700002202672700002302694700001902717700002102736700001602757700002302773700002402796700001302820700001702833700002002850700002202870700002202892700002902914700002002943700002602963700002402989700002203013700002503035700002003060700001903080700002203099700001803121700001703139700002103156700002403177700002103201700001703222700002003239700002303259700002403282700001903306700002403325700002003349700002303369700002403392700002103416700002203437700001903459700001903478700001903497700001503516700002303531700001903554700002303573700002203596700001803618700002003636700002703656700002403683700002203707700002103729700002403750700002203774700001803796856003603814 2018 eng d a2574-830000aCommon and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.0 aCommon and Rare Coding Genetic Variation Underlying the Electroc c2018 May ae0020370 v113 aBACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.
METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.
RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.
CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
1 aLin, Honghuang1 avan Setten, Jessica1 aSmith, Albert, V1 aBihlmeyer, Nathan, A1 aWarren, Helen, R1 aBrody, Jennifer, A1 aRadmanesh, Farid1 aHall, Leanne1 aGrarup, Niels1 aMüller-Nurasyid, Martina1 aBoutin, Thibaud1 aVerweij, Niek1 aLin, Henry, J1 aLi-Gao, Ruifang1 avan den Berg, Marten, E1 aMarten, Jonathan1 aWeiss, Stefan1 aPrins, Bram, P1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aMei, Hao1 aHarris, Tamara, B1 aLauner, Lenore, J1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aConnell, John, M1 aHuang, Paul, L1 aWeng, Lu-Chen1 aJameson, Heather, S1 aHucker, William1 aHanley, Alan1 aTucker, Nathan, R1 aChen, Yii-Der Ida1 aBis, Joshua, C1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aKors, Jan, A1 aXie, Zhijun1 aWen, Chengping1 aMagnani, Jared, W1 aNelson, Christopher, P1 aKanters, Jørgen, K1 aSinner, Moritz, F1 aStrauch, Konstantin1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aBork-Jensen, Jette1 aPedersen, Oluf1 aLinneberg, Allan1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aYao, Jie1 aGuo, Xiuqing1 aTaylor, Kent, D1 aSotoodehnia, Nona1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aEijgelsheim, Mark1 aPadmanabhan, Sandosh1 aSmith, Blair, H1 aVölzke, Henry1 aFelix, Stephan, B1 aHomuth, Georg1 aVölker, Uwe1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aKähönen, Mika1 aRaitakari, Olli, T1 aGudnason, Vilmundur1 aArking, Dan, E1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aBenjamin, Emelia, J1 aRosand, Jonathan1 aSamani, Nilesh, J1 aHansen, Torben1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aJukema, Wouter1 aStricker, Bruno, H1 aHayward, Caroline1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aWilson, James, G1 aEllinor, Patrick, T1 aLubitz, Steven, A1 aIsaacs, Aaron uhttps://chs-nhlbi.org/node/780103950nas a2200685 4500008004100000022001400041245009900055210006900154260001300223300001200236490000700248520197400255100002002229700002302249700001902272700002302291700001702314700001902331700002102350700002202371700002202393700001802415700002402433700001902457700001302476700002202489700002102511700001902532700002302551700002402574700001902598700002402617700002502641700001902666700002902685700001802714700002302732700002602755700001902781700002102800700003002821700002202851700002602873700002302899700002302922700002402945700001702969700002202986700002403008700002203032700002503054700002103079700002003100700002003120700002103140700002103161700002203182700002403204856003603228 2018 eng d a2574-830000aCommon Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction.0 aCommon Coding Variants in Are Associated With the Nav18 Late Cur c2018 May ae0016630 v113 aBACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.
METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.
RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( ≥0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, =0.03, and I962V+V1073A, 22.4±0.8%, =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, =0.03).
CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.
1 aMacri, Vincenzo1 aBrody, Jennifer, A1 aArking, Dan, E1 aHucker, William, J1 aYin, Xiaoyan1 aLin, Honghuang1 aMills, Robert, W1 aSinner, Moritz, F1 aLubitz, Steven, A1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aAlonso, Alvaro1 aLi, Ning1 aFedorov, Vadim, V1 aJanssen, Paul, M1 aBis, Joshua, C1 aHeckbert, Susan, R1 aDolmatova, Elena, V1 aLumley, Thomas1 aSitlani, Colleen, M1 aCupples, Adrienne, L1 aPulit, Sara, L1 aNewton-Cheh, Christopher1 aBarnard, John1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aChung, Mina, K1 aVlahakes, Gus, J1 aO'Donnell, Christopher, J1 aRotter, Jerome, I1 aMargulies, Kenneth, B1 aMorley, Michael, P1 aCappola, Thomas, P1 aBenjamin, Emelia, J1 aMuzny, Donna1 aGibbs, Richard, A1 aJackson, Rebecca, D1 aMagnani, Jared, W1 aHerndon, Caroline, N1 aRich, Stephen, S1 aPsaty, Bruce, M1 aMilan, David, J1 aBoerwinkle, Eric1 aMohler, Peter, J1 aSotoodehnia, Nona1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/780200593nas a2200193 4500008004100000022001400041245008200055210006900137260001500206300001200221490000800233653001100241653002300252653002400275100002000299700002100319700002300340856003600363 2018 eng d a1538-359800aComparison of 2 Treatment Models: Precision Medicine and Preventive Medicine.0 aComparison of 2 Treatment Models Precision Medicine and Preventi c2018 08 28 a751-7520 v32010aHumans10aPrecision Medicine10aPreventive Medicine1 aPsaty, Bruce, M1 aDekkers, Olaf, M1 aCooper, Richard, S uhttps://chs-nhlbi.org/node/780804206nas a2200889 4500008004100000022001400041245008500055210006900140260001600209520162400225100002001849700002501869700002501894700002901919700002301948700003001971700001502001700002202016700001502038700002002053700002102073700002202094700001902116700001702135700002202152700002102174700001902195700002202214700001802236700002202254700002302276700002202299700002602321700001702347700001802364700001202382700002302394700002102417700001802438700001902456700002002475700002202495700002202517700002402539700002302563700003002586700002002616700002402636700002402660700002802684700001902712700002502731700002502756700002002781700002402801700002702825700002202852700002702874700002402901700002202925700002002947700001802967700002002985700002303005700001803028700002303046700002203069700001903091700001903110700001903129700002003148700002403168700001903192700002203211710004703233856003603280 2018 eng d a1522-964500aA comprehensive evaluation of the genetic architecture of sudden cardiac arrest.0 acomprehensive evaluation of the genetic architecture of sudden c c2018 Aug 283 aAims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.
Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.
Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.
1 aAshar, Foram, N1 aMitchell, Rebecca, N1 aAlbert, Christine, M1 aNewton-Cheh, Christopher1 aBrody, Jennifer, A1 aMüller-Nurasyid, Martina1 aMoes, Anna1 aMeitinger, Thomas1 aMak, Angel1 aHuikuri, Heikki1 aJunttila, Juhani1 aGoyette, Philippe1 aPulit, Sara, L1 aPazoki, Raha1 aTanck, Michael, W1 aBlom, Marieke, T1 aZhao, XiaoQing1 aHavulinna, Aki, S1 aJabbari, Reza1 aGlinge, Charlotte1 aTragante, Vinicius1 aEscher, Stefan, A1 aChakravarti, Aravinda1 aEhret, Georg1 aCoresh, Josef1 aLi, Man1 aPrineas, Ronald, J1 aFranco, Oscar, H1 aKwok, Pui-Yan1 aLumley, Thomas1 aDumas, Florence1 aMcKnight, Barbara1 aRotter, Jerome, I1 aLemaitre, Rozenn, N1 aHeckbert, Susan, R1 aO'Donnell, Christopher, J1 aHwang, Shih-Jen1 aTardif, Jean-Claude1 aVanDenburgh, Martin1 aUitterlinden, André, G1 aHofman, Albert1 aStricker, Bruno, H C1 ade Bakker, Paul, I W1 aFranks, Paul, W1 aJansson, Jan-Håkan1 aAsselbergs, Folkert, W1 aHalushka, Marc, K1 aMaleszewski, Joseph, J1 aTfelt-Hansen, Jacob1 aEngstrøm, Thomas1 aSalomaa, Veikko1 aVirmani, Renu1 aKolodgie, Frank1 aWilde, Arthur, A M1 aTan, Hanno, L1 aBezzina, Connie, R1 aEijgelsheim, Mark1 aRioux, John, D1 aJouven, Xavier1 aKääb, Stefan1 aPsaty, Bruce, M1 aSiscovick, David, S1 aArking, Dan, E1 aSotoodehnia, Nona1 aSCD working group of the CHARGE Consortium uhttps://chs-nhlbi.org/node/777804088nas a2201045 4500008004100000245012800041210006900169260000700238300001400245490000700259520133900266100001401605700001301619700002501632700001301657700001601670700001201686700002501698700001901723700001801742700001701760700001401777700001801791700001601809700001401825700002101839700002701860700001601887700001601903700001701919700001901936700001601955700002401971700002001995700002302015700001602038700001702054700001802071700002202089700001602111700001802127700001802145700001702163700001902180700001802199700002202217700002102239700001702260700001502277700001902292700001802311700002202329700001702351700001902368700002002387700001702407700001802424700001602442700002002458700001702478700001502495700002502510700002502535700001602560700001702576700001902593700001602612700001802628700001802646700001602664700002002680700001302700700001902713700002002732700002402752700002102776700001902797700001902816700001502835700001302850700001602863700001902879700002002898700001502918700002002933700002502953700001702978700001102995856003603006 2018 eng d00a{Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies0 aDairy Consumption and Body Mass Index Among Adults Mendelian Ran c01 a183–1910 v643 aAssociations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined.\ We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies.\ Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00-0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14-0.25) serving/day higher dairy intake (P = 3.15 × 10-12) and 0.12 (95% CI, 0.06-0.17) kg/m2 higher BMI (P = 2.11 × 10-5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27-0.92; P = 3.0 × 10-4).\ The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.1 aHuang, T.1 aDing, M.1 aBergholdt, H., K. M.1 aWang, T.1 aHeianza, Y.1 aSun, D.1 aFrazier-Wood, A., C.1 aAslibekyan, S.1 aNorth, K., E.1 aVoortman, T.1 aGraff, M.1 aSmith, C., E.1 aLai, C., Q.1 aVarbo, A.1 aLemaitre, R., N.1 ade Jonge, M., E. A. L.1 aFumeron, F.1 aCorella, D.1 aWang, C., A.1 aTj?nneland, A.1 aOvervad, K.1 aS?rensen, T., I. A.1 aFeitosa, M., F.1 aWojczynski, M., K.1 aK?h?nen, M.1 aRenstr?m, F.1 aPsaty, B., M.1 aSiscovick, D., S.1 aBarroso, I.1 aJohansson, I.1 aHernandez, D.1 aFerrucci, L.1 aBandinelli, S.1 aLinneberg, A.1 aZillikens, M., C.1 aSandholt, C., H.1 aPedersen, O.1 aHansen, T.1 aSchulz, C., A.1 aSonestedt, E.1 aOrho-Melander, M.1 aChen, T., A.1 aRotter, J., I.1 aAllison, M., A.1 aRich, S., S.1 aSorl?, J., V.1 aColtell, O.1 aPennell, C., E.1 aEastwood, P.1 aHofman, A.1 aUitterlinden, A., G.1 avan Rooij, F., J. A.1 aChu, A., Y.1 aRose, L., M.1 aRidker, P., M.1 aViikari, J.1 aRaitakari, O.1 aLehtim?ki, T.1 aMikkil?, V.1 aWillett, W., C.1 aWang, Y.1 aTucker, K., L.1 aOrdovas, J., M.1 aKilpel?inen, T., O.1 aProvince, M., A.1 aFranks, P., W.1 aArnett, D., K.1 aTanaka, T.1 aToft, U.1 aEricson, U.1 aFranco, O., H.1 aMozaffarian, D.1 aHu, F., B.1 aChasman, D., I.1 aNordestgaard, B., G.1 aEllervik, C.1 aQi, L. uhttps://chs-nhlbi.org/node/853603689nas a2200553 4500008004100000022001400041245023400055210006900289260001600358300001400374490000700388520195100395100002602346700002102372700001602393700002202409700002002431700001902451700001902470700002502489700002202514700002802536700002302564700002902587700001902616700002102635700001802656700001302674700001902687700002502706700002402731700003002755700001902785700002102804700002102825700001802846700002302864700001602887700002202903700002302925700002002948700001902968700001902987700002703006700001903033700002303052700002403075856003603099 2018 eng d a1460-208300aDiscovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.0 aDiscovery finemapping and conditional analyses of genetic varian c2018 Aug 15 a2940-29530 v273 aC-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.
1 aKocarnik, Jonathan, M1 aRichard, Melissa1 aGraff, Misa1 aHaessler, Jeffrey1 aBien, Stephanie1 aCarlson, Chris1 aCarty, Cara, L1 aReiner, Alexander, P1 aAvery, Christy, L1 aBallantyne, Christie, M1 aLaCroix, Andrea, Z1 aAssimes, Themistocles, L1 aBarbalic, Maja1 aPankratz, Nathan1 aTang, Weihong1 aTao, Ran1 aChen, Dongquan1 aTalavera, Gregory, A1 aDaviglus, Martha, L1 aChirinos-Medina, Diana, A1 aPereira, Rocio1 aNishimura, Katie1 aBůzková, Petra1 aBest, Lyle, G1 aAmbite, Jose, Luis1 aCheng, Iona1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aFornage, Myriam1 aHeiss, Gerardo1 aNorth, Kari, E1 aHaiman, Christopher, A1 aPeters, Ulrike1 aLe Marchand, Loïc1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/779803942nas a2200757 4500008004100000022001400041245010600055210006900161260001600230520175200246100002801998700002502026700001702051700002002068700002202088700001602110700001702126700002302143700002102166700001202187700002502199700002202224700002602246700002202272700001602294700002102310700002102331700003002352700001702382700001602399700001702415700002102432700003202453700001802485700002402503700002102527700002202548700002202570700001702592700002002609700002102629700002202650700002302672700002102695700001802716700001402734700001802748700002402766700002602790700002802816700002102844700001802865700002802883700002102911700002302932700001902955700002902974700001903003700001903022700002303041700001903064700002203083700002303105700002003128856003603148 2018 eng d a1528-002000aDNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis.0 aDNA methylation age is associated with an altered hemostatic pro c2018 Jul 243 aMany hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.
1 aWard-Caviness, Cavin, K1 aHuffman, Jennifer, E1 aEvertt, Karl1 aGermain, Marine1 avan Dongen, Jenny1 aHill, David1 aJhun, Min, A1 aBrody, Jennifer, A1 aGhanbari, Mohsen1 aDu, Lei1 aRoetker, Nicholas, S1 ade Vries, Paul, S1 aWaldenberger, Melanie1 aGieger, Christian1 aWolf, Petra1 aProkisch, Holger1 aKoenig, Wolfgang1 aO'Donnell, Christopher, J1 aLevy, Daniel1 aLiu, Chunyu1 aTruong, Vinh1 aWells, Philip, S1 aTrégouët, David-Alexandre1 aTang, Weihong1 aMorrison, Alanna, C1 aBoerwinkle, Eric1 aWiggins, Kerri, L1 aMcKnight, Barbara1 aGuo, Xiuqing1 aPsaty, Bruce, M1 aSotoodenia, Nona1 aBoomsa, Dorret, I1 aWillemsen, Gonneke1 aLigthart, Lannie1 aDeary, Ian, J1 aZhao, Wei1 aWare, Erin, B1 aKardia, Sharon, L R1 avan Meurs, Joyce, B J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aEriksson, Per1 aFranco-Cereceda, Anders1 aPankow, James, S1 aJohnson, Andrew, D1 aGagnon, France1 aMorange, Pierre-Emmanuel1 aGeus, Eco, J C1 aStarr, John, M1 aSmith, Jennifer, A1 aDehghan, Abbas1 aBjörck, Hanna, M1 aSmith, Nicholas, L1 aPeters, Annette uhttps://chs-nhlbi.org/node/781605662nas a2201321 4500008004100000022001400041245015200055210006900207260001600276520185700292100001902149700002102168700001702189700001902206700001802225700001502243700002102258700001902279700001902298700002202317700002202339700001802361700001802379700002402397700001802421700002202439700002002461700001902481700002802500700002202528700002102550700002102571700002302592700002302615700001402638700002402652700002202676700002202698700001902720700001802739700003102757700002202788700002002810700002202830700002302852700002202875700003002897700002002927700002102947700002402968700002302992700001903015700002503034700002503059700002403084700002203108700002003130700001603150700002203166700002303188700002403211700002303235700002203258700002203280700001803302700002203320700001903342700001903361700001903380700002103399700003503420700001903455700002203474700001603496700002003512700002003532700002103552700002003573700002603593700002003619700001703639700002303656700001903679700002103698700002103719700002003740700002103760700002303781700002003804700001903824700002503843700002003868700002103888700001903909700002903928700002503957700001603982700001703998700002204015700001904037700001804056700002004074700001904094700001704113700002004130700001904150700002504169700002304194700001704217700003004234710004004264856003604304 2018 eng d a1522-964500aEqualization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.0 aEqualization of four cardiovascular risk algorithms after system c2018 Nov 223 aAims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.
Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.
Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
1 aPennells, Lisa1 aKaptoge, Stephen1 aWood, Angela1 aSweeting, Mike1 aZhao, Xiaohui1 aWhite, Ian1 aBurgess, Stephen1 aWilleit, Peter1 aBolton, Thomas1 aMoons, Karel, G M1 aSchouw, Yvonne, T1 aSelmer, Randi1 aKhaw, Kay-Tee1 aGudnason, Vilmundur1 aAssmann, Gerd1 aAmouyel, Philippe1 aSalomaa, Veikko1 aKivimaki, Mika1 aNordestgaard, Børge, G1 aBlaha, Michael, J1 aKuller, Lewis, H1 aBrenner, Hermann1 aGillum, Richard, F1 aMeisinger, Christa1 aFord, Ian1 aKnuiman, Matthew, W1 aRosengren, Annika1 aLawlor, Debbie, A1 aVölzke, Henry1 aCooper, Cyrus1 aIbañez, Alejandro, Marín1 aCasiglia, Edoardo1 aKauhanen, Jussi1 aCooper, Jackie, A1 aRodriguez, Beatriz1 aSundström, Johan1 aBarrett-Connor, Elizabeth1 aDankner, Rachel1 aNietert, Paul, J1 aDavidson, Karina, W1 aWallace, Robert, B1 aBlazer, Dan, G1 aBjörkelund, Cecilia1 aDonfrancesco, Chiara1 aKrumholz, Harlan, M1 aNissinen, Aulikki1 aDavis, Barry, R1 aCoady, Sean1 aWhincup, Peter, H1 aJørgensen, Torben1 aDucimetiere, Pierre1 aTrevisan, Maurizio1 aEngström, Gunnar1 aCrespo, Carlos, J1 aMeade, Tom, W1 aVisser, Marjolein1 aKromhout, Daan1 aKiechl, Stefan1 aDaimon, Makoto1 aPrice, Jackie, F1 ade la Cámara, Agustin, Gómez1 aJukema, Wouter1 aLamarche, Benoît1 aOnat, Altan1 aSimons, Leon, A1 aKavousi, Maryam1 aBen-Shlomo, Yoav1 aGallacher, John1 aDekker, Jacqueline, M1 aArima, Hisatomi1 aShara, Nawar1 aTipping, Robert, W1 aRoussel, Ronan1 aBrunner, Eric, J1 aKoenig, Wolfgang1 aSakurai, Masaru1 aPavlovic, Jelena1 aGansevoort, Ron, T1 aNagel, Dorothea1 aGoldbourt, Uri1 aBarr, Elizabeth, L M1 aPalmieri, Luigi1 aNjølstad, Inger1 aSato, Shinichi1 aVerschuren, W, M Monique1 aVarghese, Cherian, V1 aGraham, Ian1 aOnuma, Oyere1 aGreenland, Philip1 aWoodward, Mark1 aEzzati, Majid1 aPsaty, Bruce, M1 aSattar, Naveed1 aJackson, Rod1 aRidker, Paul, M1 aCook, Nancy, R1 aD'Agostino, Ralph, B1 aThompson, Simon, G1 aDanesh, John1 aDi Angelantonio, Emanuele1 aEmerging Risk Factors Collaboration uhttps://chs-nhlbi.org/node/792305244nas a2201057 4500008004100000022001400041245014200055210006900197260001600266520216400282100001702446700002602463700002102489700002402510700001902534700002302553700001802576700001802594700001702612700002502629700002102654700001902675700002202694700001302716700002202729700001402751700002302765700001802788700001902806700002002825700002402845700001802869700002202887700001602909700002102925700002402946700002402970700001902994700002303013700002603036700001903062700002403081700002203105700002303127700001803150700003703168700001903205700002103224700002003245700002103265700002003286700001603306700002403322700001903346700002003365700002503385700002803410700002703438700002003465700002203485700002503507700002103532700002303553700002103576700002703597700002603624700001703650700002503667700002303692700002303715700002203738700002303760700002003783700002203803700002403825700002203849700002203871700002103893700001803914700002003932700002403952700002003976700002303996700001904019700002004038700002004058700002204078700002004100710003004120856003604150 2018 eng d a1524-462800aExome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.0 aExome Chip Analysis Identifies LowFrequency and Rare Variants in c2018 Jul 123 aBACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.
METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.
RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).
CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
1 aJian, Xueqiu1 aSatizabal, Claudia, L1 aSmith, Albert, V1 aWittfeld, Katharina1 aBis, Joshua, C1 aSmith, Jennifer, A1 aHsu, Fang-Chi1 aNho, Kwangsik1 aHofer, Edith1 aHagenaars, Saskia, P1 aNyquist, Paul, A1 aMishra, Aniket1 aAdams, Hieab, H H1 aLi, Shuo1 aTeumer, Alexander1 aZhao, Wei1 aFreedman, Barry, I1 aSaba, Yasaman1 aYanek, Lisa, R1 aChauhan, Ganesh1 avan Buchem, Mark, A1 aCushman, Mary1 aRoyle, Natalie, A1 aBryan, Nick1 aNiessen, Wiro, J1 aWindham, Beverly, G1 aDeStefano, Anita, L1 aHabes, Mohamad1 aHeckbert, Susan, R1 aPalmer, Nicholette, D1 aLewis, Cora, E1 aEiriksdottir, Gudny1 aMaillard, Pauline1 aMathias, Rasika, A1 aHomuth, Georg1 aValdés-Hernández, Maria, Del C1 aDivers, Jasmin1 aBeiser, Alexa, S1 aLangner, Sönke1 aRice, Kenneth, M1 aBastin, Mark, E1 aYang, Qiong1 aMaldjian, Joseph, A1 aStarr, John, M1 aSidney, Stephen1 aRisacher, Shannon, L1 aUitterlinden, André, G1 aGudnason, Vilmundur, G1 aNauck, Matthias1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aBoerwinkle, Eric1 aDuijn, Cornelia, M1 aMazoyer, Bernard1 avon Sarnowski, Bettina1 aGottesman, Rebecca, F1 aLevy, Daniel1 aSigurdsson, Sigurdur1 aVernooij, Meike, W1 aTurner, Stephen, T1 aSchmidt, Reinhold1 aWardlaw, Joanna, M1 aPsaty, Bruce, M1 aMosley, Thomas, H1 aDeCarli, Charles, S1 aSaykin, Andrew, J1 aBowden, Donald, W1 aBecker, Diane, M1 aDeary, Ian, J1 aSchmidt, Helena1 aKardia, Sharon, L R1 aIkram, Arfan, M1 aDebette, Stephanie1 aGrabe, Hans, J1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aFornage, Myriam1 aneuroCHARGE Working Group uhttps://chs-nhlbi.org/node/779605658nas a2201489 4500008004100000022001400041245010600055210006900161260001500230300000700245490000700252520146500259100001901724700002101743700002301764700002701787700001901814700002501833700002501858700002301883700002501906700002901931700002201960700002301982700001702005700001702022700001802039700002202057700002002079700002102099700001802120700002002138700001902158700001802177700002802195700002102223700001302244700003002257700001902287700002502306700002102331700001902352700002302371700002002394700002402414700002102438700001802459700002102477700001802498700001902516700002002535700002102555700002302576700002402599700002202623700002402645700001702669700002202686700002202708700002202730700002302752700001902775700001702794700002002811700001702831700002202848700002202870700001202892700002102904700002702925700001902952700001702971700002002988700001903008700002003027700002303047700002103070700002203091700002203113700002403135700002003159700002403179700002803203700001903231700002003250700002403270700002103294700002403315700001703339700001903356700002603375700002103401700001603422700002703438700001803465700002303483700002103506700002803527700002403555700001903579700001903598700002403617700002403641700002203665700001803687700002203705700002903727700002403756700003203780700002103812700001603833700002203849700002403871700002003895700001603915700002303931700001803954700002203972700002003994700001504014700002104029700002404050700001904074700001904093700002004112856003604132 2018 eng d a1474-760X00aExome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.0 aExomechip metaanalysis identifies novel loci associated with car c2018 07 17 a870 v193 aBACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.
RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.
CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
1 aPrins, Bram, P1 aMead, Timothy, J1 aBrody, Jennifer, A1 aSveinbjornsson, Gardar1 aNtalla, Ioanna1 aBihlmeyer, Nathan, A1 avan den Berg, Marten1 aBork-Jensen, Jette1 aCappellani, Stefania1 aVan Duijvenboden, Stefan1 aKlena, Nikolai, T1 aGabriel, George, C1 aLiu, Xiaoqin1 aGulec, Cagri1 aGrarup, Niels1 aHaessler, Jeffrey1 aHall, Leanne, M1 aIorio, Annamaria1 aIsaacs, Aaron1 aLi-Gao, Ruifang1 aLin, Honghuang1 aLiu, Ching-Ti1 aLyytikäinen, Leo-Pekka1 aMarten, Jonathan1 aMei, Hao1 aMüller-Nurasyid, Martina1 aOrini, Michele1 aPadmanabhan, Sandosh1 aRadmanesh, Farid1 aRamirez, Julia1 aRobino, Antonietta1 aSchwartz, Molly1 avan Setten, Jessica1 aSmith, Albert, V1 aVerweij, Niek1 aWarren, Helen, R1 aWeiss, Stefan1 aAlonso, Alvaro1 aArnar, David, O1 aBots, Michiel, L1 ade Boer, Rudolf, A1 aDominiczak, Anna, F1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aGuo, Xiuqing1 aFelix, Stephan, B1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHuang, Paul, L1 aJukema, J, W1 aKähönen, Mika1 aKors, Jan, A1 aLambiase, Pier, D1 aLauner, Lenore, J1 aLi, Man1 aLinneberg, Allan1 aNelson, Christopher, P1 aPedersen, Oluf1 aPerez, Marco1 aPeters, Annette1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRotter, Jerome, I1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Tim, D1 aStrauch, Konstantin1 aThorsteinsdottir, Unnur1 aTinker, Andrew1 aTrompet, Stella1 aUitterlinden, Andre1 aVaartjes, Ilonca1 avan der Meer, Peter1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWilson, James, G1 aXie, Zhijun1 aAsselbergs, Folkert, W1 aDörr, Marcus1 aDuijn, Cornelia, M1 aGasparini, Paolo1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHansen, Torben1 aKääb, Stefan1 aKanters, Jørgen, K1 aKooperberg, Charles1 aLehtimäki, Terho1 aLin, Henry, J1 aLubitz, Steven, A1 aMook-Kanamori, Dennis, O1 aConti, Francesco, J1 aNewton-Cheh, Christopher, H1 aRosand, Jonathan1 aRudan, Igor1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aSmith, Blair, H1 aHolm, Hilma1 aStricker, Bruno, H1 aUlivi, Sheila1 aSotoodehnia, Nona1 aApte, Suneel, S1 aHarst, Pim1 aStefansson, Kari1 aMunroe, Patricia, B1 aArking, Dan, E1 aLo, Cecilia, W1 aJamshidi, Yalda uhttps://chs-nhlbi.org/node/780905298nas a2201333 4500008004100000022001400041245011200055210006900167260001300236300001200249490000700261520154600268100002501814700002301839700002601862700002101888700001901909700001801928700001801946700002101964700002101985700002002006700001802026700001302044700003002057700002502087700001802112700001702130700001302147700002002160700002502180700001802205700001902223700002402242700002202266700002802288700001202316700001902328700002402347700001902371700001602390700002202406700002002428700002302448700002202471700002502493700002102518700001902539700001602558700002402574700001702598700002102615700002202636700002702658700002102685700002302706700001902729700001902748700002102767700002202788700002002810700002602830700002202856700002002878700001802898700001602916700002302932700002402955700001802979700002002997700002303017700002003040700001903060700001803079700002503097700002603122700002403148700001703172700001803189700001903207700002203226700002103248700002403269700002103293700001703314700002303331700002003354700001803374700002403392700002403416700002203440700002303462700003203485700002203517700002103539700002203560700002403582700002103606700001903627700001903646700001503665700002303680700002203703700002903725700002203754700001803776700002003794700002703814700002403841700002203865700001903887700002203906856003603928 2018 eng d a2574-830000aExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.0 aExomeChipWide Analysis of 95 626 Individuals Identifies 10 Novel c2018 Jan ae0017580 v113 aBACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.
METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.
CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
1 aBihlmeyer, Nathan, A1 aBrody, Jennifer, A1 aSmith, Albert, Vernon1 aWarren, Helen, R1 aLin, Honghuang1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aMarten, Jonathan1 aRadmanesh, Farid1 aHall, Leanne, M1 aGrarup, Niels1 aMei, Hao1 aMüller-Nurasyid, Martina1 aHuffman, Jennifer, E1 aVerweij, Niek1 aGuo, Xiuqing1 aYao, Jie1 aLi-Gao, Ruifang1 avan den Berg, Marten1 aWeiss, Stefan1 aPrins, Bram, P1 avan Setten, Jessica1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aBis, Joshua, C1 aAustin, Tom1 aChen, Yii-Der Ida1 aPsaty, Bruce, M1 aHarrris, Tamara, B1 aLauner, Lenore, J1 aPadmanabhan, Sandosh1 aDominiczak, Anna1 aHuang, Paul, L1 aXie, Zhijun1 aEllinor, Patrick, T1 aKors, Jan, A1 aCampbell, Archie1 aMurray, Alison, D1 aNelson, Christopher, P1 aTobin, Martin, D1 aBork-Jensen, Jette1 aHansen, Torben1 aPedersen, Oluf1 aLinneberg, Allan1 aSinner, Moritz, F1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aPerz, Siegfried1 aKolcic, Ivana1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aLin, Henry, J1 aTaylor, Kent, D1 ade Mutsert, Renée1 aTrompet, Stella1 aJukema, Wouter1 aMaan, Arie, C1 aStricker, Bruno, H C1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aVölker, Uwe1 aHomuth, Georg1 aVölzke, Henry1 aFelix, Stephan, B1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aRaitakari, Olli, T1 aKähönen, Mika1 aMononen, Nina1 aGudnason, Vilmundur1 aMunroe, Patricia, B1 aLubitz, Steven, A1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher, H1 aHayward, Caroline1 aRosand, Jonathan1 aSamani, Nilesh, J1 aKanters, Jørgen, K1 aWilson, James, G1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aEijgelsheim, Mark1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/778402617nas a2200301 4500008004100000022001400041245008000055210006900135260001200204300001200216490000700228520176700235653001502002653002302017653003202040653002002072653001302092653001102105653002702116653002402143653001702167100001902184700002002203700001702223700002102240700001802261856003602279 2018 eng d a1098-227200aFastSKAT: Sequence kernel association tests for very large sets of markers.0 aFastSKAT Sequence kernel association tests for very large sets o c2018 09 a516-5270 v423 aThe sequence kernel association test (SKAT) is widely used to test for associations between a phenotype and a set of genetic variants that are usually rare. Evaluating tail probabilities or quantiles of the null distribution for SKAT requires computing the eigenvalues of a matrix related to the genotype covariance between markers. Extracting the full set of eigenvalues of this matrix (an n×n matrix, for n subjects) has computational complexity proportional to n . As SKAT is often used when n104 , this step becomes a major bottleneck in its use in practice. We therefore propose fastSKAT, a new computationally inexpensive but accurate approximations to the tail probabilities, in which the k largest eigenvalues of a weighted genotype covariance matrix or the largest singular values of a weighted genotype matrix are extracted, and a single term based on the Satterthwaite approximation is used for the remaining eigenvalues. While the method is not particularly sensitive to the choice of k, we also describe how to choose its value, and show how fastSKAT can automatically alert users to the rare cases where the choice may affect results. As well as providing faster implementation of SKAT, the new method also enables entirely new applications of SKAT that were not possible before; we give examples grouping variants by topologically associating domains, and comparing chromosome-wide association by class of histone marker.
10aAlgorithms10aChromosomes, Human10aGenetic Association Studies10aGenetic Markers10aHistones10aHumans10aSequence Analysis, DNA10aStatistics as Topic10aTime Factors1 aLumley, Thomas1 aBrody, Jennifer1 aPeloso, Gina1 aMorrison, Alanna1 aRice, Kenneth uhttps://chs-nhlbi.org/node/792110328nas a2203505 4500008004100000022001400041245010900055210006900164260001300233300001400246490000700260520064200267100002500909700002100934700002600955700002000981700001701001700001201018700002301030700001601053700002401069700002101093700001801114700002201132700002501154700001701179700002501196700001601221700002801237700001601265700001501281700002101296700002301317700002001340700002201360700001601382700001801398700001701416700001901433700002001452700002301472700001401495700002301509700002701532700002101559700002001580700001601600700001801616700002101634700002701655700002301682700001501705700003301720700001501753700002301768700002701791700001801818700002101836700001901857700002201876700001801898700002301916700002101939700002001960700002001980700002202000700002102022700002102043700002102064700002202085700001902107700001602126700002202142700001602164700001902180700002202199700002602221700001902247700001902266700001802285700002102303700002102324700002102345700002302366700002402389700002102413700001802434700002102452700002002473700002602493700002202519700002002541700001902561700002402580700002102604700002402625700001702649700002402666700002002690700001802710700001802728700002602746700002902772700001802801700002002819700002002839700001902859700002502878700002102903700002302924700002102947700001902968700002102987700002603008700002203034700002103056700001503077700001703092700002403109700001703133700002003150700002003170700002203190700002103212700002603233700002203259700002103281700001703302700001903319700002403338700002503362700002003387700002003407700001603427700001703443700002703460700001903487700001903506700002303525700002003548700002203568700001903590700001603609700002003625700002203645700002403667700001803691700001603709700001903725700001803744700002203762700002003784700002303804700002103827700001603848700001803864700002203882700002003904700002203924700002403946700001203970700001503982700002503997700001704022700002004039700002004059700001804079700002804097700002004125700002904145700002004174700002104194700002104215700001704236700002204253700002404275700002104299700001904320700002504339700002704364700002004391700001904411700001904430700002904449700001904478700002204497700001404519700002504533700001904558700001904577700001904596700002704615700001904642700002004661700001904681700002604700700002304726700002304749700001604772700001904788700001804807700002004825700002004845700002204865700002004887700002304907700001904930700002204949700001604971700002204987700001805009700002005027700002005047700002205067700002305089700002205112700002005134700001705154700002105171700002105192700002005213700001705233700002105250700001905271700002005290700002305310700002505333700002205358700002205380700002005402700002205422700002105444700002405465700002105489700002105510700002005531700002305551700002405574700002805598700001605626700002705642700002305669700002605692700002605718700002205744700001705766700002405783700002205807700001805829700001905847700002305866700002105889700002005910700001305930700002205943700001805965700001905983700002506002700002306027700001706050700002106067700001706088700002206105700002406127700001906151700002306170700002406193700001906217700002906236700002306265700001806288700002106306700002106327700001706348700002006365700001506385700002506400700002406425700001706449700002406466700002906490700002106519700002106540700002106561700003006582700002106612700002006633700002106653700002306674700002006697700001806717700002306735710002806758856003606786 2018 eng d a1546-171800aGenetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.0 aGenetic analysis of over 1 million people identifies 535 new loc c2018 Oct a1412-14250 v503 aHigh blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
1 aEvangelou, Evangelos1 aWarren, Helen, R1 aMosen-Ansorena, David1 aMifsud, Borbala1 aPazoki, Raha1 aGao, He1 aNtritsos, Georgios1 aDimou, Niki1 aCabrera, Claudia, P1 aKaraman, Ibrahim1 aNg, Fu, Liang1 aEvangelou, Marina1 aWitkowska, Katarzyna1 aTzanis, Evan1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aEdwards, Digna, R Velez1 aSun, Yan, V1 aCho, Kelly1 aGaziano, Michael1 aWilson, Peter, W F1 aTsao, Philip, S1 aKovesdy, Csaba, P1 aEsko, Tõnu1 aMägi, Reedik1 aMilani, Lili1 aAlmgren, Peter1 aBoutin, Thibaud1 aDebette, Stephanie1 aDing, Jun1 aGiulianini, Franco1 aHolliday, Elizabeth, G1 aJackson, Anne, U1 aLi-Gao, Ruifang1 aLin, Wei-Yu1 aLuan, Jian'an1 aMangino, Massimo1 aOldmeadow, Christopher1 aPrins, Bram, Peter1 aQian, Yong1 aSargurupremraj, Muralidharan1 aShah, Nabi1 aSurendran, Praveen1 aThériault, Sébastien1 aVerweij, Niek1 aWillems, Sara, M1 aZhao, Jing-Hua1 aAmouyel, Philippe1 aConnell, John1 ade Mutsert, Renée1 aDoney, Alex, S F1 aFarrall, Martin1 aMenni, Cristina1 aMorris, Andrew, D1 aNoordam, Raymond1 aParé, Guillaume1 aPoulter, Neil, R1 aShields, Denis, C1 aStanton, Alice1 aThom, Simon1 aAbecasis, Goncalo1 aAmin, Najaf1 aArking, Dan, E1 aAyers, Kristin, L1 aBarbieri, Caterina, M1 aBatini, Chiara1 aBis, Joshua, C1 aBlake, Tineka1 aBochud, Murielle1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrumat, Marco1 aCampbell, Archie1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChauhan, Ganesh1 aCiullo, Marina1 aCocca, Massimiliano1 aCollins, Francis1 aCordell, Heather, J1 aDavies, Gail1 ade Borst, Martin, H1 ade Geus, Eco, J1 aDeary, Ian, J1 aDeelen, Joris1 aM, Fabiola, del Greco1 aDemirkale, Cumhur, Yusuf1 aDörr, Marcus1 aEhret, Georg, B1 aElosua, Roberto1 aEnroth, Stefan1 aErzurumluoglu, Mesut1 aFerreira, Teresa1 aFrånberg, Mattias1 aFranco, Oscar, H1 aGandin, Ilaria1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGoel, Anuj1 aGow, Alan, J1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHarris, Sarah, E1 aHartman, Catharina, A1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHofer, Edith1 aHofman, Albert1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aIngelsson, Erik1 aJames, Alan1 aJansen, Rick1 aJarvelin, Marjo-Riitta1 aJoehanes, Roby1 aJohansson, Asa1 aJohnson, Andrew, D1 aJoshi, Peter, K1 aJousilahti, Pekka1 aJukema, Wouter1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKeavney, Bernard, D1 aKhaw, Kay-Tee1 aKnekt, Paul1 aKnight, Joanne1 aKolcic, Ivana1 aKooner, Jaspal, S1 aKoskinen, Seppo1 aKristiansson, Kati1 aKutalik, Zoltán1 aLaan, Maris1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLopez, Lorna, M1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aMamasoula, Chrysovalanto1 aMarrugat, Jaume1 aMarten, Jonathan1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNalls, Mike, A1 aNandakumar, Priyanka1 aNelson, Christopher, P1 aNiiranen, Teemu1 aNolte, Ilja, M1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aO'Reilly, Paul, F1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPalotie, Aarno1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPramstaller, Peter, P1 aNguyen, Quang, Tri1 aRaitakari, Olli, T1 aRen, Meixia1 aRettig, Rainer1 aRice, Kenneth1 aRidker, Paul, M1 aRied, Janina, S1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRose, Lynda, M1 aRotter, Jerome, I1 aRudan, Igor1 aRuggiero, Daniela1 aSaba, Yasaman1 aSala, Cinzia, F1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aSchmidt, Helena1 aShrine, Nick1 aSiscovick, David1 aSmith, Albert, V1 aSnieder, Harold1 aSõber, Siim1 aSorice, Rossella1 aStarr, John, M1 aStott, David, J1 aStrachan, David, P1 aStrawbridge, Rona, J1 aSundström, Johan1 aSwertz, Morris, A1 aTaylor, Kent, D1 aTeumer, Alexander1 aTobin, Martin, D1 aTomaszewski, Maciej1 aToniolo, Daniela1 aTraglia, Michela1 aTrompet, Stella1 aTuomilehto, Jaakko1 aTzourio, Christophe1 aUitterlinden, André, G1 aVaez, Ahmad1 avan der Most, Peter, J1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aVerwoert, Germaine, C1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVuckovic, Dragana1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWright, Alan, F1 aYao, Jie1 aZemunik, Tatijana1 aZhang, Weihua1 aAttia, John, R1 aButterworth, Adam, S1 aChasman, Daniel, I1 aConen, David1 aCucca, Francesco1 aDanesh, John1 aHayward, Caroline1 aHowson, Joanna, M M1 aLaakso, Markku1 aLakatta, Edward, G1 aLangenberg, Claudia1 aMelander, Olle1 aMook-Kanamori, Dennis, O1 aPalmer, Colin, N A1 aRisch, Lorenz1 aScott, Robert, A1 aScott, Rodney, J1 aSever, Peter1 aSpector, Tim, D1 aHarst, Pim1 aWareham, Nicholas, J1 aZeggini, Eleftheria1 aLevy, Daniel1 aMunroe, Patricia, B1 aNewton-Cheh, Christopher1 aBrown, Morris, J1 aMetspalu, Andres1 aHung, Adriana, M1 aO'Donnell, Christopher, J1 aEdwards, Todd, L1 aPsaty, Bruce, M1 aTzoulaki, Ioanna1 aBarnes, Michael, R1 aWain, Louise, V1 aElliott, Paul1 aCaulfield, Mark, J1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/784503171nas a2200433 4500008004100000022001400041245007800055210006900133260001600202520191900218100003002137700002002167700001802187700001702205700001902222700001802241700002002259700002302279700002302302700002002325700002102345700002502366700002102391700001902412700001902431700002302450700001602473700002102489700002002510700002202530700002102552700002202573700001902595700002202614700002002636700002002656700002502676856003602701 2018 eng d a1533-345000aGenetic Variants Associated with Circulating Fibroblast Growth Factor 23.0 aGenetic Variants Associated with Circulating Fibroblast Growth F c2018 Sep 143 aBACKGROUND: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.
METHODS: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.
RESULTS: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (=3.0×10), lies upstream of , which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within and upstream of (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within , the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.
CONCLUSIONS: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
1 aRobinson-Cohen, Cassianne1 aBartz, Traci, M1 aLai, Dongbing1 aIkizler, Alp1 aPeacock, Munro1 aImel, Erik, A1 aMichos, Erin, D1 aForoud, Tatiana, M1 aÅkesson, Kristina1 aTaylor, Kent, D1 aMalmgren, Linnea1 aMatsushita, Kunihiro1 aNethander, Maria1 aEriksson, Joel1 aOhlsson, Claes1 aMellström, Daniel1 aWolf, Myles1 aLjunggren, Osten1 aMcGuigan, Fiona1 aRotter, Jerome, I1 aKarlsson, Magnus1 aEcons, Michael, J1 aIx, Joachim, H1 aLutsey, Pamela, L1 aPsaty, Bruce, M1 ade Boer, Ian, H1 aKestenbaum, Bryan, R uhttps://chs-nhlbi.org/node/777403317nas a2200649 4500008004100000022001400041245014700055210006900202260000900271300000900280490000700289520140100296100002301697700001901720700002601739700002101765700002201786700001801808700002301826700002101849700002401870700002101894700002101915700002301936700001801959700002101977700001801998700001702016700001802033700001802051700001802069700002402087700001302111700001702124700001402141700002302155700001902178700001702197700002202214700001702236700002102253700002802274700002002302700001902322700002502341700002002366700002002386700002502406700001802431700002102449700001902470700003102489700002002520700002202540710006902562856003602631 2018 eng d a1421-982400aGenetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project.0 aGenetic Variation in Genes Underlying Diverse Dementias May Expl c2018 a1-170 v453 aBACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.
METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.
RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.
1 aBlue, Elizabeth, E1 aBis, Joshua, C1 aDorschner, Michael, O1 aTsuang, Debby, W1 aBarral, Sandra, M1 aBeecham, Gary1 aBelow, Jennifer, E1 aBush, William, S1 aButkiewicz, Mariusz1 aCruchaga, Carlos1 aDeStefano, Anita1 aFarrer, Lindsay, A1 aGoate, Alison1 aHaines, Jonathan1 aJaworski, Jim1 aJun, Gyungah1 aKunkle, Brian1 aKuzma, Amanda1 aLee, Jenny, J1 aLunetta, Kathryn, L1 aMa, Yiyi1 aMartin, Eden1 aNaj, Adam1 aNato, Alejandro, Q1 aNavas, Patrick1 aNguyen, Hiep1 aReitz, Christiane1 aReyes, Dolly1 aSalerno, William1 aSchellenberg, Gerard, D1 aSeshadri, Sudha1 aSohi, Harkirat1 aThornton, Timothy, A1 aValadares, Otto1 aDuijn, Cornelia1 aVardarajan, Badri, N1 aSan Wang, Li-1 aBoerwinkle, Eric1 aDupuis, Josée1 aPericak-Vance, Margaret, A1 aMayeux, Richard1 aWijsman, Ellen, M1 aon behalf of the Alzheimer’s Disease Sequencing Project uhttps://chs-nhlbi.org/node/778601783nas a2200193 4500008004100000022001400041245016700055210006900222260000900291300001200300490000700312520108800319100002001407700002501427700002401452700002001476710005701496856003601553 2018 eng d a2352-872900aGenetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease.0 aGenetically elevated highdensity lipoprotein cholesterol through c2018 a595-5980 v103 aIntroduction: There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein () locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.
Methods: Ten single nucleotide polymorphisms within the locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.
Results: Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the locus, we found that HDL-C was not associated with risk of AD ( > .7).
Discussion: Our study does not support the role of HDL-C on risk of AD through HDL-C altered by . This study does not rule out other mechanisms by which HDL-C affects risk of AD.
1 aPeloso, Gina, M1 avan der Lee, Sven, J1 aDeStefano, Anita, L1 aSeshardi, Sudha1 aInternational Genomics of Alzheimer's Project (IGAP) uhttps://chs-nhlbi.org/node/798711426nas a2203589 4500008004100000022001400041245015500055210006900210260001600279300001200295490000800307520141100315100002001726700001601746700001601762700002701778700002201805700001901827700002701846700002001873700001801893700001901911700001301930700002101943700001901964700001901983700001502002700001202017700001902029700001802048700002002066700002102086700002502107700001802132700001602150700002002166700001802186700002102204700001502225700001802240700002102258700002002279700002202299700002102321700002302342700001802365700002702383700002802410700002702438700001802465700001902483700001902502700002102521700001902542700001602561700002602577700002002603700002202623700001802645700001602663700001902679700002202698700001802720700001302738700002102751700002602772700002402798700002002822700002502842700002102867700001902888700002202907700001802929700002102947700002002968700002302988700001303011700001903024700001603043700001803059700002403077700001703101700002003118700002303138700002703161700002803188700001503216700002503231700001403256700002203270700002203292700001903314700001703333700001703350700001503367700001603382700001803398700002003416700001903436700002503455700002003480700001703500700002003517700001903537700001803556700002303574700002303597700001903620700002303639700002703662700002803689700002403717700002503741700002603766700001703792700002203809700002303831700002003854700002003874700002303894700002303917700002203940700001803962700002503980700001704005700002004022700002204042700002204064700002204086700002004108700001904128700002104147700002504168700002704193700001904220700002404239700002304263700002004286700002004306700002204326700002104348700001904369700002204388700002004410700002604430700001904456700002404475700002704499700002004526700002404546700002604570700001904596700002004615700002004635700002004655700001704675700002204692700002404714700001704738700002204755700002204777700002204799700002004821700002404841700002204865700003004887700002404917700002604941700002504967700002104992700001505013700002305028700002005051700002405071700002005095700002105115700002805136700002005164700002805184700001905212700002405231700001905255700002205274700002305296700001905319700002205338700001905360700002105379700002205400700002105422700002105443700002005464700001805484700002505502700001905527700002105546700001505567700001505582700002205597700002005619700002405639700002105663700002405684700001805708700002405726700002505750700002605775700002405801700002205825700002105847700001705868700002005885700002305905700002005928700002105948700002305969700002405992700002306016700002306039700002306062700001906085700002406104700002106128700002706149700001906176700002006195700002006215700001806235700002806253700002006281700002406301700001106325700002106336700002306357700002206380700002006402700002106422700002306443700001906466700002006485700001706505700002306522700002106545700002706566700002106593700002506614700001706639700002206656700001906678700002006697700002506717700002906742700002006771700002106791700002606812700002506838700002206863700002006885700001806905700001806923700002406941700001506965700001906980700002206999700001907021700002207040700002207062700002307084700002107107700002407128700002307152700002207175700001907197700001507216700002107231700002007252700002007272700002007292700002407312700002007336700002407356700002207380700002007402700002207422700001907444700002107463700002707484700002007511700001707531700001907548700001707567700002107584700002407605700002307629700001907652700002007671700001907691700002507710710002707735710003807762856003607800 2018 eng d a1537-660500aGenome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.0 aGenome Analyses of 200000 Individuals Identify 58 Loci for Chron c2018 Nov 01 a691-7060 v1033 aC-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
1 aLigthart, Symen1 aVaez, Ahmad1 aVõsa, Urmo1 aStathopoulou, Maria, G1 ade Vries, Paul, S1 aPrins, Bram, P1 avan der Most, Peter, J1 aTanaka, Toshiko1 aNaderi, Elnaz1 aRose, Lynda, M1 aWu, Ying1 aKarlsson, Robert1 aBarbalic, Maja1 aLin, Honghuang1 aPool, Rene1 aZhu, Gu1 aMace, Aurelien1 aSidore, Carlo1 aTrompet, Stella1 aMangino, Massimo1 aSabater-Lleal, Maria1 aKemp, John, P1 aAbbasi, Ali1 aKacprowski, Tim1 aVerweij, Niek1 aSmith, Albert, V1 aHuang, Tao1 aMarzi, Carola1 aFeitosa, Mary, F1 aLohman, Kurt, K1 aKleber, Marcus, E1 aMilaneschi, Yuri1 aMueller, Christian1 aHuq, Mahmudul1 aVlachopoulou, Efthymia1 aLyytikäinen, Leo-Pekka1 aOldmeadow, Christopher1 aDeelen, Joris1 aPerola, Markus1 aZhao, Jing Hua1 aFeenstra, Bjarke1 aAmini, Marzyeh1 aLahti, Jari1 aSchraut, Katharina, E1 aFornage, Myriam1 aSuktitipat, Bhoom1 aChen, Wei-Min1 aLi, Xiaohui1 aNutile, Teresa1 aMalerba, Giovanni1 aLuan, Jian'an1 aBak, Tom1 aSchork, Nicholas1 aM, Fabiola, del Greco1 aThiering, Elisabeth1 aMahajan, Anubha1 aMarioni, Riccardo, E1 aMihailov, Evelin1 aEriksson, Joel1 aOzel, Ayse, Bilge1 aZhang, Weihua1 aNethander, Maria1 aCheng, Yu-Ching1 aAslibekyan, Stella1 aAng, Wei1 aGandin, Ilaria1 aYengo, Loic1 aPortas, Laura1 aKooperberg, Charles1 aHofer, Edith1 aRajan, Kumar, B1 aSchurmann, Claudia1 aHollander, Wouter, den1 aAhluwalia, Tarunveer, S1 aZhao, Jing1 aDraisma, Harmen, H M1 aFord, Ian1 aTimpson, Nicholas1 aTeumer, Alexander1 aHuang, Hongyan1 aWahl, Simone1 aLiu, Yongmei1 aHuang, Jie1 aUh, Hae-Won1 aGeller, Frank1 aJoshi, Peter, K1 aYanek, Lisa, R1 aTrabetti, Elisabetta1 aLehne, Benjamin1 aVozzi, Diego1 aVerbanck, Marie1 aBiino, Ginevra1 aSaba, Yasaman1 aMeulenbelt, Ingrid1 aO'Connell, Jeff, R1 aLaakso, Markku1 aGiulianini, Franco1 aMagnusson, Patrik, K E1 aBallantyne, Christie, M1 aHottenga, Jouke Jan1 aMontgomery, Grant, W1 aRivadineira, Fernando1 aRueedi, Rico1 aSteri, Maristella1 aHerzig, Karl-Heinz1 aStott, David, J1 aMenni, Cristina1 aFrånberg, Mattias1 aSt Pourcain, Beate1 aFelix, Stephan, B1 aPers, Tune, H1 aBakker, Stephan, J L1 aKraft, Peter1 aPeters, Annette1 aVaidya, Dhananjay1 aDelgado, Graciela1 aSmit, Johannes, H1 aGroßmann, Vera1 aSinisalo, Juha1 aSeppälä, Ilkka1 aWilliams, Stephen, R1 aHolliday, Elizabeth, G1 aMoed, Matthijs1 aLangenberg, Claudia1 aRäikkönen, Katri1 aDing, Jingzhong1 aCampbell, Harry1 aSale, Michèle, M1 aChen, Yii-der, I1 aJames, Alan, L1 aRuggiero, Daniela1 aSoranzo, Nicole1 aHartman, Catharina, A1 aSmith, Erin, N1 aBerenson, Gerald, S1 aFuchsberger, Christian1 aHernandez, Dena1 aTiesler, Carla, M T1 aGiedraitis, Vilmantas1 aLiewald, David1 aFischer, Krista1 aMellström, Dan1 aLarsson, Anders1 aWang, Yunmei1 aScott, William, R1 aLorentzon, Matthias1 aBeilby, John1 aRyan, Kathleen, A1 aPennell, Craig, E1 aVuckovic, Dragana1 aBalkau, Beverly1 aConcas, Maria, Pina1 aSchmidt, Reinhold1 ade Leon, Carlos, F Mendes1 aBottinger, Erwin, P1 aKloppenburg, Margreet1 aPaternoster, Lavinia1 aBoehnke, Michael1 aMusk, A, W1 aWillemsen, Gonneke1 aEvans, David, M1 aMadden, Pamela, A F1 aKähönen, Mika1 aKutalik, Zoltán1 aZoledziewska, Magdalena1 aKarhunen, Ville1 aKritchevsky, Stephen, B1 aSattar, Naveed1 aLachance, Genevieve1 aClarke, Robert1 aHarris, Tamara, B1 aRaitakari, Olli, T1 aAttia, John, R1 avan Heemst, Diana1 aKajantie, Eero1 aSorice, Rossella1 aGambaro, Giovanni1 aScott, Robert, A1 aHicks, Andrew, A1 aFerrucci, Luigi1 aStandl, Marie1 aLindgren, Cecilia, M1 aStarr, John, M1 aKarlsson, Magnus1 aLind, Lars1 aLi, Jun, Z1 aChambers, John, C1 aMori, Trevor, A1 ade Geus, Eco, J C N1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aAuvinen, Juha1 aBuckley, Brendan, M1 ade Craen, Anton, J M1 aWaldenberger, Melanie1 aStrauch, Konstantin1 aMeitinger, Thomas1 aScott, Rodney, J1 aMcEvoy, Mark1 aBeekman, Marian1 aBombieri, Cristina1 aRidker, Paul, M1 aMohlke, Karen, L1 aPedersen, Nancy, L1 aMorrison, Alanna, C1 aBoomsma, Dorret, I1 aWhitfield, John, B1 aStrachan, David, P1 aHofman, Albert1 aVollenweider, Peter1 aCucca, Francesco1 aJarvelin, Marjo-Riitta1 aJukema, Wouter1 aSpector, Tim, D1 aHamsten, Anders1 aZeller, Tanja1 aUitterlinden, André, G1 aNauck, Matthias1 aGudnason, Vilmundur1 aQi, Lu1 aGrallert, Harald1 aBorecki, Ingrid, B1 aRotter, Jerome, I1 aMärz, Winfried1 aWild, Philipp, S1 aLokki, Marja-Liisa1 aBoyle, Michael1 aSalomaa, Veikko1 aMelbye, Mads1 aEriksson, Johan, G1 aWilson, James, F1 aPenninx, Brenda, W J H1 aBecker, Diane, M1 aWorrall, Bradford, B1 aGibson, Greg1 aKrauss, Ronald, M1 aCiullo, Marina1 aZaza, Gianluigi1 aWareham, Nicholas, J1 aOldehinkel, Albertine, J1 aPalmer, Lyle, J1 aMurray, Sarah, S1 aPramstaller, Peter, P1 aBandinelli, Stefania1 aHeinrich, Joachim1 aIngelsson, Erik1 aDeary, Ian, J1 aMägi, Reedik1 aVandenput, Liesbeth1 aHarst, Pim1 aDesch, Karl, C1 aKooner, Jaspal, S1 aOhlsson, Claes1 aHayward, Caroline1 aLehtimäki, Terho1 aShuldiner, Alan, R1 aArnett, Donna, K1 aBeilin, Lawrence, J1 aRobino, Antonietta1 aFroguel, Philippe1 aPirastu, Mario1 aJess, Tine1 aKoenig, Wolfgang1 aLoos, Ruth, J F1 aEvans, Denis, A1 aSchmidt, Helena1 aSmith, George Davey1 aSlagboom, Eline1 aEiriksdottir, Gudny1 aMorris, Andrew, P1 aPsaty, Bruce, M1 aTracy, Russell, P1 aNolte, Ilja, M1 aBoerwinkle, Eric1 aVisvikis-Siest, Sophie1 aReiner, Alex, P1 aGross, Myron1 aBis, Joshua, C1 aFranke, Lude1 aFranco, Oscar, H1 aBenjamin, Emelia, J1 aChasman, Daniel, I1 aDupuis, Josée1 aSnieder, Harold1 aDehghan, Abbas1 aAlizadeh, Behrooz, Z1 aLifeLines Cohort Study1 aCHARGE Inflammation Working Group uhttps://chs-nhlbi.org/node/792005787nas a2201681 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2018 eng d a2041-172300aGenome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.0 aGenomewide analyses identify a role for SLC17A4 and AADAT in thy c2018 10 26 a44550 v93 aThyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
1 aTeumer, Alexander1 aChaker, Layal1 aGroeneweg, Stefan1 aLi, Yong1 aDi Munno, Celia1 aBarbieri, Caterina1 aSchultheiss, Ulla, T1 aTraglia, Michela1 aAhluwalia, Tarunveer, S1 aAkiyama, Masato1 aAppel, Emil, Vincent R1 aArking, Dan, E1 aArnold, Alice1 aAstrup, Arne1 aBeekman, Marian1 aBeilby, John, P1 aBekaert, Sofie1 aBoerwinkle, Eric1 aBrown, Suzanne, J1 aDe Buyzere, Marc1 aCampbell, Purdey, J1 aCeresini, Graziano1 aCerqueira, Charlotte1 aCucca, Francesco1 aDeary, Ian, J1 aDeelen, Joris1 aEckardt, Kai-Uwe1 aEkici, Arif, B1 aEriksson, Johan, G1 aFerrrucci, Luigi1 aFiers, Tom1 aFiorillo, Edoardo1 aFord, Ian1 aFox, Caroline, S1 aFuchsberger, Christian1 aGalesloot, Tessel, E1 aGieger, Christian1 aGögele, Martin1 aDe Grandi, Alessandro1 aGrarup, Niels1 aGreiser, Karin, Halina1 aHaljas, Kadri1 aHansen, Torben1 aHarris, Sarah, E1 avan Heemst, Diana1 aHeijer, Martin, den1 aHicks, Andrew, A1 aHollander, Wouter, den1 aHomuth, Georg1 aHui, Jennie1 aIkram, Arfan, M1 aIttermann, Till1 aJensen, Richard, A1 aJing, Jiaojiao1 aJukema, Wouter1 aKajantie, Eero1 aKamatani, Yoichiro1 aKasbohm, Elisa1 aKaufman, Jean-Marc1 aKiemeney, Lambertus, A1 aKloppenburg, Margreet1 aKronenberg, Florian1 aKubo, Michiaki1 aLahti, Jari1 aLapauw, Bruno1 aLi, Shuo1 aLiewald, David, C M1 aLim, Ee, Mun1 aLinneberg, Allan1 aMarina, Michela1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMedenwald, Daniel1 aMeisinger, Christa1 aMeulenbelt, Ingrid1 aDe Meyer, Tim1 aMeyer zu Schwabedissen, Henriette, E1 aMikolajczyk, Rafael1 aMoed, Matthijs1 aNetea-Maier, Romana, T1 aNolte, Ilja, M1 aOkada, Yukinori1 aPala, Mauro1 aPattaro, Cristian1 aPedersen, Oluf1 aPetersmann, Astrid1 aPorcu, Eleonora1 aPostmus, Iris1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aRamos, Yolande, F M1 aRawal, Rajesh1 aRedmond, Paul1 aRichards, Brent1 aRietzschel, Ernst, R1 aRivadeneira, Fernando1 aRoef, Greet1 aRotter, Jerome, I1 aSala, Cinzia, F1 aSchlessinger, David1 aSelvin, Elizabeth1 aSlagboom, Eline1 aSoranzo, Nicole1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStarr, John, M1 aStott, David, J1 aTaes, Youri1 aTaliun, Daniel1 aTanaka, Toshiko1 aThuesen, Betina1 aTiller, Daniel1 aToniolo, Daniela1 aUitterlinden, André, G1 aVisser, Edward1 aWalsh, John, P1 aWilson, Scott, G1 aWolffenbuttel, Bruce, H R1 aYang, Qiong1 aZheng, Hou-Feng1 aCappola, Anne1 aPeeters, Robin, P1 aNaitza, Silvia1 aVölzke, Henry1 aSanna, Serena1 aKöttgen, Anna1 aVisser, Theo, J1 aMedici, Marco1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/792703876nas a2200565 4500008004100000022001400041245013500055210006900190260000900259300001300268490000700281520223900288653001602527653003402543653001102577653001202588653001202600653001202612653003602624653001902660653003402679653003002713100002902743700002402772700001202796700001902808700001802827700002102845700002102866700002102887700001502908700002002923700001702943700002302960700002502983700002503008700002103033700002203054700002203076700002003098700002003118700002003138700001703158700001503175700001703190700001803207700002403225700002503249856003603274 2018 eng d a1932-620300aGenome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium.0 aGenomewide association metaanalysis of circulating oddnumbered c c2018 ae01969510 v133 aBACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.
OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.
DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.
RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37×10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07×10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4×10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5×10-2).
CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.
10aFatty Acids10aGenome-Wide Association Study10aHumans10aIntrons10aLactase10aMyosins10aPolymorphism, Single Nucleotide10aSphingomyelins10aSphingosine N-Acyltransferase10aTumor Suppressor Proteins1 aOtto, Marcia, C de Olive1 aLemaitre, Rozenn, N1 aSun, Qi1 aKing, Irena, B1 aH Y Wu, Jason1 aManichaikul, Ani1 aRich, Stephen, S1 aTsai, Michael, Y1 aChen, Y, D1 aFornage, Myriam1 aWeihua, Guan1 aAslibekyan, Stella1 aIrvin, Marguerite, R1 aKabagambe, Edmond, K1 aArnett, Donna, K1 aJensen, Majken, K1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aSteffen, Lyn, M1 aSmith, Caren, E1 aRiserus, Ulf1 aLind, Lars1 aHu, Frank, B1 aRimm, Eric, B1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/779103238nas a2200529 4500008004100000022001400041245012300055210006900178260001600247300000900263490000600272520170300278100002301981700002302004700002002027700002202047700002902069700002402098700002302122700002502145700001202170700002402182700001402206700001502220700001902235700001302254700001702267700002002284700002302304700002202327700001902349700002502368700002002393700002202413700001902435700002102454700002702475700001802502700002302520700002002543700002002563700002202583700002402605700002202629700002102651856003602672 2018 eng d a2045-232200aGenome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy.0 aGenomewide association study and metaanalysis identify loci asso c2018 Apr 04 a56750 v83 aThe genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10) and multi-trait analysis (P = 2.9 × 10) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.
1 aNapier, Melanie, D1 aFranceschini, Nora1 aGondalia, Rahul1 aStewart, James, D1 aMéndez-Giráldez, Rául1 aSitlani, Colleen, M1 aSeyerle, Amanda, A1 aHighland, Heather, M1 aLi, Yun1 aWilhelmsen, Kirk, C1 aYan, Song1 aDuan, Qing1 aRoach, Jeffrey1 aYao, Jie1 aGuo, Xiuqing1 aTaylor, Kent, D1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aNorth, Kari, E1 aReiner, Alexander, P1 aZhang, Zhu-Ming1 aTinker, Lesley, F1 aLiao, Duanping1 aLaurie, Cathy, C1 aGogarten, Stephanie, M1 aLin, Henry, J1 aBrody, Jennifer, A1 aBartz, Traci, M1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aSoliman, Elsayed, Z1 aAvery, Christy, L1 aWhitsel, Eric, A uhttps://chs-nhlbi.org/node/766905033nas a2201381 4500008004100000022001400041245013800055210006900193260001600262300000800278490000600286520112300292100001501415700002201430700002001452700001901472700002001491700001901511700002001530700001901550700001701569700001701586700002201603700001901625700001701644700002501661700002701686700002301713700002201736700001201758700001801770700002201788700002501810700001901835700001401854700001701868700002201885700002001907700002101927700002801948700002201976700001801998700002702016700002802043700003102071700001802102700002502120700002002145700002702165700001802192700001702210700002002227700001902247700002402266700002302290700002302313700001502336700002302351700002802374700001702402700002002419700002002439700001902459700002202478700002002500700002002520700001802540700002202558700002202580700002002602700002002622700002002642700002202662700002102684700003002705700002402735700002702759700002002786700002002806700002102826700002202847700001502869700002302884700002002907700002502927700002802952700002602980700001703006700001603023700002003039700002403059700002503083700002103108700002303129700001903152700001903171700002203190700002803212700002003240700002303260700001903283700002003302700001903322700001903341700002503360700002403385700002103409700002503430700001803455700002503473700001703498700002103515700002003536700002103556700001703577700002103594856003603615 2018 eng d a2041-172300aGenome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.0 aGenomewide association study in 79366 Europeanancestry individua c2018 Jan 17 a2600 v93 aVitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
1 aJiang, Xia1 aO'Reilly, Paul, F1 aAschard, Hugues1 aHsu, Yi-Hsiang1 aRichards, Brent1 aDupuis, Josée1 aIngelsson, Erik1 aKarasik, David1 aPilz, Stefan1 aBerry, Diane1 aKestenbaum, Bryan1 aZheng, Jusheng1 aLuan, Jianan1 aSofianopoulou, Eleni1 aStreeten, Elizabeth, A1 aAlbanes, Demetrius1 aLutsey, Pamela, L1 aYao, Lu1 aTang, Weihong1 aEcons, Michael, J1 aWallaschofski, Henri1 aVölzke, Henry1 aZhou, Ang1 aPower, Chris1 aMcCarthy, Mark, I1 aMichos, Erin, D1 aBoerwinkle, Eric1 aWeinstein, Stephanie, J1 aFreedman, Neal, D1 aHuang, Wen-Yi1 avan Schoor, Natasja, M1 avan der Velde, Nathalie1 ade Groot, Lisette, C P G M1 aEnneman, Anke1 aCupples, Adrienne, L1 aBooth, Sarah, L1 aVasan, Ramachandran, S1 aLiu, Ching-Ti1 aZhou, Yanhua1 aRipatti, Samuli1 aOhlsson, Claes1 aVandenput, Liesbeth1 aLorentzon, Mattias1 aEriksson, Johan, G1 aShea, Kyla1 aHouston, Denise, K1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aLohman, Kurt, K1 aFerrucci, Luigi1 aPeacock, Munro1 aGieger, Christian1 aBeekman, Marian1 aSlagboom, Eline1 aDeelen, Joris1 avan Heemst, Diana1 aKleber, Marcus, E1 aMärz, Winfried1 ade Boer, Ian, H1 aWood, Alexis, C1 aRotter, Jerome, I1 aRich, Stephen, S1 aRobinson-Cohen, Cassianne1 aHeijer, Martin, den1 aJarvelin, Marjo-Riitta1 aCavadino, Alana1 aJoshi, Peter, K1 aWilson, James, F1 aHayward, Caroline1 aLind, Lars1 aMichaëlsson, Karl1 aTrompet, Stella1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aBroer, Linda1 aZgaga, Lina1 aCampbell, Harry1 aTheodoratou, Evropi1 aFarrington, Susan, M1 aTimofeeva, Maria1 aDunlop, Malcolm, G1 aValdes, Ana, M1 aTikkanen, Emmi1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aKähönen, Mika1 aRaitakari, Olli, T1 aMikkilä, Vera1 aIkram, Arfan, M1 aSattar, Naveed1 aJukema, Wouter1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aForouhi, Nita, G1 aGundersen, Thomas, E1 aKhaw, Kay-Tee1 aButterworth, Adam, S1 aDanesh, John1 aSpector, Timothy1 aWang, Thomas, J1 aHyppönen, Elina1 aKraft, Peter1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/766704406nas a2201225 4500008004100000022001400041245011600055210006900171260001600240300000900256490000600265520095200271100002001223700002001243700001701263700001601280700002601296700001901322700002201341700001901363700002501382700001701407700001801424700002201442700001901464700002001483700001801503700002501521700002501546700002301571700001901594700002301613700001601636700001601652700002801668700002001696700002101716700002101737700001801758700001901776700001601795700001801811700002001829700002401849700001801873700002101891700002501912700002601937700002601963700002401989700002202013700001802035700002202053700001802075700001902093700001302112700002102125700002002146700002202166700002302188700002102211700002202232700002102254700002002275700002102295700002502316700002002341700002002361700001402381700002202395700001902417700002602436700002202462700002402484700002502508700002002533700002002553700002602573700002802599700003302627700002302660700001302683700001702696700002002713700002402733700002402757700001902781700002202800700002302822700002202845700001902867700001802886700002302904700002002927700002602947700002102973700002502994700002003019700002303039700002203062700002003084700002003104700002003124856003603144 2018 eng d a2041-172300aGenome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.0 aGenomewide association study of 23500 individuals identifies 7 l c2018 Sep 26 a39450 v93 aThe volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.
1 aVojinovic, Dina1 aAdams, Hieab, H1 aJian, Xueqiu1 aYang, Qiong1 aSmith, Albert, Vernon1 aBis, Joshua, C1 aTeumer, Alexander1 aScholz, Markus1 aArmstrong, Nicola, J1 aHofer, Edith1 aSaba, Yasaman1 aLuciano, Michelle1 aBernard, Manon1 aTrompet, Stella1 aYang, Jingyun1 aGillespie, Nathan, A1 avan der Lee, Sven, J1 aNeumann, Alexander1 aAhmad, Shahzad1 aAndreassen, Ole, A1 aAmes, David1 aAmin, Najaf1 aArfanakis, Konstantinos1 aBastin, Mark, E1 aBecker, Diane, M1 aBeiser, Alexa, S1 aBeyer, Frauke1 aBrodaty, Henry1 aBryan, Nick1 aBülow, Robin1 aDale, Anders, M1 aDe Jager, Philip, L1 aDeary, Ian, J1 aDeCarli, Charles1 aFleischman, Debra, A1 aGottesman, Rebecca, F1 avan der Grond, Jeroen1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHomuth, Georg1 aKnopman, David, S1 aKwok, John, B1 aLewis, Cora, E1 aLi, Shuo1 aLoeffler, Markus1 aLopez, Oscar, L1 aMaillard, Pauline1 aMarroun, Hanan, El1 aMather, Karen, A1 aMosley, Thomas, H1 aMuetzel, Ryan, L1 aNauck, Matthias1 aNyquist, Paul, A1 aPanizzon, Matthew, S1 aPausova, Zdenka1 aPsaty, Bruce, M1 aRice, Ken1 aRotter, Jerome, I1 aRoyle, Natalie1 aSatizabal, Claudia, L1 aSchmidt, Reinhold1 aSchofield, Peter, R1 aSchreiner, Pamela, J1 aSidney, Stephen1 aStott, David, J1 aThalamuthu, Anbupalam1 aUitterlinden, André, G1 aHernández, Maria, C Valdés1 aVernooij, Meike, W1 aWen, Wei1 aWhite, Tonya1 aWitte, Veronica1 aWittfeld, Katharina1 aWright, Margaret, J1 aYanek, Lisa, R1 aTiemeier, Henning1 aKremen, William, S1 aBennett, David, A1 aJukema, Wouter1 aPaus, Tomáš1 aWardlaw, Joanna, M1 aSchmidt, Helena1 aSachdev, Perminder, S1 aVillringer, Arno1 aGrabe, Hans, Jörgen1 aLongstreth, W T1 aDuijn, Cornelia, M1 aLauner, Lenore, J1 aSeshadri, Sudha1 aIkram, Arfan, M1 aFornage, Myriam uhttps://chs-nhlbi.org/node/784905032nas a2201033 4500008004100000022001400041245016100055210006900216260001600285520189700301100002502198700002502223700002202248700002102270700002802291700001302319700002102332700002802353700001902381700002002400700002502420700001702445700002002462700002602482700002002508700002502528700001802553700001902571700002102590700002002611700002002631700001802651700002002669700002002689700002202709700002402731700002102755700002502776700002202801700001602823700002302839700002002862700002202882700002502904700001902929700003002948700001902978700001802997700002003015700002203035700002203057700002003079700001603099700002103115700001503136700002603151700002803177700001903205700002103224700001803245700002003263700002903283700002203312700002203334700003003356700002103386700001903407700002403426700002103450700002203471700002003493700002003513700002403533700002403557700002103581700002003602700002003622700001903642700001903661700003203680700002403712700002303736700003003759700002303789700002703812700002303839710010003862856003603962 2018 eng d a1524-453900aGenome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.0 aGenomeWide Association TransEthnic MetaAnalyses Identifies Novel c2018 Nov 203 aBACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.
METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.
RESULTS: We identified 13 novel genome-wide significant (p≤2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.
CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMarten, Jonathan1 aMastrangelo, Michael, A1 aSong, Ci1 aPankratz, Nathan1 aWard-Caviness, Cavin, K1 aYanek, Lisa, R1 aTrompet, Stella1 aDelgado, Graciela, E1 aGuo, Xiuqing1 aBartz, Traci, M1 aMartinez-Perez, Angel1 aGermain, Marine1 ade Haan, Hugoline, G1 aOzel, Ayse, B1 aPolasek, Ozren1 aSmith, Albert, V1 aEicher, John, D1 aReiner, Alex, P1 aTang, Weihong1 aDavies, Neil, M1 aStott, David, J1 aRotter, Jerome, I1 aTofler, Geoffrey, H1 aBoerwinkle, Eric1 ade Maat, Moniek, P M1 aKleber, Marcus, E1 aWelsh, Paul1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aVaidya, Dhananjay1 aSoria, José, Manuel1 aSuchon, Pierre1 aVlieg, Astrid, van Hylcka1 aDesch, Karl, C1 aKolcic, Ivana1 aJoshi, Peter, K1 aLauner, Lenore, J1 aHarris, Tamara, B1 aCampbell, Harry1 aRudan, Igor1 aBecker, Diane, M1 aLi, Jun, Z1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aCushman, Mary1 aPsaty, Bruce, M1 aMorange, Pierre-Emmanuel1 aMcKnight, Barbara1 aChong, Michael, R1 aFernandez-Cadenas, Israel1 aRosand, Jonathan1 aLindgren, Arne1 aGudnason, Vilmundur1 aWilson, James, F1 aHayward, Caroline1 aGinsburg, David1 aFornage, Myriam1 aRosendaal, Frits, R1 aSouto, Juan, Carlos1 aBecker, Lewis, C1 aJenny, Nancy, S1 aMärz, Winfried1 aJukema, Wouter1 aDehghan, Abbas1 aTrégouët, David-Alexandre1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aLowenstein, Charles, J1 aSmith, Nicholas, L1 aINVENT Consortium; MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC) uhttps://chs-nhlbi.org/node/792402814nas a2200313 4500008004100000022001400041245017100055210006900226260001600295490000600311520179000317100002802107700002202135700002402157700002002181700001902201700001902220700002302239700002202262700002402284700002202308700002702330700002202357700001902379700002302398700002402421700001902445856003602464 2018 eng d a2047-998000aGenome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study).0 aGenomeWide Associations of Global Electrical Heterogeneity ECG P c2018 Apr 050 v73 aBACKGROUND: ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome-wide association study would identify genetic loci related to GEH.
METHODS AND RESULTS: We tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS-T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12-lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome-wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near ) was associated with QRS-T angle (white standardized β+0.16 [95% CI 0.13-0.19]; =1.5×10), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; =2.1×10), and spatial ventricular gradient magnitude (-0.12 [95% CI -0.15 to -0.09]; =5.9×10). Altogether, GEH-SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near ), 5 (), 11 (11p11.2 region cluster), and 7 (near ) are novel ECG phenotype-associated loci. Several loci significantly associated with gene expression in the left ventricle ( locus-with ; locus-with ), and atria ( locus-with expression of a long non-coding RNA and ).
CONCLUSIONS: We identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH-loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.
1 aTereshchenko, Larisa, G1 aSotoodehnia, Nona1 aSitlani, Colleen, M1 aAshar, Foram, N1 aKabir, Muammar1 aBiggs, Mary, L1 aMorley, Michael, P1 aWaks, Jonathan, W1 aSoliman, Elsayed, Z1 aBuxton, Alfred, E1 aBiering-Sørensen, Tor1 aSolomon, Scott, D1 aPost, Wendy, S1 aCappola, Thomas, P1 aSiscovick, David, S1 aArking, Dan, E uhttps://chs-nhlbi.org/node/767203848nas a2200577 4500008004100000022001400041245013100055210006900186260001300255300001300268490000700281520216000288100001802448700002202466700002302488700002202511700001902533700002102552700002102573700002402594700002002618700002102638700002002659700002102679700001802700700002102718700002002739700001902759700002202778700001702800700002402817700002202841700001702863700002002880700002402900700001902924700002002943700001902963700001902982700002203001700002603023700002103049700002303070700002503093700002003118700002203138700002303160700002403183700002703207856003603234 2018 eng d a1553-740400aGenome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.0 aGenomewide metaanalysis of 158000 individuals of European ancest c2018 Sep ae10076010 v143 aBack pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).
1 aSuri, Pradeep1 aPalmer, Melody, R1 aTsepilov, Yakov, A1 aFreidin, Maxim, B1 aBoer, Cindy, G1 aYau, Michelle, S1 aEvans, Daniel, S1 aGelemanovic, Andrea1 aBartz, Traci, M1 aNethander, Maria1 aArbeeva, Liubov1 aKarssen, Lennart1 aNeogi, Tuhina1 aCampbell, Archie1 aMellström, Dan1 aOhlsson, Claes1 aMarshall, Lynn, M1 aOrwoll, Eric1 aUitterlinden, Andre1 aRotter, Jerome, I1 aLauc, Gordan1 aPsaty, Bruce, M1 aKarlsson, Magnus, K1 aLane, Nancy, E1 aJarvik, Gail, P1 aPolasek, Ozren1 aHochberg, Marc1 aJordan, Joanne, M1 avan Meurs, Joyce, B J1 aJackson, Rebecca1 aNielson, Carrie, M1 aMitchell, Braxton, D1 aSmith, Blair, H1 aHayward, Caroline1 aSmith, Nicholas, L1 aAulchenko, Yurii, S1 aWilliams, Frances, M K uhttps://chs-nhlbi.org/node/784802630nas a2200421 4500008004100000022001400041245015400055210006900209260001600278520131200294100002501606700002401631700002101655700002301676700001901699700002001718700001201738700001901750700003301769700001901802700002301821700002901844700002201873700002501895700001801920700002001938700002101958700002801979700002202007700002102029700001502050700002302065700002202088700002102110700002002131700002102151856003602172 2018 eng d a1473-115000aGenome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry.0 aGenomewide metaanalysis of SNPby9ACEIARB and SNPbythiazide diure c2018 Jun 013 aWe evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.
1 aIrvin, Marguerite, R1 aSitlani, Colleen, M1 aNoordam, Raymond1 aAvery, Christie, L1 aBis, Joshua, C1 aFloyd, James, S1 aLi, Jin1 aLimdi, Nita, A1 aSrinivasasainagendra, Vinodh1 aStewart, James1 ade Mutsert, Renée1 aMook-Kanamori, Dennis, O1 aLipovich, Leonard1 aKleinbrink, Erica, L1 aSmith, Albert1 aBartz, Traci, M1 aWhitsel, Eric, A1 aUitterlinden, André, G1 aWiggins, Kerri, L1 aWilson, James, G1 aZhi, Degui1 aStricker, Bruno, H1 aRotter, Jerome, I1 aArnett, Donna, K1 aPsaty, Bruce, M1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/779407247nas a2202185 4500008004100000022001400041245013000055210006900185260001500254300000900269490000600278520110800284653002001392653003101412653003501443653002101478653003801499653003401537653001101571653001401582653002801596653003601624653002801660653001701688100002301705700002801728700002201756700001701778700001901795700002401814700002201838700002401860700002301884700001601907700002001923700001901943700002101962700001701983700003002000700001902030700001502049700001902064700003302083700002102116700002002137700002002157700002102177700002502198700002002223700002302243700001802266700001902284700001802303700001902321700002302340700001902363700002202382700001902404700002802423700001702451700002102468700002002489700001902509700002002528700002002548700001602568700002102584700002302605700002302628700002502651700002402676700002002700700002502720700002302745700002002768700001502788700001902803700002002822700001702842700002102859700002002880700002002900700002102920700002602941700001902967700002002986700001903006700002003025700002003045700001903065700002003084700001803104700001903122700002503141700002203166700001603188700002303204700002003227700002003247700002003267700001703287700001803304700002003322700001903342700003103361700001503392700002303407700002203430700002003452700001803472700002103490700002103511700002103532700001803553700001903571700001903590700001903609700002003628700002103648700002603669700001903695700002203714700002203736700002003758700001803778700001703796700001803813700002103831700002103852700001903873700002203892700002303914700002303937700002503960700002203985700001604007700001604023700002104039700002004060700002004080700001704100700002304117700001604140700002204156700002204178700002504200700001504225700001804240700002104258700002304279700001604302700001804318700002004336700001704356700001804373700001904391700002204410700002404432700002004456700002004476700002304496700002304519700002904542700002204571700002004593700002104613700002104634700002204655700002304677700002004700700001904720700002804739700002104767700002204788700002304810700002404833700001704857700002404874700002404898700002804922700001904950700003004969710002604999856003605025 2018 eng d a2041-172300aGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.0 aGWAS and colocalization analyses implicate carotid intimamedia t c2018 12 03 a51410 v93 aCarotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
10aADAMTS9 Protein10aAmino Acid Oxidoreductases10aCarotid Intima-Media Thickness10aCoronary Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLod Score10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors1 aFranceschini, Nora1 aGiambartolomei, Claudia1 ade Vries, Paul, S1 aFinan, Chris1 aBis, Joshua, C1 aHuntley, Rachael, P1 aLovering, Ruth, C1 aTajuddin, Salman, M1 aWinkler, Thomas, W1 aGraff, Misa1 aKavousi, Maryam1 aDale, Caroline1 aSmith, Albert, V1 aHofer, Edith1 avan Leeuwen, Elisabeth, M1 aNolte, Ilja, M1 aLu, Lingyi1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aPitkänen, Niina1 aFranzén, Oscar1 aJoshi, Peter, K1 aNoordam, Raymond1 aMarioni, Riccardo, E1 aHwang, Shih-Jen1 aMusani, Solomon, K1 aSchminke, Ulf1 aPalmas, Walter1 aIsaacs, Aaron1 aCorrea, Adolfo1 aZonderman, Alan, B1 aHofman, Albert1 aTeumer, Alexander1 aCox, Amanda, J1 aUitterlinden, André, G1 aWong, Andrew1 aSmit, Andries, J1 aNewman, Anne, B1 aBritton, Annie1 aRuusalepp, Arno1 aSennblad, Bengt1 aHedblad, Bo1 aPasaniuc, Bogdan1 aPenninx, Brenda, W1 aLangefeld, Carl, D1 aWassel, Christina, L1 aTzourio, Christophe1 aFava, Cristiano1 aBaldassarre, Damiano1 aO'Leary, Daniel, H1 aTeupser, Daniel1 aKuh, Diana1 aTremoli, Elena1 aMannarino, Elmo1 aGrossi, Enzo1 aBoerwinkle, Eric1 aSchadt, Eric, E1 aIngelsson, Erik1 aVeglia, Fabrizio1 aRivadeneira, Fernando1 aBeutner, Frank1 aChauhan, Ganesh1 aHeiss, Gerardo1 aSnieder, Harold1 aCampbell, Harry1 aVölzke, Henry1 aMarkus, Hugh, S1 aDeary, Ian, J1 aJukema, Wouter1 ade Graaf, Jacqueline1 aPrice, Jacqueline1 aPott, Janne1 aHopewell, Jemma, C1 aLiang, Jingjing1 aThiery, Joachim1 aEngmann, Jorgen1 aGertow, Karl1 aRice, Kenneth1 aTaylor, Kent, D1 aDhana, Klodian1 aKiemeney, Lambertus, A L M1 aLind, Lars1 aRaffield, Laura, M1 aLauner, Lenore, J1 aHoldt, Lesca, M1 aDörr, Marcus1 aDichgans, Martin1 aTraylor, Matthew1 aSitzer, Matthias1 aKumari, Meena1 aKivimaki, Mika1 aNalls, Mike, A1 aMelander, Olle1 aRaitakari, Olli1 aFranco, Oscar, H1 aRueda-Ochoa, Oscar, L1 aRoussos, Panos1 aWhincup, Peter, H1 aAmouyel, Philippe1 aGiral, Philippe1 aAnugu, Pramod1 aWong, Quenna1 aMalik, Rainer1 aRauramaa, Rainer1 aBurkhardt, Ralph1 aHardy, Rebecca1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aMorris, Richard, W1 aStrawbridge, Rona, J1 aWannamethee, Goya1 aHägg, Sara1 aShah, Sonia1 aMcLachlan, Stela1 aTrompet, Stella1 aSeshadri, Sudha1 aKurl, Sudhir1 aHeckbert, Susan, R1 aRing, Susan1 aHarris, Tamara, B1 aLehtimäki, Terho1 aGalesloot, Tessel, E1 aShah, Tina1 ade Faire, Ulf1 aPlagnol, Vincent1 aRosamond, Wayne, D1 aPost, Wendy1 aZhu, Xiaofeng1 aZhang, Xiaoling1 aGuo, Xiuqing1 aSaba, Yasaman1 aDehghan, Abbas1 aSeldenrijk, Adrie1 aMorrison, Alanna, C1 aHamsten, Anders1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLawlor, Deborah, A1 aMook-Kanamori, Dennis, O1 aBowden, Donald, W1 aSchmidt, Helena1 aWilson, James, F1 aWilson, James, G1 aRotter, Jerome, I1 aWardlaw, Joanna, M1 aDeanfield, John1 aHalcox, Julian1 aLyytikäinen, Leo-Pekka1 aLoeffler, Markus1 aEvans, Michele, K1 aDebette, Stephanie1 aHumphries, Steve, E1 aVölker, Uwe1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aBjörkegren, Johan, L M1 aCasas, Juan, P1 aO'Donnell, Christopher, J1 aMEGASTROKE Consortium uhttps://chs-nhlbi.org/node/791312060nas a2203745 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2018 eng d a1537-660500aA Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.0 aLargeScale Multiancestry Genomewide Study Accounting for Smoking c2018 Mar 01 a375-4000 v1023 aGenome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
1 aSung, Yun, J1 aWinkler, Thomas, W1 aFuentes, Lisa, de Las1 aBentley, Amy, R1 aBrown, Michael, R1 aKraja, Aldi, T1 aSchwander, Karen1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aKilpeläinen, Tuomas, O1 aRichard, Melissa, A1 aNoordam, Raymond1 aAslibekyan, Stella1 aAschard, Hugues1 aBartz, Traci, M1 aDorajoo, Rajkumar1 aLiu, Yongmei1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, Vernon1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aWarren, Helen, R1 aZhao, Wei1 aZhou, Yanhua1 aMatoba, Nana1 aSofer, Tamar1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGiulianini, Franco1 aGoel, Anuj1 aHarris, Sarah, E1 aHartwig, Fernando, Pires1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKuhnel, Brigitte1 aLeander, Karin1 aLee, Wen-Jane1 aLin, Keng-Hung1 aLuan, Jian, 'an1 aMcKenzie, Colin, A1 aMeian, He1 aNelson, Christopher, P1 aRauramaa, Rainer1 aSchupf, Nicole1 aScott, Robert, A1 aSheu, Wayne, H H1 aStančáková, Alena1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Heming1 aWang, Yajuan1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAlfred, Tamuno1 aAmin, Najaf1 aArking, Dan1 aAung, Tin1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCabrera, Claudia, P1 aCade, Brian1 aCaizheng, Yu1 aCampbell, Archie1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aChauhan, Ganesh1 aChristensen, Kaare1 aCocca, Massimiliano1 aCollins, Francis, S1 aConnell, John, M1 ade Mutsert, Renée1 ade Silva, Janaka1 aDebette, Stephanie1 aDörr, Marcus1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFisher, Virginia, A1 aForouhi, Nita, G1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGraff, Misa1 aGu, Charles1 aGu, Dongfeng1 aGupta, Preeti1 aHagenaars, Saskia, P1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHofman, Albert1 aHoward, Barbara, V1 aHunt, Steven1 aIrvin, Marguerite, R1 aJia, Yucheng1 aJoehanes, Roby1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKaufman, Joel1 aKerrison, Nicola, D1 aKhor, Chiea, Chuen1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKomulainen, Pirjo1 aKooperberg, Charles1 aKrieger, Jose, E1 aKubo, Michiaki1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLim, Sing, Hui1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Jingmin1 aLiu, Kiang1 aLiu, Yeheng1 aLoh, Marie1 aLohman, Kurt, K1 aLong, Jirong1 aLouie, Tin1 aMägi, Reedik1 aMahajan, Anubha1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilani, Lili1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMosley, Thomas, H1 aMunson, Peter1 aMurray, Alison, D1 aNalls, Mike, A1 aNasri, Ubaydah1 aNorris, Jill, M1 aNorth, Kari1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmas, Walter, R1 aPalmer, Nicholette, D1 aPankow, James, S1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRenstrom, Frida1 aRice, Treva, K1 aRidker, Paul, M1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSandow, Kevin1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSeshadri, Sudha1 aSever, Peter1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, X1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYuan, Jian-Min1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aChen, Yii-Der Ida1 ade Faire, Ulf1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aForrester, Terrence1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, Lessa1 aHung, Yi-Jen1 aJonas, Jost, B1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLehtimäki, Terho1 aLiang, Kae-Woei1 aMagnusson, Patrik, K E1 aNewman, Anne, B1 aOldehinkel, Albertine, J1 aPereira, Alexandre, C1 aRedline, Susan1 aRettig, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aKamatani, Yoichiro1 aLaurie, Cathy, C1 aBouchard, Claude1 aCooper, Richard, S1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aO'Connell, Jeff, R1 aPsaty, Bruce, M1 avan Dam, Rob, M1 aSims, Mario1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aFornage, Myriam1 aRotimi, Charles, N1 aProvince, Michael, A1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aReiner, Alex, P1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aCaulfield, Mark, J1 aElliott, Paul1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aChasman, Daniel, I1 aCHARGE Neurology Working Group1 aCOGENT-Kidney Consortium1 aGIANT Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/768603116nas a2200673 4500008004100000022001400041245012500055210006900180260001500249300000900264490000600273520115900279653001001438653003801448653004501486653001101531653002601542653002701568653003101595653003801626653003301664653001401697100001801711700001301729700002301742700001901765700001901784700002501803700001601828700002001844700003001864700001901894700001301913700001901926700002101945700002001966700001701986700001302003700001902016700002102035700002402056700001902080700001302099700002802112700001902140700001602159700002202175700002102197700001902218700002202237700002302259700002102282700002002303700002102323700002102344700002202365700001902387856003602406 2018 eng d a2041-172300aLarge-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.0 aLargescale wholeexome sequencing association studies identify ra c2018 10 12 a42280 v93 aElevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.
10aExome10aGenetic Predisposition to Disease10aGlucose Transport Proteins, Facilitative10aHumans10aKidney Function Tests10aMeta-Analysis as Topic10aOrganic Anion Transporters10aOrganic Cation Transport Proteins10aProtein Structure, Secondary10aUric Acid1 aTin, Adrienne1 aLi, Yong1 aBrody, Jennifer, A1 aNutile, Teresa1 aChu, Audrey, Y1 aHuffman, Jennifer, E1 aYang, Qiong1 aChen, Ming-Huei1 aRobinson-Cohen, Cassianne1 aMace, Aurelien1 aLiu, Jun1 aDemirkan, Ayse1 aSorice, Rossella1 aSedaghat, Sanaz1 aSwen, Melody1 aYu, Bing1 aGhasemi, Sahar1 aTeumer, Alexanda1 aVollenweider, Peter1 aCiullo, Marina1 aLi, Meng1 aUitterlinden, André, G1 aKraaij, Robert1 aAmin, Najaf1 avan Rooij, Jeroen1 aKutalik, Zoltán1 aDehghan, Abbas1 aMcKnight, Barbara1 aDuijn, Cornelia, M1 aMorrison, Alanna1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aFox, Caroline, S1 aWoodward, Owen, M1 aKöttgen, Anna uhttps://chs-nhlbi.org/node/792804696nas a2201189 4500008004100000245011800041210006900159260000700228300001300235490000800248520156600256100002101822700001701843700001901860700001301879700001401892700002201906700002601928700001201954700002001966700001801986700001302004700002002017700001802037700001202055700001502067700001602082700001802098700001402116700002002130700001902150700002202169700001802191700001902209700002102228700002102249700001302270700001502283700002002298700001302318700001602331700001602347700002202363700001802385700001802403700001302421700002102434700001202455700002102467700001702488700001902505700002002524700002002544700001802564700002202582700001902604700001502623700002402638700001902662700001602681700002002697700001902717700001602736700003002752700002202782700002002804700001602824700001802840700001802858700001702876700001902893700001902912700001702931700002302948700001902971700001502990700001803005700001403023700002103037700001803058700002203076700001903098700001903117700001803136700001703154700001603171700001503187700002303202700001703225700001703242700001803259700002103277700002303298700002103321700001803342700002503360700002803385700001903413700001803432700002003450856003603470 2018 eng d00a{Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects0 aLifeCourse Genomewide Association Study Metaanalysis of Total Bo c01 a88–1020 v1023 aBone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.1 aMedina-Gomez, C.1 aKemp, J., P.1 aTrajanoska, K.1 aLuan, J.1 aChesi, A.1 aAhluwalia, T., S.1 aMook-Kanamori, D., O.1 aHam, A.1 aHartwig, F., P.1 aEvans, D., S.1 aJoro, R.1 aNedeljkovic, I.1 aZheng, H., F.1 aZhu, K.1 aAtalay, M.1 aLiu, C., T.1 aNethander, M.1 aBroer, L.1 aPorleifsson, G.1 aMullin, B., H.1 aHandelman, S., K.1 aNalls, M., A.1 aJessen, L., E.1 aHeppe, D., H. M.1 aRichards, J., B.1 aWang, C.1 aChawes, B.1 aSchraut, K., E.1 aAmin, N.1 aWareham, N.1 aKarasik, D.1 aVan der Velde, N.1 aIkram, M., A.1 aZemel, B., S.1 aZhou, Y.1 aCarlsson, C., J.1 aLiu, Y.1 aMcGuigan, F., E.1 aBoer, C., G.1 aB?nnelykke, K.1 aRalston, S., H.1 aRobbins, J., A.1 aWalsh, J., P.1 aZillikens, M., C.1 aLangenberg, C.1 aLi-Gao, R.1 aWilliams, F., M. K.1 aHarris, T., B.1 aAkesson, K.1 aJackson, R., D.1 aSigurdsson, G.1 aHeijer, den1 avan der Eerden, B., C. J.1 avan de Peppel, J.1 aSpector, T., D.1 aPennell, C.1 aHorta, B., L.1 aFelix, J., F.1 aZhao, J., H.1 aWilson, S., G.1 ade Mutsert, R.1 aBisgaard, H.1 aStyrk?rsd?ttir, U.1 aJaddoe, V., W.1 aOrwoll, E.1 aLakka, T., A.1 aScott, R.1 aGrant, S., F. A.1 aLorentzon, M.1 avan Duijn, C., M.1 aWilson, J., F.1 aStefansson, K.1 aPsaty, B., M.1 aKiel, D., P.1 aOhlsson, C.1 aNtzani, E.1 avan Wijnen, A., J.1 aForgetta, V.1 aGhanbari, M.1 aLogan, J., G.1 aWilliams, G., R.1 aBassett, J., H. D.1 aCroucher, P., I.1 aEvangelou, E.1 aUitterlinden, A., G.1 aAckert-Bicknell, C., L.1 aTobias, J., H.1 aEvans, D., M.1 aRivadeneira, F. uhttps://chs-nhlbi.org/node/853802788nas a2200325 4500008004100000022001400041245013300055210006900188260001300257300001200270490000700282520178400289100002402073700002302097700002402120700002002144700002002164700002302184700002002207700002102227700001902248700002402267700002202291700002402313700002202337700002602359700002002385700002102405856003602426 2018 eng d a1941-329700aLong-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study).0 aLongTerm Cognitive Decline After Newly Diagnosed Heart Failure L c2018 Mar ae0044760 v113 aBACKGROUND: Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction.
METHODS AND RESULTS: Participants were 4864 men and women aged ≥65 years without a history of HF and free of clinical stroke in the CHS (Cardiovascular Health Study)-a community-based prospective cohort study in the United States, with cognition assessed annually from 1989/1990 through 1998/1999. We identified 496 participants with incident HF by review of hospital discharge summaries and Medicare claims data, with adjudication according to standard criteria. Global cognitive ability was measured by the Modified Mini-Mental State Examination. In adjusted models, 5-year decline in model-predicted mean Modified Mini-Mental State Examination score was 10.2 points (95% confidence interval, 8.6-11.8) after incident HF diagnosed at 80 years of age, compared with a mean 5-year decline of 5.8 points (95% confidence interval, 5.3-6.2) from 80 to 85 years of age without HF. The association was stronger at older ages than at younger ages, did not vary significantly in the presence versus absence of atrial fibrillation (=0.084), and did not vary significantly by reduced versus preserved ejection fraction (=0.734).
CONCLUSIONS: Decline in global cognitive ability tends to be faster after HF diagnosis than without HF. Clinical and public health implications of this finding warrant further attention.
1 aHammond, Christa, A1 aBlades, Natalie, J1 aChaudhry, Sarwat, I1 aDodson, John, A1 aLongstreth, W T1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aArnold, Alice, M1 aDublin, Sascha1 aSitlani, Colleen, M1 aGardin, Julius, M1 aThielke, Stephen, M1 aNanna, Michael, G1 aGottesman, Rebecca, F1 aNewman, Anne, B1 aThacker, Evan, L uhttps://chs-nhlbi.org/node/768003623nas a2200589 4500008004100000022001400041245009600055210006900151260001600220520189500236100002702131700002202158700002102180700002002201700002402221700002202245700002002267700002402287700001502311700001802326700001802344700002102362700002202383700001802405700002002423700002502443700002002468700002102488700002202509700002302531700002002554700002502574700002502599700001902624700002502643700002002668700002202688700002102710700001902731700001902750700002302769700002102792700002102813700001902834700001702853700002202870700002102892700002402913700002602937710003402963856003602997 2018 eng d a1460-238500aLow thyroid function is not associated with an accelerated deterioration in renal function.0 aLow thyroid function is not associated with an accelerated deter c2018 Apr 183 aBackground: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.
Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.
Results: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.
Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.
1 aMeuwese, Christiaan, L1 avan Diepen, Merel1 aCappola, Anne, R1 aSarnak, Mark, J1 aShlipak, Michael, G1 aBauer, Douglas, C1 aFried, Linda, P1 aIacoviello, Massimo1 aVaes, Bert1 aDegryse, Jean1 aKhaw, Kay-Tee1 aLuben, Robert, N1 aAsvold, Bjørn, O1 aBjøro, Trine1 aVatten, Lars, J1 ade Craen, Anton, J M1 aTrompet, Stella1 aIervasi, Giorgio1 aMolinaro, Sabrina1 aCeresini, Graziano1 aFerrucci, Luigi1 aDullaart, Robin, P F1 aBakker, Stephan, J L1 aJukema, Wouter1 aKearney, Patricia, M1 aStott, David, J1 aPeeters, Robin, P1 aFranco, Oscar, H1 aVölzke, Henry1 aWalsh, John, P1 aBremner, Alexandra1 aSgarbi, José, A1 aMaciel, Rui, M B1 aImaizumi, Misa1 aOhishi, Waka1 aDekker, Friedo, W1 aRodondi, Nicolas1 aGussekloo, Jacobijn1 aElzen, Wendy, P J den1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/780503699nas a2200673 4500008004100000022001400041245018700055210006900242260001600311300000900327520167400336100001402010700002002024700002102044700002402065700002402089700001602113700002302129700001402152700002002166700002202186700002002208700002002228700002802248700002202276700002402298700002202322700001902344700001602363700002302379700002102402700002802423700002302451700002402474700002202498700002102520700002602541700002102567700002002588700002202608700002102630700002202651700002002673700002302693700002202716700002002738700002502758700001702783700001902800700002002819700001902839700002502858700001902883700002102902700002002923700002102943700002502964856003602989 2018 eng d a1475-266200aMeta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.0 aMetaanalysis across Cohorts for Heart and Aging Research in Geno c2018 Sep 12 a1-123 aThe role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
1 aXu, Jiayi1 aBartz, Traci, M1 aChittoor, Geetha1 aEiriksdottir, Gudny1 aManichaikul, Ani, W1 aSun, Fangui1 aTerzikhan, Natalie1 aZhou, Xia1 aBooth, Sarah, L1 aBrusselle, Guy, G1 ade Boer, Ian, H1 aFornage, Myriam1 aFrazier-Wood, Alexis, C1 aGraff, Mariaelisa1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHofman, Albert1 aHou, Ruixue1 aHouston, Denise, K1 aJacobs, David, R1 aKritchevsky, Stephen, B1 aLatourelle, Jeanne1 aLemaitre, Rozenn, N1 aLutsey, Pamela, L1 aO'Connor, George1 aOelsner, Elizabeth, C1 aPankow, James, S1 aPsaty, Bruce, M1 aRohde, Rebecca, R1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Lewis, J1 aStricker, Bruno, H1 aVoruganti, Saroja1 aWang, Thomas, J1 aZillikens, Carola, M1 aBarr, Graham1 aDupuis, Josée1 aGharib, Sina, A1 aLahousse, Lies1 aLondon, Stephanie, J1 aNorth, Kari, E1 aSmith, Albert, V1 aSteffen, Lyn, M1 aHancock, Dana, B1 aCassano, Patricia, A uhttps://chs-nhlbi.org/node/777505089nas a2201429 4500008004100000022001400041245009100055210006900146260000900215300000600224490000600230520111900236100002501355700002601380700002001406700002101426700002001447700002001467700001901487700002501506700001301531700002001544700002301564700002501587700002801612700001801640700001201658700002401670700002101694700002101715700002101736700002301757700002001780700002401800700002001824700001901844700001901863700002201882700001601904700002801920700002401948700002301972700002401995700002302019700001802042700001602060700001602076700001702092700001602109700001702125700002302142700002502165700002102190700002102211700001802232700002102250700002502271700002002296700001702316700002402333700002602357700002202383700001902405700001502424700002202439700001802461700001802479700002002497700001902517700002002536700002302556700001202579700002002591700002802611700001702639700001602656700002402672700001902696700001902715700001902734700002102753700001902774700002102793700002902814700001902843700002002862700002802882700001802910700002302928700002402951700001902975700002002994700001603014700002003030700002403050700001903074700002203093700001903115700002403134700002103158700002403179700002203203700001603225700001803241700001703259700002303276700002003299700002203319700002003341700002603361700001803387700002403405700002203429700002303451700001903474700002403493700001703517700002103534700002503555710004303580856003603623 2018 eng d a2398-502X00aMeta-analysis of exome array data identifies six novel genetic loci for lung function.0 aMetaanalysis of exome array data identifies six novel genetic lo c2018 a40 v33 a Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
1 aJackson, Victoria, E1 aLatourelle, Jeanne, C1 aWain, Louise, V1 aSmith, Albert, V1 aGrove, Megan, L1 aBartz, Traci, M1 aObeidat, Ma'en1 aProvince, Michael, A1 aGao, Wei1 aQaiser, Beenish1 aPorteous, David, J1 aCassano, Patricia, A1 aAhluwalia, Tarunveer, S1 aGrarup, Niels1 aLi, Jin1 aAltmaier, Elisabeth1 aMarten, Jonathan1 aHarris, Sarah, E1 aManichaikul, Ani1 aPottinger, Tess, D1 aLi-Gao, Ruifang1 aLind-Thomsen, Allan1 aMahajan, Anubha1 aLahousse, Lies1 aImboden, Medea1 aTeumer, Alexander1 aPrins, Bram1 aLyytikäinen, Leo-Pekka1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aSitlani, Colleen, M1 aBrody, Jennifer, A1 aBossé, Yohan1 aTimens, Wim1 aKraja, Aldi1 aLoukola, Anu1 aTang, Wenbo1 aLiu, Yongmei1 aBork-Jensen, Jette1 aJustesen, Johanne, M1 aLinneberg, Allan1 aLange, Leslie, A1 aRawal, Rajesh1 aKarrasch, Stefan1 aHuffman, Jennifer, E1 aSmith, Blair, H1 aDavies, Gail1 aBurkart, Kristin, M1 aMychaleckyj, Josyf, C1 aBonten, Tobias, N1 aEnroth, Stefan1 aLind, Lars1 aBrusselle, Guy, G1 aKumar, Ashish1 aStubbe, Beate1 aKähönen, Mika1 aWyss, Annah, B1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aHao, Ke1 aRantanen, Taina1 aKritchevsky, Stephen, B1 aLohman, Kurt1 aSkaaby, Tea1 aPisinger, Charlotta1 aHansen, Torben1 aSchulz, Holger1 aPolasek, Ozren1 aCampbell, Archie1 aStarr, John, M1 aRich, Stephen, S1 aMook-Kanamori, Dennis, O1 aJohansson, Asa1 aIngelsson, Erik1 aUitterlinden, André, G1 aWeiss, Stefan1 aRaitakari, Olli, T1 aGudnason, Vilmundur1 aNorth, Kari, E1 aGharib, Sina, A1 aSin, Don, D1 aTaylor, Kent, D1 aO'Connor, George, T1 aKaprio, Jaakko1 aHarris, Tamara, B1 aPederson, Oluf1 aVestergaard, Henrik1 aWilson, James, G1 aStrauch, Konstantin1 aHayward, Caroline1 aKerr, Shona1 aDeary, Ian, J1 aBarr, Graham1 ade Mutsert, Renée1 aGyllensten, Ulf1 aMorris, Andrew, P1 aIkram, Arfan, M1 aProbst-Hensch, Nicole1 aGläser, Sven1 aZeggini, Eleftheria1 aLehtimäki, Terho1 aStrachan, David, P1 aDupuis, Josée1 aMorrison, Alanna, C1 aHall, Ian, P1 aTobin, Martin, D1 aLondon, Stephanie, J1 aUnderstanding Society Scientific Group uhttps://chs-nhlbi.org/node/779507136nas a2202245 4500008004100000022001400041245011700055210006900172260001300241300001000254490000700264520074900271100002301020700003301043700002401076700002601100700002301126700001301149700001701162700002001179700002101199700001701220700001901237700003201256700002101288700002301309700002301332700002501355700003101380700002101411700002201432700002201454700002401476700001701500700002201517700002101539700003101560700002001591700002001611700001801631700002501649700003101674700002501705700002101730700001701751700002301768700002001791700002101811700002101832700002401853700002201877700001801899700001901917700002001936700001801956700001801974700002001992700002102012700002002033700002402053700002802077700001902105700002302124700001902147700002202166700002402188700002002212700002102232700002002253700002402273700001902297700001802316700002002334700002202354700001602376700001902392700002102411700002502432700001602457700002102473700002702494700002002521700001802541700002502559700002202584700002102606700002002627700002102647700002602668700002402694700002502718700002402743700001902767700001902786700001802805700001802823700002102841700001902862700002002881700002302901700001802924700001702942700001802959700002202977700002302999700002103022700001203043700001803055700002003073700002503093700001803118700002103136700002003157700002603177700002503203700002303228700002103251700001803272700002203290700001703312700001703329700002003346700001703366700002003383700002003403700002103423700003003444700001903474700002403493700002603517700002303543700001903566700001903585700002203604700002203626700002203648700002203670700002603692700002303718700002203741700002303763700002603786700002103812700002403833700002103857700002303878700002003901700002203921700001803943700002603961700002203987700002004009700002104029700002004050700002204070700001804092700002104110700002304131700002304154700002304177700002404200700002504224700002804249700002404277700002304301700002304324700002804347700002804375700001904403700002204422700002104444700002204465700002004487700002004507700002104527700002004548700002004568700002004588700002104608700002304629700002004652700002104672700001904693700001904712700002304731700001704754700002004771710006304791856003604854 2018 eng d a1546-171800aMultiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.0 aMultiancestry association study identifies new asthma risk loci c2018 Jan a42-530 v503 aWe examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
1 aDemenais, Florence1 aMargaritte-Jeannin, Patricia1 aBarnes, Kathleen, C1 aCookson, William, O C1 aAltmüller, Janine1 aAng, Wei1 aBarr, Graham1 aBeaty, Terri, H1 aBecker, Allan, B1 aBeilby, John1 aBisgaard, Hans1 aBjornsdottir, Unnur, Steina1 aBleecker, Eugene1 aBønnelykke, Klaus1 aBoomsma, Dorret, I1 aBouzigon, Emmanuelle1 aBrightling, Christopher, E1 aBrossard, Myriam1 aBrusselle, Guy, G1 aBurchard, Esteban1 aBurkart, Kristin, M1 aBush, Andrew1 aChan-Yeung, Moira1 aChung, Kian, Fan1 aAlves, Alexessander, Couto1 aCurtin, John, A1 aCustovic, Adnan1 aDaley, Denise1 ade Jongste, Johan, C1 aDel-Rio-Navarro, Blanca, E1 aDonohue, Kathleen, M1 aDuijts, Liesbeth1 aEng, Celeste1 aEriksson, Johan, G1 aFarrall, Martin1 aFedorova, Yuliya1 aFeenstra, Bjarke1 aFerreira, Manuel, A1 aFreidin, Maxim, B1 aGajdos, Zofia1 aGauderman, Jim1 aGehring, Ulrike1 aGeller, Frank1 aGenuneit, Jon1 aGharib, Sina, A1 aGilliland, Frank1 aGranell, Raquel1 aGraves, Penelope, E1 aGudbjartsson, Daniel, F1 aHaahtela, Tari1 aHeckbert, Susan, R1 aHeederik, Dick1 aHeinrich, Joachim1 aHeliövaara, Markku1 aHenderson, John1 aHimes, Blanca, E1 aHirose, Hiroshi1 aHirschhorn, Joel, N1 aHofman, Albert1 aHolt, Patrick1 aHottenga, Jouke1 aHudson, Thomas, J1 aHui, Jennie1 aImboden, Medea1 aIvanov, Vladimir1 aJaddoe, Vincent, W V1 aJames, Alan1 aJanson, Christer1 aJarvelin, Marjo-Riitta1 aJarvis, Deborah1 aJones, Graham1 aJonsdottir, Ingileif1 aJousilahti, Pekka1 aKabesch, Michael1 aKähönen, Mika1 aKantor, David, B1 aKarunas, Alexandra, S1 aKhusnutdinova, Elza1 aKoppelman, Gerard, H1 aKozyrskyj, Anita, L1 aKreiner, Eskil1 aKubo, Michiaki1 aKumar, Rajesh1 aKumar, Ashish1 aKuokkanen, Mikko1 aLahousse, Lies1 aLaitinen, Tarja1 aLaprise, Catherine1 aLathrop, Mark1 aLau, Susanne1 aLee, Young-Ae1 aLehtimäki, Terho1 aLetort, Sébastien1 aLevin, Albert, M1 aLi, Guo1 aLiang, Liming1 aLoehr, Laura, R1 aLondon, Stephanie, J1 aLoth, Daan, W1 aManichaikul, Ani1 aMarenholz, Ingo1 aMartinez, Fernando, J1 aMatheson, Melanie, C1 aMathias, Rasika, A1 aMatsumoto, Kenji1 aMbarek, Hamdi1 aMcArdle, Wendy, L1 aMelbye, Mads1 aMelén, Erik1 aMeyers, Deborah1 aMichel, Sven1 aMohamdi, Hamida1 aMusk, Arthur, W1 aMyers, Rachel, A1 aNieuwenhuis, Maartje, A E1 aNoguchi, Emiko1 aO'Connor, George, T1 aOgorodova, Ludmila, M1 aPalmer, Cameron, D1 aPalotie, Aarno1 aPark, Julie, E1 aPennell, Craig, E1 aPershagen, Göran1 aPolonikov, Alexey1 aPostma, Dirkje, S1 aProbst-Hensch, Nicole1 aPuzyrev, Valery, P1 aRaby, Benjamin, A1 aRaitakari, Olli, T1 aRamasamy, Adaikalavan1 aRich, Stephen, S1 aRobertson, Colin, F1 aRomieu, Isabelle1 aSalam, Muhammad, T1 aSalomaa, Veikko1 aSchlünssen, Vivi1 aScott, Robert1 aSelivanova, Polina, A1 aSigsgaard, Torben1 aSimpson, Angela1 aSiroux, Valérie1 aSmith, Lewis, J1 aSolodilova, Maria1 aStandl, Marie1 aStefansson, Kari1 aStrachan, David, P1 aStricker, Bruno, H1 aTakahashi, Atsushi1 aThompson, Philip, J1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiesler, Carla, M T1 aTorgerson, Dara, G1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 avan der Valk, Ralf, J P1 aVaysse, Amaury1 aVedantam, Sailaja1 avon Berg, Andrea1 avon Mutius, Erika1 aVonk, Judith, M1 aWaage, Johannes1 aWareham, Nick, J1 aWeiss, Scott, T1 aWhite, Wendy, B1 aWickman, Magnus1 aWiden, Elisabeth1 aWillemsen, Gonneke1 aWilliams, Keoki1 aWouters, Inge, M1 aYang, James, J1 aZhao, Jing Hua1 aMoffatt, Miriam, F1 aOber, Carole1 aNicolae, Dan, L1 aAustralian Asthma Genetics Consortium (AAGC) collaborators uhttps://chs-nhlbi.org/node/755816401nas a2205425 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2018 eng d a1546-171800aMultiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.0 aMultiancestry genomewide association study of 520000 subjects id c2018 Apr a524-5370 v503 aStroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aBis, Joshua, C1 aPastinen, Tomi1 aRuusalepp, Arno1 aSchadt, Eric, E1 aKoplev, Simon1 aBjörkegren, Johan, L M1 aCodoni, Veronica1 aCivelek, Mete1 aSmith, Nicholas, L1 aTrégouët, David, A1 aChristophersen, Ingrid, E1 aRoselli, Carolina1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aTai, Shyong, E1 aKooner, Jaspal, S1 aKato, Norihiro1 aHe, Jiang1 aHarst, Pim1 aElliott, Paul1 aChambers, John, C1 aTakeuchi, Fumihiko1 aJohnson, Andrew, D1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aAmin, Najaf1 aAparicio, Hugo, S1 aArnett, Donna, K1 aAttia, John1 aBeiser, Alexa, S1 aBerr, Claudine1 aBuring, Julie, E1 aBustamante, Mariana1 aCaso, Valeria1 aCheng, Yu-Ching1 aChoi, Seung, Hoan1 aChowhan, Ayesha1 aCullell, Natalia1 aDartigues, Jean-François1 aDelavaran, Hossein1 aDelgado, Pilar1 aDörr, Marcus1 aEngström, Gunnar1 aFord, Ian1 aGurpreet, Wander, S1 aHamsten, Anders1 aHeitsch, Laura1 aHozawa, Atsushi1 aIbanez, Laura1 aIlinca, Andreea1 aIngelsson, Martin1 aIwasaki, Motoki1 aJackson, Rebecca, D1 aJood, Katarina1 aJousilahti, Pekka1 aKaffashian, Sara1 aKalra, Lalit1 aKamouchi, Masahiro1 aKitazono, Takanari1 aKjartansson, Olafur1 aKloss, Manja1 aKoudstaal, Peter, J1 aKrupinski, Jerzy1 aLabovitz, Daniel, L1 aLaurie, Cathy, C1 aLevi, Christopher, R1 aLi, Linxin1 aLind, Lars1 aLindgren, Cecilia, M1 aLioutas, Vasileios1 aLiu, Yong, Mei1 aLopez, Oscar, L1 aMakoto, Hirata1 aMartinez-Majander, Nicolas1 aMatsuda, Koichi1 aMinegishi, Naoko1 aMontaner, Joan1 aMorris, Andrew, P1 aMuiño, Elena1 aMüller-Nurasyid, Martina1 aNorrving, Bo1 aOgishima, Soichi1 aParati, Eugenio, A1 aPeddareddygari, Leema, Reddy1 aPedersen, Nancy, L1 aPera, Joanna1 aPerola, Markus1 aPezzini, Alessandro1 aPileggi, Silvana1 aRabionet, Raquel1 aRiba-Llena, Iolanda1 aRibasés, Marta1 aRomero, Jose, R1 aRoquer, Jaume1 aRudd, Anthony, G1 aSarin, Antti-Pekka1 aSarju, Ralhan1 aSarnowski, Chloe1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSatoh, Mamoru1 aSattar, Naveed1 aSawada, Norie1 aSibolt, Gerli1 aSigurdsson, Ásgeir1 aSmith, Albert1 aSobue, Kenji1 aSoriano-Tárraga, Carolina1 aStanne, Tara1 aStine, Colin1 aStott, David, J1 aStrauch, Konstantin1 aTakai, Takako1 aTanaka, Hideo1 aTanno, Kozo1 aTeumer, Alexander1 aTomppo, Liisa1 aTorres-Aguila, Nuria, P1 aTouze, Emmanuel1 aTsugane, Shoichiro1 aUitterlinden, André, G1 aValdimarsson, Einar, M1 avan der Lee, Sven, J1 aVölzke, Henry1 aWakai, Kenji1 aWeir, David1 aWilliams, Stephen, R1 aWolfe, Charles, D A1 aWong, Quenna1 aXu, Huichun1 aYamaji, Taiki1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aAFGen Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium1 aInternational Genomics of Blood Pressure (iGEN-BP) Consortium1 aINVENT Consortium1 aSTARNET1 aBioBank Japan Cooperative Hospital Group1 aCOMPASS Consortium1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aInternational Stroke Genetics Consortium (ISGC)1 aMETASTROKE Consortium1 aNeurology Working Group of the CHARGE Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aUK Young Lacunar DNA Study1 aMEGASTROKE Consortium1 aMEGASTROKE Consortium: uhttps://chs-nhlbi.org/node/768308664nas a2202749 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2018 eng d a1546-171800aMulti-ethnic genome-wide association study for atrial fibrillation.0 aMultiethnic genomewide association study for atrial fibrillation c2018 Sep a1225-12330 v503 aAtrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
1 aRoselli, Carolina1 aChaffin, Mark, D1 aWeng, Lu-Chen1 aAeschbacher, Stefanie1 aAhlberg, Gustav1 aAlbert, Christine, M1 aAlmgren, Peter1 aAlonso, Alvaro1 aAnderson, Christopher, D1 aAragam, Krishna, G1 aArking, Dan, E1 aBarnard, John1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aBihlmeyer, Nathan, A1 aBis, Joshua, C1 aBloom, Heather, L1 aBoerwinkle, Eric1 aBottinger, Erwin, B1 aBrody, Jennifer, A1 aCalkins, Hugh1 aCampbell, Archie1 aCappola, Thomas, P1 aCarlquist, John1 aChasman, Daniel, I1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aChoi, Eue-Keun1 aChoi, Seung, Hoan1 aChristophersen, Ingrid, E1 aChung, Mina, K1 aCole, John, W1 aConen, David1 aCook, James1 aCrijns, Harry, J1 aCutler, Michael, J1 aDamrauer, Scott, M1 aDaniels, Brian, R1 aDarbar, Dawood1 aDelgado, Graciela1 aDenny, Joshua, C1 aDichgans, Martin1 aDörr, Marcus1 aDudink, Elton, A1 aDudley, Samuel, C1 aEsa, Nada1 aEsko, Tõnu1 aEskola, Markku1 aFatkin, Diane1 aFelix, Stephan, B1 aFord, Ian1 aFranco, Oscar, H1 aGeelhoed, Bastiaan1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGupta, Namrata1 aGustafsson, Stefan1 aGutmann, Rebecca1 aHamsten, Anders1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHernesniemi, Jussi1 aHocking, Lynne, J1 aHofman, Albert1 aHorimoto, Andrea, R V R1 aHuang, Jie1 aHuang, Paul, L1 aHuffman, Jennifer1 aIngelsson, Erik1 aIpek, Esra, Gucuk1 aIto, Kaoru1 aJimenez-Conde, Jordi1 aJohnson, Renee1 aJukema, Wouter1 aKääb, Stefan1 aKähönen, Mika1 aKamatani, Yoichiro1 aKane, John, P1 aKastrati, Adnan1 aKathiresan, Sekar1 aKatschnig-Winter, Petra1 aKavousi, Maryam1 aKessler, Thorsten1 aKietselaer, Bas, L1 aKirchhof, Paulus1 aKleber, Marcus, E1 aKnight, Stacey1 aKrieger, Jose, E1 aKubo, Michiaki1 aLauner, Lenore, J1 aLaurikka, Jari1 aLehtimäki, Terho1 aLeineweber, Kirsten1 aLemaitre, Rozenn, N1 aLi, Man1 aLim, Hong, Euy1 aLin, Henry, J1 aLin, Honghuang1 aLind, Lars1 aLindgren, Cecilia, M1 aLokki, Marja-Liisa1 aLondon, Barry1 aLoos, Ruth, J F1 aLow, Siew-Kee1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMacfarlane, Peter, W1 aMagnusson, Patrik, K1 aMahajan, Anubha1 aMalik, Rainer1 aMansur, Alfredo, J1 aMarcus, Gregory, M1 aMargolin, Lauren1 aMargulies, Kenneth, B1 aMärz, Winfried1 aMcManus, David, D1 aMelander, Olle1 aMohanty, Sanghamitra1 aMontgomery, Jay, A1 aMorley, Michael, P1 aMorris, Andrew, P1 aMüller-Nurasyid, Martina1 aNatale, Andrea1 aNazarian, Saman1 aNeumann, Benjamin1 aNewton-Cheh, Christopher1 aNiemeijer, Maartje, N1 aNikus, Kjell1 aNilsson, Peter1 aNoordam, Raymond1 aOellers, Heidi1 aOlesen, Morten, S1 aOrho-Melander, Marju1 aPadmanabhan, Sandosh1 aPak, Hui-Nam1 aParé, Guillaume1 aPedersen, Nancy, L1 aPera, Joanna1 aPereira, Alexandre1 aPorteous, David1 aPsaty, Bruce, M1 aPulit, Sara, L1 aPullinger, Clive, R1 aRader, Daniel, J1 aRefsgaard, Lena1 aRibasés, Marta1 aRidker, Paul, M1 aRienstra, Michiel1 aRisch, Lorenz1 aRoden, Dan, M1 aRosand, Jonathan1 aRosenberg, Michael, A1 aRost, Natalia1 aRotter, Jerome, I1 aSaba, Samir1 aSandhu, Roopinder, K1 aSchnabel, Renate, B1 aSchramm, Katharina1 aSchunkert, Heribert1 aSchurman, Claudia1 aScott, Stuart, A1 aSeppälä, Ilkka1 aShaffer, Christian1 aShah, Svati1 aShalaby, Alaa, A1 aShim, Jaemin1 aShoemaker, Benjamin1 aSiland, Joylene, E1 aSinisalo, Juha1 aSinner, Moritz, F1 aSlowik, Agnieszka1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Gustav1 aSmith, Jonathan, D1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSun, Albert1 aSun, Han1 aSvendsen, Jesper, H1 aTanaka, Toshihiro1 aTanriverdi, Kahraman1 aTaylor, Kent, D1 aTeder-Laving, Maris1 aTeumer, Alexander1 aThériault, Sébastien1 aTrompet, Stella1 aTucker, Nathan, R1 aTveit, Arnljot1 aUitterlinden, André, G1 aHarst, Pim1 aVan Gelder, Isabelle, C1 aVan Wagoner, David, R1 aVerweij, Niek1 aVlachopoulou, Efthymia1 aVölker, Uwe1 aWang, Biqi1 aWeeke, Peter, E1 aWeijs, Bob1 aWeiss, Raul1 aWeiss, Stefan1 aWells, Quinn, S1 aWiggins, Kerri, L1 aWong, Jorge, A1 aWoo, Daniel1 aWorrall, Bradford, B1 aYang, Pil-Sung1 aYao, Jie1 aYoneda, Zachary, T1 aZeller, Tanja1 aZeng, Lingyao1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/781104963nas a2201357 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2018 eng d a2041-172300aMultiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.0 aMultiethnic metaanalysis identifies ancestryspecific and crossan c2018 Jul 30 a29760 v93 aNearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
1 aWyss, Annah, B1 aSofer, Tamar1 aLee, Mi, Kyeong1 aTerzikhan, Natalie1 aNguyen, Jennifer, N1 aLahousse, Lies1 aLatourelle, Jeanne, C1 aSmith, Albert, Vernon1 aBartz, Traci, M1 aFeitosa, Mary, F1 aGao, Wei1 aAhluwalia, Tarunveer, S1 aTang, Wenbo1 aOldmeadow, Christopher1 aDuan, Qing1 ade Jong, Kim1 aWojczynski, Mary, K1 aWang, Xin-Qun1 aNoordam, Raymond1 aHartwig, Fernando, Pires1 aJackson, Victoria, E1 aWang, Tianyuan1 aObeidat, Ma'en1 aHobbs, Brian, D1 aHuan, Tianxiao1 aGui, Hongsheng1 aParker, Margaret, M1 aHu, Donglei1 aMogil, Lauren, S1 aKichaev, Gleb1 aJin, Jianping1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aKalhan, Ravi1 aHeckbert, Susan, R1 aPaternoster, Lavinia1 aBurkart, Kristin, M1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aWilson, James, G1 aVonk, Judith, M1 aSanders, Jason, L1 aBarr, Graham1 ade Mutsert, Renée1 aMenezes, Ana, Maria Bapt1 aAdams, Hieab, H H1 avan den Berge, Maarten1 aJoehanes, Roby1 aLevin, Albert, M1 aLiberto, Jennifer1 aLauner, Lenore, J1 aMorrison, Alanna, C1 aSitlani, Colleen, M1 aCeledón, Juan, C1 aKritchevsky, Stephen, B1 aScott, Rodney, J1 aChristensen, Kaare1 aRotter, Jerome, I1 aBonten, Tobias, N1 aWehrmeister, Fernando, César1 aBossé, Yohan1 aXiao, Shujie1 aOh, Sam1 aFranceschini, Nora1 aBrody, Jennifer, A1 aKaplan, Robert, C1 aLohman, Kurt1 aMcEvoy, Mark1 aProvince, Michael, A1 aRosendaal, Frits, R1 aTaylor, Kent, D1 aNickle, David, C1 aWilliams, Keoki1 aBurchard, Esteban, G1 aWheeler, Heather, E1 aSin, Don, D1 aGudnason, Vilmundur1 aNorth, Kari, E1 aFornage, Myriam1 aPsaty, Bruce, M1 aMyers, Richard, H1 aO'Connor, George1 aHansen, Torben1 aLaurie, Cathy, C1 aCassano, Patricia, A1 aSung, Joohon1 aKim, Woo, Jin1 aAttia, John, R1 aLange, Leslie1 aBoezen, Marike1 aThyagarajan, Bharat1 aRich, Stephen, S1 aMook-Kanamori, Dennis, O1 aHorta, Bernardo, Lessa1 aUitterlinden, André, G1 aIm, Hae, Kyung1 aCho, Michael, H1 aBrusselle, Guy, G1 aGharib, Sina, A1 aDupuis, Josée1 aManichaikul, Ani1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/781904205nas a2200877 4500008004100000022001400041245012500055210006900180260001300249300001200262490000700274520175300281100001402034700001902048700002202067700002302089700002302112700001702135700002402152700002502176700001802201700002002219700002002239700002302259700001502282700002102297700001602318700002802334700002002362700002202382700002002404700002102424700002202445700001902467700002102486700002402507700002002531700001902551700002002570700002002590700002202610700002002632700002802652700001902680700002102699700001902720700002202739700001402761700002202775700002002797700001902817700001502836700002002851700001802871700001902889700001702908700002002925700002202945700002502967700002302992700001903015700001703034700002003051700002003071700002003091700002003111700002103131700002403152700002103176700001803197700002303215700001803238700001603256700001903272856003603291 2018 eng d a1535-498900aMultiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.0 aMultiethnic MetaAnalysis Identifies RAI1 as a Possible Obstructi c2018 Mar a391-4010 v583 aObstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.
1 aChen, Han1 aCade, Brian, E1 aGleason, Kevin, J1 aBjonnes, Andrew, C1 aStilp, Adrienne, M1 aSofer, Tamar1 aConomos, Matthew, P1 aAncoli-Israel, Sonia1 aArens, Raanan1 aAzarbarzin, Ali1 aBell, Graeme, I1 aBelow, Jennifer, E1 aChun, Sung1 aEvans, Daniel, S1 aEwert, Ralf1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aHaba-Rubio, José1 aHagen, Erika, W1 aHeinzer, Raphael1 aHillman, David, R1 aJohnson, Craig1 aKutalik, Zoltán1 aLane, Jacqueline, M1 aLarkin, Emma, K1 aLee, Seung, Ku1 aLiang, Jingjing1 aLoredo, Jose, S1 aMukherjee, Sutapa1 aPalmer, Lyle, J1 aPapanicolaou, George, J1 aPenzel, Thomas1 aPeppard, Paul, E1 aPost, Wendy, S1 aRamos, Alberto, R1 aRice, Ken1 aRotter, Jerome, I1 aSands, Scott, A1 aShah, Neomi, A1 aShin, Chol1 aStone, Katie, L1 aStubbe, Beate1 aSul, Jae, Hoon1 aTafti, Mehdi1 aTaylor, Kent, D1 aTeumer, Alexander1 aThornton, Timothy, A1 aTranah, Gregory, J1 aWang, Chaolong1 aWang, Heming1 aWarby, Simon, C1 aWellman, Andrew1 aZee, Phyllis, C1 aHanis, Craig, L1 aLaurie, Cathy, C1 aGottlieb, Daniel, J1 aPatel, Sanjay, R1 aZhu, Xiaofeng1 aSunyaev, Shamil, R1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/767511027nas a2203421 4500008004100000022001400041245014400055210006900199260000900268300001300277490000700290520159600297100002101893700001901914700002301933700001701956700002301973700001901996700001702015700002302032700002002055700001702075700002002092700002102112700002302133700001702156700002002173700002202193700002102215700002402236700002102260700002002281700002002301700002402321700002202345700002102367700002502388700002802413700002002441700002202461700002002483700002102503700002402524700002402548700001702572700002202589700001602611700002102627700002002648700001302668700001902681700001502700700001502715700002302730700002102753700001402774700001802788700002102806700002002827700002902847700002202876700002102898700002202919700001802941700001702959700001902976700002502995700001903020700001703039700002303056700001903079700002103098700001703119700002503136700002303161700002203184700002703206700002003233700002203253700001703275700001803292700002103310700001803331700001703349700001903366700001803385700001903403700001603422700001603438700001903454700001903473700001403492700002103506700002003527700002103547700001803568700001803586700002203604700002203626700002603648700002803674700002303702700002103725700001903746700002603765700002303791700002103814700001503835700002003850700001503870700002203885700001703907700002203924700002503946700002103971700002203992700002104014700002404035700002104059700002504080700001904105700001204124700002104136700001904157700001604176700001704192700002504209700002104234700002204255700001404277700002004291700002004311700001904331700002304350700002004373700001704393700002204410700002304432700002804455700001904483700002104502700002804523700001904551700002204570700001904592700002304611700002404634700002204658700002004680700001904700700001304719700001504732700001704747700001704764700001504781700001504796700001804811700002304829700002204852700002104874700002104895700001704916700002104933700002304954700001904977700002704996700002205023700002005045700002305065700002605088700001805114700002305132700002005155700002405175700001805199700002205217700002305239700001805262700001905280700002405299700002205323700002405345700002505369700001905394700002205413700002005435700001405455700002005469700001605489700002405505700002305529700002005552700001905572700002405591700002605615700002305641700001405664700002005678700001905698700002105717700002305738700002805761700002405789700002605813700001605839700001905855700001705874700002405891700001305915700001705928700001905945700001405964700002305978700002106001700002106022700002206043700002206065700001806087700001606105700002006121700002006141700002306161700002206184700002106206700002206227700002306249700002306272700001906295700002206314700002106336700001906357700002106376700001906397700002206416700002906438700002706467700002906494700002706523700001906550700002306569700002106592700002206613700001706635700001706652700001506669700002606684700002506710700001806735700001906753700003006772700001706802700001506819700002106834700002306855700002206878700002406900700002306924700002406947700001706971700002606988700002007014700002007034700002007054700002107074700001807095700002907113700002007142700002307162700002507185700002107210700001807231700002207249700002307271700001907294700002007313700002407333700001907357700001807376700002407394700001807418700002307436700002407459700002007483700002507503700001707528710002407545856003607569 2018 eng d a1932-620300aNovel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.0 aNovel genetic associations for blood pressure identified via gen c2018 ae01981660 v133 aHeavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1 aFeitosa, Mary, F1 aKraja, Aldi, T1 aChasman, Daniel, I1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aBentley, Amy, R1 aBrown, Michael, R1 aSchwander, Karen1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aWojczynski, Mary, K1 aAlver, Maris1 aBoissel, Mathilde1 aCai, Qiuyin1 aCampbell, Archie1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLuan, Jian'an1 aMatoba, Nana1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRiaz, Muhammad1 aRueedi, Rico1 aRobino, Antonietta1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVitart, Veronique1 aWang, Yajuan1 aWare, Erin, B1 aWarren, Helen, R1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBoerwinkle, Eric1 aBorecki, Ingrid1 aBroeckel, Ulrich1 aBrown, Morris1 aBrumat, Marco1 aBurke, Gregory, L1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aCharumathi, Sabanayagam1 aChen, Yii-Der, Ida1 aConnell, John, M1 aCorrea, Adolfo1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDeng, Xuan1 aDing, Jingzhong1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEppinga, Ruben, N1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFelix, Stephan, B1 aForouhi, Nita, G1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGigante, Bruna1 aGu, Charles1 aGu, Dongfeng1 aHagenaars, Saskia, P1 aHallmans, Göran1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJohn, Ulrich1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLin, Shiow1 aLiu, Jianjun1 aLiu, Jingmin1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aNalls, Mike, A1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aNorris, Jill, M1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPerls, Thomas1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRoll, Kathryn1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRotter, Jerome, I1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aSchupf, Nicole1 aScott, William, R1 aSever, Peter, S1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVollenweider, Peter1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, Xing1 aBin Wei, Wen1 aWilliams, Christine1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLaakso, Markku1 aLaurie, Cathy, C1 aLeander, Karin1 aLehtimäki, Terho1 aStudy, Lifelines, Cohort1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPolasek, Ozren1 aPorteous, David, J1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aBouchard, Claude1 aChristensen, Kaare1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPereira, Alexandre, C1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aGauderman, James1 aZhu, Xiaofeng1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aKooperberg, Charles1 aPalmas, Walter1 aRice, Kenneth1 aMorrison, Alanna, C1 aElliott, Paul1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aRao, Dabeeru, C1 aProvince, Michael, A1 aLevy, Daniel1 aInterAct Consortium uhttps://chs-nhlbi.org/node/779204010nas a2200709 4500008004100000022001400041245010600055210006900161260001600230520196000246100001402206700002202220700002002242700001602262700002402278700002102302700002102323700001602344700002302360700002702383700002302410700001802433700002002451700002202471700002402493700001402517700002002531700002202551700002202573700002002595700002102615700002202636700002402658700002102682700002602703700002002729700002702749700002202776700002102798700002202819700002002841700002002861700002202881700002102903700002802924700002202952700001502974700002102989700002003010700002503030700002503055700001703080700001903097700002003116700002403136700001903160700001903179700002003198700002503218700002103243856003603264 2018 eng d a1535-497000aOmega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.0 aOmega3 Fatty Acids and Genomewide Interaction Analyses Reveal DP c2018 Sep 103 aRATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.
OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.
METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.
RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4×10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (P=2.1×10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1×10; β=36.2mL).
CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.
1 aXu, Jiayi1 aGaddis, Nathan, C1 aBartz, Traci, M1 aHou, Ruixue1 aManichaikul, Ani, W1 aPankratz, Nathan1 aSmith, Albert, V1 aSun, Fangui1 aTerzikhan, Natalie1 aMarkunas, Christina, A1 aPatchen, Bonnie, K1 aSchu, Matthew1 aBeydoun, May, A1 aBrusselle, Guy, G1 aEiriksdottir, Gudny1 aZhou, Xia1 aWood, Alexis, C1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aIkram, Arfan, M1 aJacobs, David, R1 aLauner, Lenore, J1 aLemaitre, Rozenn, N1 aO'Connor, George1 aOelsner, Elizabeth, C1 aPsaty, Bruce, M1 aRamachandran, Vasan, S1 aRohde, Rebecca, R1 aRich, Stephen, S1 aRotter, Jerome, I1 aSeshadri, Sudha1 aSmith, Lewis, J1 aTiemeier, Henning1 aTsai, Michael, Y1 aUitterlinden, André, G1 aVoruganti, Saroja1 aXu, Hanfei1 aZilhão, Nuno, R1 aFornage, Myriam1 aZillikens, Carola, M1 aLondon, Stephanie, J1 aBarr, Graham1 aDupuis, Josée1 aGharib, Sina, A1 aGudnason, Vilmundur1 aLahousse, Lies1 aNorth, Kari, E1 aSteffen, Lyn, M1 aCassano, Patricia, A1 aHancock, Dana, B uhttps://chs-nhlbi.org/node/777602793nas a2200289 4500008004100000022001400041245010900055210006900164260001600233300001200249490000800261520193000269100002002199700002402219700002302243700001702266700002302283700002002306700001802326700001902344700002202363700002402385700002302409700001402432700002102446856003602467 2018 eng d a1873-675000aOutdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study.0 aOutdoor air pollution and mosaic loss of chromosome Y in older m c2018 Apr 23 a239-2470 v1163 aBACKGROUND: Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear.
OBJECTIVE: We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY.
METHODS: We analyzed baseline (1989-1993) blood samples from 933 men ≥65 years of age from the prospective Cardiovascular Health Study. Particulate matter ≤10 μm (PM), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR.
RESULTS: Increased PM was associated with mLOY, namely decreased mLRR (p-trend = 0.03). Compared with the lowest tertile (≤28.5 μg/m), the middle (28.5-31.0 μg/m; β = -0.0044, p = 0.09) and highest (≥31 μg/m; β = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (β = -0.00035, p = 0.06) and smoking pack-years (β = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants.
CONCLUSIONS: PM may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.
1 aY Y Wong, Jason1 aMargolis, Helene, G1 aMachiela, Mitchell1 aZhou, Weiyin1 aOdden, Michelle, C1 aPsaty, Bruce, M1 aRobbins, John1 aJones, Rena, R1 aRotter, Jerome, I1 aChanock, Stephen, J1 aRothman, Nathaniel1 aLan, Qing1 aLee, Jennifer, S uhttps://chs-nhlbi.org/node/766305872nas a2201645 4500008004100000022001400041245013800055210006900193260001600262300000900278490000600287520118400293100002401477700002301501700002001524700002401544700002001568700002001588700002601608700002101634700001901655700002801674700002201702700002201724700002801746700002301774700003001797700001901827700002501846700002401871700002301895700002101918700002201939700002001961700002201981700002002003700001802023700001802041700001702059700002002076700002702096700001902123700001802142700001402160700002402174700002102198700001902219700002402238700001902262700001902281700002202300700001902322700002402341700002002365700002202385700002402407700002202431700002102453700001702474700002202491700001602513700001902529700002102548700002002569700001802589700001702607700002302624700002202647700001902669700001802688700002002706700002202726700002502748700002202773700002402795700002202819700002502841700002002866700002802886700002002914700001802934700002602952700002302978700002203001700001603023700002203039700002403061700002903085700002203114700002303136700002003159700002403179700002403203700002003227700002403247700002303271700002803294700002803322700002603350700001703376700001903393700002603412700002203438700002103460700001803481700001903499700002203518700002503540700002403565700002103589700001803610700002003628700002103648700002403669700002203693700002303715700002103738700001903759700001903778700002203797700001703819700002403836700001803860700001903878700002003897700001803917700002403935700002403959700002103983700002304004700001504027700002304042700002104065700002004086700002504106700001804131700001904149700002204168856003604190 2018 eng d a2041-172300aPR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.0 aPR interval genomewide association metaanalysis identifies 50 lo c2018 Jul 25 a29040 v93 aElectrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
1 avan Setten, Jessica1 aBrody, Jennifer, A1 aJamshidi, Yalda1 aSwenson, Brenton, R1 aButler, Anne, M1 aCampbell, Harry1 aDel Greco, Fabiola, M1 aEvans, Daniel, S1 aGibson, Quince1 aGudbjartsson, Daniel, F1 aKerr, Kathleen, F1 aKrijthe, Bouwe, P1 aLyytikäinen, Leo-Pekka1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRitchie, Marylyn, D1 aRobino, Antonietta1 aSmith, Albert, V1 aSteri, Maristella1 aTanaka, Toshiko1 aTeumer, Alexander1 aTrompet, Stella1 aUlivi, Sheila1 aVerweij, Niek1 aYin, Xiaoyan1 aArnar, David, O1 aAsselbergs, Folkert, W1 aBader, Joel, S1 aBarnard, John1 aBis, Josh1 aBlankenberg, Stefan1 aBoerwinkle, Eric1 aBradford, Yuki1 aBuckley, Brendan, M1 aChung, Mina, K1 aCrawford, Dana1 aHoed, Marcel, den1 aDenny, Josh, C1 aDominiczak, Anna, F1 aEhret, Georg, B1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aFelix, Stephan, B1 aFranco, Oscar, H1 aFranke, Lude1 aHarris, Tamara, B1 aHolm, Hilma1 aIlaria, Gandin1 aIorio, Annamaria1 aKähönen, Mika1 aKolcic, Ivana1 aKors, Jan, A1 aLakatta, Edward, G1 aLauner, Lenore, J1 aLin, Honghuang1 aLin, Henry, J1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aLeach, Irene, Mateo1 aMeitinger, Thomas1 aMitchell, Braxton, D1 aMünzel, Thomas1 aPapanicolaou, George, J1 aPeters, Annette1 aPfeufer, Arne1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRotter, Jerome, I1 aRudan, Igor1 aSamani, Nilesh, J1 aSchlessinger, David1 aAldana, Claudia, T Silva1 aSinner, Moritz, F1 aSmith, Jonathan, D1 aSnieder, Harold1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStott, David, J1 aStrauch, Konstantin1 aTarasov, Kirill, V1 aThorsteinsdottir, Unnur1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWestra, Harm, Jan1 aWild, Philipp, S1 aZeller, Tanja1 aAlonso, Alvaro1 aAvery, Christy, L1 aBandinelli, Stefania1 aBenjamin, Emelia, J1 aCucca, Francesco1 aDörr, Marcus1 aFerrucci, Luigi1 aGasparini, Paolo1 aGudnason, Vilmundur1 aHayward, Caroline1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aJukema, Wouter1 aKääb, Stefan1 aLehtimäki, Terho1 aLiu, Yongmei1 aMunroe, Patricia, B1 aParsa, Afshin1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRoden, Dan, M1 aSchnabel, Renate, B1 aSinagra, Gianfranco1 aStefansson, Kari1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aWilson, James, F1 aGharib, Sina, A1 ade Bakker, Paul, I W1 aIsaacs, Aaron1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/781505160nas a2201237 4500008004100000022001400041245019700055210006900252260000900321300001300330490000700343520163700350653000901987653002801996653003502024653001102059653001102070653003202081653000902113653001602122653001402138653001702152100002402169700001202193700002502205700002902230700002702259700002302286700001702309700002102326700001902347700002102366700001702387700001802404700002802422700001502450700002002465700002502485700001902510700002102529700002302550700001702573700002002590700002302610700002002633700002702653700001802680700002302698700002302721700001902744700002202763700002002785700002102805700001702826700001902843700002102862700002302883700002402906700001602930700002202946700002602968700002102994700001903015700001803034700002003052700002003072700002103092700001803113700001603131700001903147700001903166700001503185700002203200700002303222700002403245700003003269700002103299700002103320700002303341700002003364700001903384700001803403700002103421700002003442700002603462700001903488700002103507700001803528700002003546700001903566700002603585700002503611700002403636700001903660700002003679700002003699700001403719700002503733700002003758700001903778700002103797700002003818700002303838710002503861856003603886 2018 eng d a1932-620300aPredictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.0 aPredictive value for cardiovascular events of common carotid int c2018 ae01911720 v133 aAIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C.
CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
10aAged10aCardiovascular Diseases10aCarotid Intima-Media Thickness10aFemale10aHumans10aIntersectoral Collaboration10aMale10aMiddle Aged10aPrognosis10aRisk Factors1 aLorenz, Matthias, W1 aGao, Lu1 aZiegelbauer, Kathrin1 aNorata, Giuseppe, Danilo1 aEmpana, Jean, Philippe1 aSchmidtmann, Irene1 aLin, Hung-Ju1 aMcLachlan, Stela1 aBokemark, Lena1 aRonkainen, Kimmo1 aAmato, Mauro1 aSchminke, Ulf1 aSrinivasan, Sathanur, R1 aLind, Lars1 aOkazaki, Shuhei1 aStehouwer, Coen, D A1 aWilleit, Peter1 aPolak, Joseph, F1 aSteinmetz, Helmuth1 aSander, Dirk1 aPoppert, Holger1 aDesvarieux, Moïse1 aIkram, Arfan, M1 aJohnsen, Stein, Harald1 aStaub, Daniel1 aSirtori, Cesare, R1 aIglseder, Bernhard1 aBeloqui, Oscar1 aEngström, Gunnar1 aFriera, Alfonso1 aRozza, Francesco1 aXie, Wuxiang1 aParraga, Grace1 aGrigore, Liliana1 aPlichart, Matthieu1 aBlankenberg, Stefan1 aSu, Ta-Chen1 aSchmidt, Caroline1 aTuomainen, Tomi-Pekka1 aVeglia, Fabrizio1 aVölzke, Henry1 aNijpels, Giel1 aWilleit, Johann1 aSacco, Ralph, L1 aFranco, Oscar, H1 aUthoff, Heiko1 aHedblad, Bo1 aSuarez, Carmen1 aIzzo, Raffaele1 aZhao, Dong1 aWannarong, Thapat1 aCatapano, Alberico1 aDucimetiere, Pierre1 aEspinola-Klein, Christine1 aChien, Kuo-Liong1 aPrice, Jackie, F1 aBergström, Göran1 aKauhanen, Jussi1 aTremoli, Elena1 aDörr, Marcus1 aBerenson, Gerald1 aKitagawa, Kazuo1 aDekker, Jacqueline, M1 aKiechl, Stefan1 aSitzer, Matthias1 aBickel, Horst1 aRundek, Tatjana1 aHofman, Albert1 aMathiesen, Ellisiv, B1 aCastelnuovo, Samuela1 aLandecho, Manuel, F1 aRosvall, Maria1 aGabriel, Rafael1 ade Luca, Nicola1 aLiu, Jing1 aBaldassarre, Damiano1 aKavousi, Maryam1 ade Groot, Eric1 aBots, Michiel, L1 aYanez, David, N1 aThompson, Simon, G1 aPROG-IMT Study Group uhttps://chs-nhlbi.org/node/784603473nas a2200565 4500008004100000022001400041245008900055210006900144260001200213300001200225490000700237520190000244653004102144653001202185653001002197653000902207653002202216653002202238653002002260653002502280653002202305653002802327653003002355653001902385653001102404653001102415653002502426653002002451653000902471653001602480653002102496653002702517653002602544100001902570700001702589700002302606700002002629700001902649700001902668700001902687700002202706700002102728700002102749700002002770700002002790700002102810700002102831700001902852856003602871 2018 eng d a1468-328800aProtein and glycomic plasma markers for early detection of adenoma and colon cancer.0 aProtein and glycomic plasma markers for early detection of adeno c2018 03 a473-4840 v673 aOBJECTIVE: To discover and confirm blood-based colon cancer early-detection markers.
DESIGN: We created a high-density antibody microarray to detect differences in protein levels in plasma from individuals diagnosed with colon cancer <3 years after blood was drawn (ie, prediagnostic) and cancer-free, matched controls. Potential markers were tested on plasma samples from people diagnosed with adenoma or cancer, compared with controls. Components of an optimal 5-marker panel were tested via immunoblotting using a third sample set, Luminex assay in a large fourth sample set and immunohistochemistry (IHC) on tissue microarrays.
RESULTS: In the prediagnostic samples, we found 78 significantly (t-test) increased proteins, 32 of which were confirmed in the diagnostic samples. From these 32, optimal 4-marker panels of BAG family molecular chaperone regulator 4 (BAG4), interleukin-6 receptor subunit beta (IL6ST), von Willebrand factor (VWF) and CD44 or epidermal growth factor receptor (EGFR) were established. Each panel member and the panels also showed increases in the diagnostic adenoma and cancer samples in independent third and fourth sample sets via immunoblot and Luminex, respectively. IHC results showed increased levels of BAG4, IL6ST and CD44 in adenoma and cancer tissues. Inclusion of EGFR and CD44 sialyl Lewis-A and Lewis-X content increased the panel performance. The protein/glycoprotein panel was statistically significantly higher in colon cancer samples, characterised by a range of area under the curves from 0.90 (95% CI 0.82 to 0.98) to 0.86 (95% CI 0.83 to 0.88), for the larger second and fourth sets, respectively.
CONCLUSIONS: A panel including BAG4, IL6ST, VWF, EGFR and CD44 protein/glycomics performed well for detection of early stages of colon cancer and should be further examined in larger studies.
10aAdaptor Proteins, Signal Transducing10aAdenoma10aAdult10aAged10aAged, 80 and over10aBiomarkers, Tumor10aCA-19-9 Antigen10aCase-Control Studies10aColonic Neoplasms10aCytokine Receptor gp13010aEarly Detection of Cancer10aErbB Receptors10aFemale10aHumans10aHyaluronan Receptors10aLewis X Antigen10aMale10aMiddle Aged10aOligosaccharides10aProtein Array Analysis10avon Willebrand Factor1 aRho, Jung-Hyun1 aLadd, Jon, J1 aLi, Christopher, I1 aPotter, John, D1 aZhang, Yuzheng1 aShelley, David1 aShibata, David1 aCoppola, Domenico1 aYamada, Hiroyuki1 aToyoda, Hidenori1 aTada, Toshifumi1 aKumada, Takashi1 aBrenner, Dean, E1 aHanash, Samir, M1 aLampe, Paul, D uhttps://chs-nhlbi.org/node/837502530nas a2200313 4500008004100000022001400041245008500055210006900140260001600209520156200225100002801787700002101815700002301836700002401859700002401883700002001907700002201927700002601949700002601975700002102001700001702022700002202039700002002061700002202081700001902103700002002122710003802142856003602180 2018 eng d a1432-120300aRare loss of function variants in candidate genes and risk of colorectal cancer.0 aRare loss of function variants in candidate genes and risk of co c2018 Sep 283 aAlthough ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.
1 aRosenthal, Elisabeth, A1 aShirts, Brian, H1 aAmendola, Laura, M1 aHorike-Pyne, Martha1 aRobertson, Peggy, D1 aHisama, Fuki, M1 aBennett, Robin, L1 aDorschner, Michael, O1 aNickerson, Deborah, A1 aStanaway, Ian, B1 aNassir, Rami1 aVickers, Kathy, T1 aLi, Christopher1 aGrady, William, M1 aPeters, Ulrike1 aJarvik, Gail, P1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/784709584nas a2203049 4500008004100000022001400041245011700055210006900172260001300241300001200254490000700266520112500273100002001398700002101418700002101439700001401460700002301474700001901497700001301516700002401529700001901553700002001572700001701592700001801609700001201627700002301639700001201662700001801674700002001692700001801712700001901730700002301749700002001772700001801792700003601810700002001846700002001866700002001886700002301906700003001929700002101959700002001980700002002000700002102020700001202041700002602053700001302079700002002092700002302112700002202135700001902157700002702176700003202203700002102235700002102256700002002277700002402297700002102321700002502342700002102367700002002388700002002408700002402428700002102452700001602473700001802489700001902507700001902526700001602545700001702561700002202578700002302600700002302623700002102646700002302667700001902690700002202709700002202731700001902753700002402772700002402796700002102820700002002841700002202861700002602883700002002909700002502929700002202954700001402976700001502990700002603005700002503031700001503056700002003071700002503091700002303116700002903139700001703168700001903185700002503204700001803229700002203247700002403269700001803293700002103311700001803332700002003350700001703370700001903387700002103406700001803427700001303445700001503458700001803473700002203491700002703513700002103540700001803561700002103579700001903600700002403619700002303643700001803666700002103684700001503705700002103720700002603741700002203767700002103789700002503810700002303835700002003858700002403878700002103902700002503923700001803948700001803966700001803984700002104002700002004023700001904043700001304062700001604075700001704091700002204108700001904130700002104149700002404170700001904194700002404213700002204237700001904259700002004278700002304298700002004321700002004341700002304361700002404384700002204408700002304430700002404453700002204477700002204499700001504521700002204536700002404558700002204582700002504604700002104629700002204650700001904672700002104691700001804712700002204730700002204752700002304774700002504797700002304822700001904845700002004864700002504884700001804909700002004927700002604947700002404973700002504997700002005022700002105042700001605063700002005079700002405099700002805123700001705151700002305168700002205191700002505213700002905238700002305267700001705290700002005307700001905327700002105346700002005367700002205387700002105409700001605430700001805446700001905464700002605483700002205509700002005531700002405551700001905575700002605594700001905620700002005639700001905659700001205678700001505690700001705705700002005722700002305742700002105765700002605786700002805812700002305840700002105863700001905884700002005903700002105923700001905944700002505963700002005988700002406008700002106032700002206053700002806075700002206103700002306125700002506148700002106173700002406194700002106218700001906239700002506258700002206283700002006305700002106325700002106346700002206367700002206389700002206411710002306433710002106456710002106477856003606498 2018 eng d a1546-171800aRefining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.0 aRefining the accuracy of validated target identification through c2018 Apr a559-5710 v503 aWe aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
1 aMahajan, Anubha1 aWessel, Jennifer1 aWillems, Sara, M1 aZhao, Wei1 aRobertson, Neil, R1 aChu, Audrey, Y1 aGan, Wei1 aKitajima, Hidetoshi1 aTaliun, Daniel1 aRayner, William1 aGuo, Xiuqing1 aLu, Yingchang1 aLi, Man1 aJensen, Richard, A1 aHu, Yao1 aHuo, Shaofeng1 aLohman, Kurt, K1 aZhang, Weihua1 aCook, James, P1 aPrins, Bram, Peter1 aFlannick, Jason1 aGrarup, Niels1 aTrubetskoy, Vassily, Vladimirov1 aKravic, Jasmina1 aKim, Young, Jin1 aRybin, Denis, V1 aYaghootkar, Hanieh1 aMüller-Nurasyid, Martina1 aMeidtner, Karina1 aLi-Gao, Ruifang1 aVarga, Tibor, V1 aMarten, Jonathan1 aLi, Jin1 aSmith, Albert, Vernon1 aAn, Ping1 aLigthart, Symen1 aGustafsson, Stefan1 aMalerba, Giovanni1 aDemirkan, Ayse1 aTajes, Juan, Fernandez1 aSteinthorsdottir, Valgerdur1 aWuttke, Matthias1 aLecoeur, Cécile1 aPreuss, Michael1 aBielak, Lawrence, F1 aGraff, Marielisa1 aHighland, Heather, M1 aJustice, Anne, E1 aLiu, Dajiang, J1 aMarouli, Eirini1 aPeloso, Gina, Marie1 aWarren, Helen, R1 aAfaq, Saima1 aAfzal, Shoaib1 aAhlqvist, Emma1 aAlmgren, Peter1 aAmin, Najaf1 aBang, Lia, B1 aBertoni, Alain, G1 aBombieri, Cristina1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBurtt, Noel, P1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aCho, Yoon Shin1 aChristensen, Cramer1 aEastwood, Sophie, V1 aEckardt, Kai-Uwe1 aFischer, Krista1 aGambaro, Giovanni1 aGiedraitis, Vilmantas1 aGrove, Megan, L1 ade Haan, Hugoline, G1 aHackinger, Sophie1 aHai, Yang1 aHan, Sohee1 aTybjærg-Hansen, Anne1 aHivert, Marie-France1 aIsomaa, Bo1 aJäger, Susanne1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKäräjämäki, AnneMari1 aKim, Bong-Jo1 aKim, Sung, Soo1 aKoistinen, Heikki, A1 aKovacs, Peter1 aKriebel, Jennifer1 aKronenberg, Florian1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Jung-Jin1 aLehne, Benjamin1 aLi, Huaixing1 aLin, Keng-Hung1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jun1 aLoh, Marie1 aMägi, Reedik1 aMamakou, Vasiliki1 aMcKean-Cowdin, Roberta1 aNadkarni, Girish1 aNeville, Matt1 aNielsen, Sune, F1 aNtalla, Ioanna1 aPeyser, Patricia, A1 aRathmann, Wolfgang1 aRice, Kenneth1 aRich, Stephen, S1 aRode, Line1 aRolandsson, Olov1 aSchönherr, Sebastian1 aSelvin, Elizabeth1 aSmall, Kerrin, S1 aStančáková, Alena1 aSurendran, Praveen1 aTaylor, Kent, D1 aTeslovich, Tanya, M1 aThorand, Barbara1 aThorleifsson, Gudmar1 aTin, Adrienne1 aTönjes, Anke1 aVarbo, Anette1 aWitte, Daniel, R1 aWood, Andrew, R1 aYajnik, Pranav1 aYao, Jie1 aYengo, Loic1 aYoung, Robin1 aAmouyel, Philippe1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aChowdhury, Raj1 aCollins, Francis, S1 aDedoussis, George1 aDehghan, Abbas1 aDeloukas, Panos1 aFerrario, Marco, M1 aFerrieres, Jean1 aFlorez, Jose, C1 aFrossard, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHowson, Joanna, M M1 aIngelsson, Martin1 aKathiresan, Sekar1 aKee, Frank1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLindgren, Cecilia, M1 aMännistö, Satu1 aMeitinger, Thomas1 aMelander, Olle1 aMohlke, Karen, L1 aMoitry, Marie1 aMorris, Andrew, D1 aMurray, Alison, D1 ade Mutsert, Renée1 aOrho-Melander, Marju1 aOwen, Katharine, R1 aPerola, Markus1 aPeters, Annette1 aProvince, Michael, A1 aRasheed, Asif1 aRidker, Paul, M1 aRivadineira, Fernando1 aRosendaal, Frits, R1 aRosengren, Anders, H1 aSalomaa, Veikko1 aSheu, Wayne, H-H1 aSladek, Rob1 aSmith, Blair, H1 aStrauch, Konstantin1 aUitterlinden, André, G1 aVarma, Rohit1 aWiller, Cristen, J1 aBlüher, Matthias1 aButterworth, Adam, S1 aChambers, John, Campbell1 aChasman, Daniel, I1 aDanesh, John1 aDuijn, Cornelia1 aDupuis, Josée1 aFranco, Oscar, H1 aFranks, Paul, W1 aFroguel, Philippe1 aGrallert, Harald1 aGroop, Leif1 aHan, Bok-Ghee1 aHansen, Torben1 aHattersley, Andrew, T1 aHayward, Caroline1 aIngelsson, Erik1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKooner, Jaspal, Singh1 aKöttgen, Anna1 aKuulasmaa, Kari1 aLaakso, Markku1 aLin, Xu1 aLind, Lars1 aLiu, Yongmei1 aLoos, Ruth, J F1 aMarchini, Jonathan1 aMetspalu, Andres1 aMook-Kanamori, Dennis1 aNordestgaard, Børge, G1 aPalmer, Colin, N A1 aPankow, James, S1 aPedersen, Oluf1 aPsaty, Bruce, M1 aRauramaa, Rainer1 aSattar, Naveed1 aSchulze, Matthias, B1 aSoranzo, Nicole1 aSpector, Timothy, D1 aStefansson, Kari1 aStumvoll, Michael1 aThorsteinsdottir, Unnur1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aWareham, Nicholas, J1 aWilson, James, G1 aZeggini, Eleftheria1 aScott, Robert, A1 aBarroso, Inês1 aFrayling, Timothy, M1 aGoodarzi, Mark, O1 aMeigs, James, B1 aBoehnke, Michael1 aSaleheen, Danish1 aMorris, Andrew, P1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aExomeBP Consortium1 aMAGIC Consortium1 aGIANT Consortium uhttps://chs-nhlbi.org/node/766803682nas a2200577 4500008004100000022001400041245010400055210006900159260001600228520196600244100002302210700002202233700002202255700001902277700002302296700002502319700002202344700002102366700002302387700001802410700002502428700001902453700002002472700002102492700002102513700002402534700002102558700001902579700001902598700001802617700002102635700002202656700002002678700002202698700002202720700002002742700001802762700002502780700002702805700002002832700001502852700002602867700001902893700002602912700002102938700002502959700002402984700002603008710003403034856003603068 2018 eng d a1945-719700aThe relation between thyroid function and anemia: a pooled analysis of individual participant data.0 arelation between thyroid function and anemia a pooled analysis o c2018 Aug 023 aContext: Anemia and thyroid dysfunction often co-occur and both increase with age. Human data on the relationship between thyroid disease and anemia are scarce.
Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia.
Design: Individual participant data meta-analysis.
Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n=42 162).
Main outcome measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women).
Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants (overt hypothyroidism, pooled odds ratio 1.84 [95% CI: 1.35-2.50], subclinical hypothyroidism 1.21 [1.02-1.43], subclinical hyperthyroidism 1.27 [1.03-1.57], overt hyperthyroidism 1.69 [1.00-2.87]). Hemoglobin levels were lower in all groups compared to participants with euthyroidism. In the longitudinal analyses (n=25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 [95% CI: 0.86-2.20] for overt hypothyroidism, 1.18 [1.00-1.38] for subclinical hypothyroidism, 1.15 [0.94-1.42] for subclinical hyperthyroidism and 1.47 [0.91-2.38] for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.
Conclusion: Higher odds of having anemia were observed in both participants with hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.
1 aWopereis, Daisy, M1 aPuy, Robert, S Du1 avan Heemst, Diana1 aWalsh, John, P1 aBremner, Alexandra1 aBakker, Stephan, J L1 aBauer, Douglas, C1 aCappola, Anne, R1 aCeresini, Graziano1 aDegryse, Jean1 aDullaart, Robin, P F1 aFeller, Martin1 aFerrucci, Luigi1 aFloriani, Carmen1 aFranco, Oscar, H1 aIacoviello, Massimo1 aIervasi, Georgio1 aImaizumi, Misa1 aJukema, Wouter1 aKhaw, Kay-Tee1 aLuben, Robert, N1 aMolinaro, Sabrina1 aNauck, Matthias1 aPatel, Kushang, V1 aPeeters, Robin, P1 aPsaty, Bruce, M1 aRazvi, Salman1 aSchindhelm, Roger, K1 avan Schoor, Natasja, M1 aStott, David, J1 aVaes, Bert1 aVanderpump, Mark, P J1 aVölzke, Henry1 aWestendorp, Rudi, G J1 aRodondi, Nicolas1 aCobbaert, Christa, M1 aGussekloo, Jacobijn1 aElzen, Wendy, P J den1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/781703720nas a2200445 4500008004100000022001400041245015900055210006900214260001600283520232600299100002102625700002102646700002102667700001802688700002102706700002102727700002302748700002602771700002102797700002102818700002402839700001702863700002402880700002302904700002102927700002402948700002302972700002702995700002103022700002003043700002403063700001703087700002503104700002103129700002203150700001903172700001803191710002903209856003603238 2018 eng d a1523-683800aRelationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium.0 aRelationship of Estimated GFR and Albuminuria to Concurrent Labo c2018 Oct 193 aRATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.
STUDY DESIGN: Cross-sectional individual participant-level analyses in a global consortium.
SETTING & STUDY POPULATIONS: 17 CKD and 38 general population and high-risk cohorts.
SELECTION CRITERIA FOR STUDIES: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.
DATA EXTRACTION: Data were obtained and analyzed between July 2015 and January 2018.
ANALYTICAL APPROACH: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.
RESULTS: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).
LIMITATIONS: Variations in study era, health care delivery system, typical diet, and laboratory assays.
CONCLUSIONS: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.
1 aInker, Lesley, A1 aGrams, Morgan, E1 aLevey, Andrew, S1 aCoresh, Josef1 aCirillo, Massimo1 aCollins, John, F1 aGansevoort, Ron, T1 aGutierrez, Orlando, M1 aHamano, Takayuki1 aHeine, Gunnar, H1 aIshikawa, Shizukiyo1 aJee, Sun, Ha1 aKronenberg, Florian1 aLandray, Martin, J1 aMiura, Katsuyuki1 aNadkarni, Girish, N1 aPeralta, Carmen, A1 aRothenbacher, Dietrich1 aSchaeffner, Elke1 aSedaghat, Sanaz1 aShlipak, Michael, G1 aZhang, Luxia1 avan Zuilen, Arjan, D1 aHallan, Stein, I1 aKovesdy, Csaba, P1 aWoodward, Mark1 aLevin, Adeera1 aCKD Prognosis Consortium uhttps://chs-nhlbi.org/node/791502623nas a2200265 4500008004100000022001400041245011400055210006900169260001600238490000600254520180700260100003002067700001902097700002702116700001702143700001302160700002002173700001702193700002602210700001802236700001902254700002402273710002402297856003602321 2018 eng d a2047-998000aReversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces.0 aReversal of AgingInduced Increases in Aortic Stiffness by Target c2018 Jul 180 v73 aBACKGROUND: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening.
METHODS AND RESULTS: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome-wide association study of carotid-femoral pulse wave velocity. Common genetic variation in the N-WASP () locus is associated with carotid-femoral pulse wave velocity (rs600420, =0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N-WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N-WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin-vinculin interfaces similarly decreased aging-induced ex vivo active stiffness by on-target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound-targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness.
CONCLUSIONS: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein-protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein-protein interfaces may lead to substantive dynamic modulation of aortic stiffness.
1 aNicholson, Christopher, J1 aSingh, Kuldeep1 aSaphirstein, Robert, J1 aGao, Yuan, Z1 aLi, Qian1 aChiu, Joanna, G1 aLeavis, Paul1 aVerwoert, Germaine, C1 aMitchell, G F1 aPorter, Tyrone1 aMorgan, Kathleen, G1 aAortaGen Consortium uhttps://chs-nhlbi.org/node/780708059nas a2201585 4500008004100000022001400041245015200055210006900207260001500276300001400291490000800305520349800313100002003811700002103831700002503852700001903877700002403896700001903920700001703939700001803956700002203974700002103996700001704017700001904034700001904053700002004072700002104092700002904113700001904142700002104161700001904182700002004201700002804221700001604249700002104265700001904286700002104305700002104326700002004347700002104367700002204388700001804410700001804428700002104446700002104467700002004488700003504508700001904543700002304562700002204585700002504607700002204632700002204654700001804676700002004694700001904714700002404733700002304757700002004780700002304800700002604823700002404849700002104873700002404894700002304918700001804941700002004959700001904979700002104998700001905019700002205038700002005060700001605080700002105096700002605117700002105143700002005164700001905184700003105203700001905234700002405253700001705277700002005294700002105314700001805335700002205353700002205375700002005397700002005417700003305437700002205470700002605492700001805518700002605536700003005562700002405592700001905616700001705635700002005652700001805672700002405690700001805714700002005732700002605752700001805778700002205796700002505818700002005843700002205863700002105885700002005906700002305926700002205949700002105971700002005992700002406012700002106036700001806057700002306075700002306098700001406121700001906135700001806154700002306172700002006195700001906215700002406234700001806258700001706276700001706293700003006310700001706340710008006357856003606437 2018 eng d a1474-547X00aRisk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.0 aRisk thresholds for alcohol consumption combined analysis of ind c2018 04 14 a1513-15230 v3913 aBACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.
METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies.
FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.
INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.
FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.
1 aWood, Angela, M1 aKaptoge, Stephen1 aButterworth, Adam, S1 aWilleit, Peter1 aWarnakula, Samantha1 aBolton, Thomas1 aPaige, Ellie1 aPaul, Dirk, S1 aSweeting, Michael1 aBurgess, Stephen1 aBell, Steven1 aAstle, William1 aStevens, David1 aKoulman, Albert1 aSelmer, Randi, M1 aVerschuren, W, M Monique1 aSato, Shinichi1 aNjølstad, Inger1 aWoodward, Mark1 aSalomaa, Veikko1 aNordestgaard, Børge, G1 aYeap, Bu, B1 aFletcher, Astrid1 aMelander, Olle1 aKuller, Lewis, H1 aBalkau, Beverley1 aMarmot, Michael1 aKoenig, Wolfgang1 aCasiglia, Edoardo1 aCooper, Cyrus1 aArndt, Volker1 aFranco, Oscar, H1 aWennberg, Patrik1 aGallacher, John1 ade la Cámara, Agustin, Gómez1 aVölzke, Henry1 aDahm, Christina, C1 aDale, Caroline, E1 aBergmann, Manuela, M1 aCrespo, Carlos, J1 aSchouw, Yvonne, T1 aKaaks, Rudolf1 aSimons, Leon, A1 aLagiou, Pagona1 aSchoufour, Josje, D1 aBoer, Jolanda, M A1 aKey, Timothy, J1 aRodriguez, Beatriz1 aMoreno-Iribas, Conchi1 aDavidson, Karina, W1 aTaylor, James, O1 aSacerdote, Carlotta1 aWallace, Robert, B1 aQuiros, Ramon1 aTumino, Rosario1 aBlazer, Dan, G1 aLinneberg, Allan1 aDaimon, Makoto1 aPanico, Salvatore1 aHoward, Barbara1 aSkeie, Guri1 aStrandberg, Timo1 aWeiderpass, Elisabete1 aNietert, Paul, J1 aPsaty, Bruce, M1 aKromhout, Daan1 aSalamanca-Fernandez, Elena1 aKiechl, Stefan1 aKrumholz, Harlan, M1 aGrioni, Sara1 aPalli, Domenico1 aHuerta, José, M1 aPrice, Jackie1 aSundström, Johan1 aArriola, Larraitz1 aArima, Hisatomi1 aTravis, Ruth, C1 aPanagiotakos, Demosthenes, B1 aKarakatsani, Anna1 aTrichopoulou, Antonia1 aKühn, Tilman1 aGrobbee, Diederick, E1 aBarrett-Connor, Elizabeth1 avan Schoor, Natasja1 aBoeing, Heiner1 aOvervad, Kim1 aKauhanen, Jussi1 aWareham, Nick1 aLangenberg, Claudia1 aForouhi, Nita1 aWennberg, Maria1 aDesprés, Jean-Pierre1 aCushman, Mary1 aCooper, Jackie, A1 aRodriguez, Carlos, J1 aSakurai, Masaru1 aShaw, Jonathan, E1 aKnuiman, Matthew1 aVoortman, Trudy1 aMeisinger, Christa1 aTjønneland, Anne1 aBrenner, Hermann1 aPalmieri, Luigi1 aDallongeville, Jean1 aBrunner, Eric, J1 aAssmann, Gerd1 aTrevisan, Maurizio1 aGillum, Richard, F1 aFord, Ian1 aSattar, Naveed1 aLazo, Mariana1 aThompson, Simon, G1 aFerrari, Pietro1 aLeon, David, A1 aSmith, George Davey1 aPeto, Richard1 aJackson, Rod1 aBanks, Emily1 aDi Angelantonio, Emanuele1 aDanesh, John1 aEmerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group uhttps://chs-nhlbi.org/node/766402992nas a2200277 4500008004100000022001400041245014600055210006900201260001600270300001400286490000800300520211900308100002102427700001602448700001702464700002102481700001702502700002202519700002102541700002202562700002202584700002402606700002702630700002102657856003602678 2018 eng d a1524-453900aSex and Race Differences in Lifetime Risk of Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction.0 aSex and Race Differences in Lifetime Risk of Heart Failure With c2018 Apr 24 a1814-18230 v1373 aBACKGROUND: Lifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.
METHODS: Participant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.
RESULTS: We included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.
CONCLUSIONS: Lifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.
1 aPandey, Ambarish1 aOmar, Wally1 aAyers, Colby1 aLaMonte, Michael1 aKlein, Liviu1 aAllen, Norrina, B1 aKuller, Lewis, H1 aGreenland, Philip1 aEaton, Charles, B1 aGottdiener, John, S1 aLloyd-Jones, Donald, M1 aBerry, Jarett, D uhttps://chs-nhlbi.org/node/768502716nas a2200337 4500008004100000022001400041245006000055210005900115260001300174300001400187490000700201520176600208100002801974700001902002700002302021700002202044700001702066700002202083700002402105700001902129700002102148700002002169700002102189700002202210700002002232700002202252700002202274700002302296700002302319856003602342 2018 eng d a1556-387100aSleep characteristics that predict atrial fibrillation.0 aSleep characteristics that predict atrial fibrillation c2018 Sep a1289-12950 v153 aBACKGROUND: The relationship between sleep disruption, independent of obstructive sleep apnea (OSA), and atrial fibrillation (AF) is unknown.
OBJECTIVE: The purpose of this study was to determine whether poor sleep itself is a risk factor for AF.
METHODS: We first performed an analysis of participants in the Health eHeart Study and validated those findings in the longitudinal Cardiovascular Health Study, including a subset of patients undergoing polysomnography. To determine whether the observed relationships readily translated to medical practice, we examined 2005-2009 data from the California Healthcare Cost and Utilization Project.
RESULTS: Among 4553 Health eHeart participants, the 526 with AF exhibited more frequent nighttime awakening (odd ratio [OR] 1.47; 95% confidence interval [CI] 1.14-1.89; P = .003). In 5703 Cardiovascular Health Study participants followed for a median 11.6 years, frequent nighttime awakening predicted a 33% greater risk of AF (hazard ratio [HR] 1.33; 95% CI 1.17-1.51; P <.001). In patients with polysomnography (N = 1127), every standard deviation percentage decrease in rapid eye movement (REM) sleep was associated with a 18% higher risk of developing AF (HR 1.18; 95% CI 1.00-1.38; P = .047). Among 14,330,651 California residents followed for a median 3.9 years, an insomnia diagnosis predicted a 36% increased risk of new AF (HR 1.36; 95% CI 1.30-1.42; P <.001).
CONCLUSION: Sleep disruption consistently predicted AF before and after adjustment for OSA and other potential confounders across several different populations. Sleep quality itself may be important in the pathogenesis of AF, potentially representing a novel target for prevention.
1 aChristensen, Matthew, A1 aDixit, Shalini1 aDewland, Thomas, A1 aWhitman, Isaac, R1 aNah, Gregory1 aVittinghoff, Eric1 aMukamal, Kenneth, J1 aRedline, Susan1 aRobbins, John, A1 aNewman, Anne, B1 aPatel, Sanjay, R1 aMagnani, Jared, W1 aPsaty, Bruce, M1 aOlgin, Jeffrey, E1 aPletcher, Mark, J1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/778708823nas a2202773 4500008004100000022001400041245011300055210006900168260001600237300000900253490000600262520111900268100001701387700001301404700002101417700002201438700002201460700001601482700002501498700002301523700002501546700002501571700002401596700002101620700002301641700002601664700001801690700001901708700002601727700002501753700002001778700002101798700002101819700002301840700002301863700002501886700002201911700001701933700002001950700002101970700001801991700001602009700001802025700001302043700002102056700001802077700001802095700002702113700002202140700001902162700001702181700002002198700002502218700003302243700001902276700002302295700002102318700002302339700002602362700002002388700002502408700001802433700001802451700002402469700001802493700001202511700001602523700001602539700002202555700002302577700002502600700002302625700001902648700001902667700002802686700002202714700002102736700002302757700001902780700002002799700002202819700002602841700001902867700002702886700001802913700001802931700002002949700001902969700001902988700002203007700002303029700002503052700002103077700001403098700002303112700001203135700001803147700002503165700002103190700002603211700002503237700002403262700002203286700002503308700002303333700001903356700002703375700002003402700002003422700002403442700001803466700002103484700002203505700002203527700001903549700001803568700002603586700001603612700002203628700001703650700001403667700001803681700001903699700002403718700002003742700001703762700001703779700002503796700002203821700002803843700002403871700002503895700002203920700001803942700002103960700001703981700002003998700002104018700001904039700001904058700002504077700002004102700002304122700002904145700002104174700002204195700001904217700001904236700001804255700001804273700002604291700002604317700002104343700002104364700002204385700002204407700002004429700002204449700002104471700002304492700002004515700002304535700001904558700002104577700002004598700002104618700002404639700002404663700002204687700002804709700001904737700002004756700001904776700002104795700001504816700002104831700001604852700001404868700002204882700001904904700002204923700001904945700002104964700002304985700001805008700002405026700002305050700001805073700001805091700002805109700001805137700002005155700001605175700002405191700002105215700001805236700001905254700002005273700002305293700002305316700001905339700002405358700001905382700002305401700002005424700002305444700002305467700002305490700002105513700001905534700001605553700002205569700002005591700002405611700002405635700001905659700002005678700002305698700002205721700002305743700002105766700002605787700001905813700002105832700001905853700002405872700002305896700002005919700002205939700001805961700001605979700001805995856003606013 2018 eng d a2041-172300aStudy of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.0 aStudy of 300486 individuals identifies 148 independent genetic l c2018 May 29 a20980 v93 aGeneral cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
1 aDavies, Gail1 aLam, Max1 aHarris, Sarah, E1 aTrampush, Joey, W1 aLuciano, Michelle1 aHill, David1 aHagenaars, Saskia, P1 aRitchie, Stuart, J1 aMarioni, Riccardo, E1 aFawns-Ritchie, Chloe1 aLiewald, David, C M1 aOkely, Judith, A1 aAhola-Olli, Ari, V1 aBarnes, Catriona, L K1 aBertram, Lars1 aBis, Joshua, C1 aBurdick, Katherine, E1 aChristoforou, Andrea1 aDeRosse, Pamela1 aDjurovic, Srdjan1 aEspeseth, Thomas1 aGiakoumaki, Stella1 aGiddaluru, Sudheer1 aGustavson, Daniel, E1 aHayward, Caroline1 aHofer, Edith1 aIkram, Arfan, M1 aKarlsson, Robert1 aKnowles, Emma1 aLahti, Jari1 aLeber, Markus1 aLi, Shuo1 aMather, Karen, A1 aMelle, Ingrid1 aMorris, Derek1 aOldmeadow, Christopher1 aPalviainen, Teemu1 aPayton, Antony1 aPazoki, Raha1 aPetrovic, Katja1 aReynolds, Chandra, A1 aSargurupremraj, Muralidharan1 aScholz, Markus1 aSmith, Jennifer, A1 aSmith, Albert, V1 aTerzikhan, Natalie1 aThalamuthu, Anbupalam1 aTrompet, Stella1 avan der Lee, Sven, J1 aWare, Erin, B1 aWindham, Gwen1 aWright, Margaret, J1 aYang, Jingyun1 aYu, Jin1 aAmes, David1 aAmin, Najaf1 aAmouyel, Philippe1 aAndreassen, Ole, A1 aArmstrong, Nicola, J1 aAssareh, Amelia, A1 aAttia, John, R1 aAttix, Deborah1 aAvramopoulos, Dimitrios1 aBennett, David, A1 aBöhmer, Anne, C1 aBoyle, Patricia, A1 aBrodaty, Henry1 aCampbell, Harry1 aCannon, Tyrone, D1 aCirulli, Elizabeth, T1 aCongdon, Eliza1 aConley, Emily, Drabant1 aCorley, Janie1 aCox, Simon, R1 aDale, Anders, M1 aDehghan, Abbas1 aDick, Danielle1 aDickinson, Dwight1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFord, Ian1 aFreimer, Nelson, A1 aGao, He1 aGiegling, Ina1 aGillespie, Nathan, A1 aGordon, Scott, D1 aGottesman, Rebecca, F1 aGriswold, Michael, E1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartmann, Annette, M1 aHatzimanolis, Alex1 aHeiss, Gerardo1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKähönen, Mika1 aKardia, Sharon, L R1 aKarlsson, Ida1 aKleineidam, Luca1 aKnopman, David, S1 aKochan, Nicole, A1 aKonte, Bettina1 aKwok, John, B1 aLe Hellard, Stephanie1 aLee, Teresa1 aLehtimäki, Terho1 aLi, Shu-Chen1 aLiu, Tian1 aKoini, Marisa1 aLondon, Edythe1 aLongstreth, Will, T1 aLopez, Oscar, L1 aLoukola, Anu1 aLuck, Tobias1 aLundervold, Astri, J1 aLundquist, Anders1 aLyytikäinen, Leo-Pekka1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aMurray, Alison, D1 aNeed, Anna, C1 aNoordam, Raymond1 aNyberg, Lars1 aOllier, William1 aPapenberg, Goran1 aPattie, Alison1 aPolasek, Ozren1 aPoldrack, Russell, A1 aPsaty, Bruce, M1 aReppermund, Simone1 aRiedel-Heller, Steffi, G1 aRose, Richard, J1 aRotter, Jerome, I1 aRoussos, Panos1 aRovio, Suvi, P1 aSaba, Yasaman1 aSabb, Fred, W1 aSachdev, Perminder, S1 aSatizabal, Claudia, L1 aSchmid, Matthias1 aScott, Rodney, J1 aScult, Matthew, A1 aSimino, Jeannette1 aSlagboom, Eline1 aSmyrnis, Nikolaos1 aSoumaré, Aïcha1 aStefanis, Nikos, C1 aStott, David, J1 aStraub, Richard, E1 aSundet, Kjetil1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, Andre1 aVitart, Veronique1 aVoineskos, Aristotle, N1 aKaprio, Jaakko1 aWagner, Michael1 aWagner, Holger1 aWeinhold, Leonie1 aWen, Hoyan1 aWiden, Elisabeth1 aYang, Qiong1 aZhao, Wei1 aAdams, Hieab, H H1 aArking, Dan, E1 aBilder, Robert, M1 aBitsios, Panos1 aBoerwinkle, Eric1 aChiba-Falek, Ornit1 aCorvin, Aiden1 aDe Jager, Philip, L1 aDebette, Stephanie1 aDonohoe, Gary1 aElliott, Paul1 aFitzpatrick, Annette, L1 aGill, Michael1 aGlahn, David, C1 aHägg, Sara1 aHansell, Narelle, K1 aHariri, Ahmad, R1 aIkram, Kamran1 aJukema, Wouter1 aVuoksimaa, Eero1 aKeller, Matthew, C1 aKremen, William, S1 aLauner, Lenore1 aLindenberger, Ulman1 aPalotie, Aarno1 aPedersen, Nancy, L1 aPendleton, Neil1 aPorteous, David, J1 aRäikkönen, Katri1 aRaitakari, Olli, T1 aRamirez, Alfredo1 aReinvang, Ivar1 aRudan, Igor1 aSchmidt, Reinhold1 aSchmidt, Helena1 aSchofield, Peter, W1 aSchofield, Peter, R1 aStarr, John, M1 aSteen, Vidar, M1 aTrollor, Julian, N1 aTurner, Steven, T1 aDuijn, Cornelia, M1 aVillringer, Arno1 aWeinberger, Daniel, R1 aWeir, David, R1 aWilson, James, F1 aMalhotra, Anil1 aMcIntosh, Andrew, M1 aGale, Catharine, R1 aSeshadri, Sudha1 aMosley, Thomas, H1 aBressler, Jan1 aLencz, Todd1 aDeary, Ian, J uhttps://chs-nhlbi.org/node/778804864nas a2200733 4500008004100000022001400041245018700055210006900242260001300311300001200324490000700336520267100343100002303014700002203037700001603059700002403075700003203099700002003131700002003151700002203171700002403193700001703217700002103234700002803255700002903283700001603312700001903328700003103347700001903378700002203397700002403419700002503443700003203468700001703500700002003517700001503537700001903552700002003571700001803591700002003609700002003629700002003649700002403669700001903693700002003712700002003732700002203752700002803774700001903802700002403821700002103845700001903866700002503885700001903910700002503929700002103954700002303975700001103998700002204009700002104031700002204052700002004074856003604094 2018 eng d a1432-042800aSugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis.0 aSugarsweetened beverage intake associations with fasting glucose c2018 Feb a317-3300 v613 aAIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits.
METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway.
RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant.
CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.
TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).
1 aMcKeown, Nicola, M1 aDashti, Hassan, S1 aMa, Jiantao1 aHaslam, Danielle, E1 ade Jong, Jessica, C Kiefte-1 aSmith, Caren, E1 aTanaka, Toshiko1 aGraff, Mariaelisa1 aLemaitre, Rozenn, N1 aRybin, Denis1 aSonestedt, Emily1 aFrazier-Wood, Alexis, C1 aMook-Kanamori, Dennis, O1 aLi, Yanping1 aWang, Carol, A1 aLeermakers, Elisabeth, T M1 aMikkilä, Vera1 aYoung, Kristin, L1 aMukamal, Kenneth, J1 aCupples, Adrienne, L1 aSchulz, Christina-Alexandra1 aChen, Tzu-An1 aLi-Gao, Ruifang1 aHuang, Tao1 aOddy, Wendy, H1 aRaitakari, Olli1 aRice, Kenneth1 aMeigs, James, B1 aEricson, Ulrika1 aSteffen, Lyn, M1 aRosendaal, Frits, R1 aHofman, Albert1 aKähönen, Mika1 aPsaty, Bruce, M1 aBrunkwall, Louise1 aUitterlinden, André, G1 aViikari, Jorma1 aSiscovick, David, S1 aSeppälä, Ilkka1 aNorth, Kari, E1 aMozaffarian, Dariush1 aDupuis, Josée1 aOrho-Melander, Marju1 aRich, Stephen, S1 ade Mutsert, Renée1 aQi, Lu1 aPennell, Craig, E1 aFranco, Oscar, H1 aLehtimäki, Terho1 aHerman, Mark, A uhttps://chs-nhlbi.org/node/757602601nas a2200229 4500008004100000022001400041245011100055210006900166260001600235520189100251100001802142700002502160700001602185700002202201700001902223700001802242700001702260700001602277700002002293710002202313856003602335 2018 eng d a1538-783600aTargeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.0 aTargeted sequencing to identify novel genetic risk factors for d c2018 Aug 313 aBACKGROUND: Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained.
OBJECTIVES: We aimed to identify novel genetic determinants using targeted DNA sequencing.
PATIENTS/METHODS: We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, MEGA, and THE-VTE) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF]≥1%) and gene-based tests for rare variants (MAF≤1%), accounting for multiple testing by the false discovery rate (FDR).
RESULTS: Sixty-two out of 3,617 common variants were associated with DVT risk (FDR<0.10). Most of these mapped to F5, ABO, FGA-FGG, and CYP4V2-KLKB1-F11. Lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29-1.92), in moderate linkage with known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10-1.69). Two novel variant associations were observed, in CBS and MASP1, but these did not replicate in the meta-analysis data from the INVENT consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR>0.2).
CONCLUSIONS: We confirmed associations between DVT and common variants in F5, ABO, FGA-FGG, and CYP4V2-KLKB1-F11 and observed secondary signals in F5 and CYP4V2-KLKB1-F11 that warrant replication and fine-mapping in larger studies. This article is protected by copyright. All rights reserved.
1 ade Haan, H, G1 aVlieg, van, Hylckama1 aLotta, L, A1 aGorski, Marcin, M1 aBucciarelli, P1 aMartinelli, I1 aBaglin, T, P1 aPeyvandi, F1 aRosendaal, F, R1 aINVENT Consortium uhttps://chs-nhlbi.org/node/778902743nas a2200241 4500008004100000022001400041245013300055210006900188260001300257300001200270490000600282520198600288100002002274700001602294700002202310700002202332700002002354700002002374700002402394700002002418700002702438856003602465 2018 eng d a2213-178700aTemporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction.0 aTemporal Trends in the Incidence of and Mortality Associated Wit c2018 Aug a678-6850 v63 aOBJECTIVES: This study aimed to determine temporal trends in the incidence of and mortality associated with heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart rate with preserved ejection fraction [HFpEF]) in the community.
BACKGROUND: Major shifts in cardiovascular disease risk factor prevalence and advances in therapies may have influenced HF incidence and mortality.
METHODS: In the FHS (Framingham Heart Study) and CHS (Cardiovascular Health Study), for participants who were ≥60 years of age and free of HF (n = 15,217; 60% women; 2,524 incident HF cases; 115,703 person-years of follow-up), we estimated adjusted incidence rate ratios of HF, HFrEF, and HFpEF from 1990 to 1999 and 2000 to 2009. We compared the cumulative incidence of and mortality associated with HFrEF versus HFpEF within and between decades.
RESULTS: Across the 2 decades, HF incidence rate ratio was similar (p = 0.13). The incidence rate ratio of HFrEF declined (p = 0.0029), whereas HFpEF increased (p < 0.001). Although HFrEF incidence declined more in men than in women, men had a higher incidence of HFrEF than women in each decade (p < 0.001). The incidence of HFpEF significantly increased over time in both men and women (p < 0.001 and p = 0.02, respectively). During follow-up after HF, 1,701 individuals died (67.4%; HFrEF, n = 557 [33%]; HFpEF, n = 474 [29%]). There were no significant differences in mortality rates (overall, cardiovascular disease, and noncardiovascular disease) across decades within HF subtypes or between HFrEF and HFpEF within decade.
CONCLUSIONS: In several U.S. community-based samples from 1990 to 2009, we observed divergent trends of decreasing HFrEF and increasing HFpEF incidence, with stable overall HF incidence and high risk for mortality. Our findings highlight the need to elucidate factors contributing to these observations.
1 aTsao, Connie, W1 aLyass, Asya1 aEnserro, Danielle1 aLarson, Martin, G1 aHo, Jennifer, E1 aKizer, Jorge, R1 aGottdiener, John, S1 aPsaty, Bruce, M1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/781401866nas a2200181 4500008004100000022001400041245007400055210006900129260001600198520129900214100002301513700002601536700002101562700002501583700002001608700002001628856003601648 2018 eng d a1476-625600aTrajectories of Nonagenarian Health: Gender, Age, and Period Effects.0 aTrajectories of Nonagenarian Health Gender Age and Period Effect c2018 Nov 083 aThe US population aged 90 years and older is growing rapidly and there are limited data on their health. The Cardiovascular Health Study is a prospective study of black and white adults ≥65 years recruited in two waves (1989-90 and 1992-93) from Medicare eligibility lists in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. We created a synthetic cohort of the 1,889 participants who had reached age 90 at baseline or during follow-up through July 16th, 2015. Participants entered the cohort at 90 years and we evaluated their changes in health after age 90 (median [IQR] follow-up: 3 [1.3-5] years). Measures of health included cardiovascular events, cognitive function, depressive symptoms, prescription medications, self-rated health, and measures of functional status. The mortality rate was high: 19.0 (95% CI: 17.8, 20.3) per 100 person-years in women and 20.9 (95% CI: 19.2, 22.8) in men. Cognitive function and all measures of functional status declined with age; these changes were similar by gender. When we isolated period effects, we found that medications use increased over time. These estimates can help inform future research and health care systems to meet the needs of this growing population.
1 aOdden, Michelle, C1 aKoh, William, Jen Hoe1 aArnold, Alice, M1 aRawlings, Andreea, M1 aPsaty, Bruce, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/792203387nas a2200709 4500008004100000022001400041245009000055210006900145260001300214300001200227490000700239520164600246100001201892700002001904700002401924700001601948700001201964700001301976700001101989700001002000700001302010700001502023700001602038700001602054700001802070700001602088700001302104700001102117700001502128700001502143700001902158700001402177700001602191700001302207700001302220700001602233700001902249700001402268700001502282700001602297700002002313700001802333700001702351700001202368700001702380700001302397700001602410700001802426700001502444700001402459700001502473700001802488700001402506700001902520700001902539700001702558700001902575700001702594700001602611700001402627856003602641 2018 eng d a1476-549700aTrans-ethnic analysis of metabochip data identifies two new loci associated with BMI.0 aTransethnic analysis of metabochip data identifies two new loci c2018 Mar a384-3900 v423 aOBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.
SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.
RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue.
CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.
1 aGong, J1 aNishimura, K, K1 aFernandez-Rhodes, L1 aHaessler, J1 aBien, S1 aGraff, M1 aLim, U1 aLu, Y1 aGross, M1 aFornage, M1 aYoneyama, S1 aIsasi, C, R1 aBůžková, P1 aDaviglus, M1 aLin, D-Y1 aTao, R1 aGoodloe, R1 aBush, W, S1 aFarber-Eger, E1 aBoston, J1 aDilks, H, H1 aEhret, G1 aGu, C, C1 aLewis, C, E1 aNguyen, K-D, H1 aCooper, R1 aLeppert, M1 aIrvin, M, R1 aBottinger, E, P1 aWilkens, L, R1 aHaiman, C, A1 aPark, L1 aMonroe, K, R1 aCheng, I1 aStram, D, O1 aCarlson, C, S1 aJackson, R1 aKuller, L1 aHouston, D1 aKooperberg, C1 aBuyske, S1 aHindorff, L, A1 aCrawford, D, C1 aLoos, R, J F1 aLe Marchand, L1 aMatise, T, C1 aNorth, K, E1 aPeters, U uhttps://chs-nhlbi.org/node/767904313nas a2200829 4500008004100000022001400041245011600055210006900171260001600240520189900256100001902155700002502174700002702199700002002226700002202246700002002268700002302288700001502311700001802326700002202344700002302366700001902389700003002408700002302438700001802461700002502479700002202504700001902526700001902545700002102564700002402585700002202609700002202631700002302653700002302676700001802699700001902717700001702736700002002753700002502773700002602798700002202824700002002846700002202866700002102888700001702909700002002926700001902946700002302965700002302988700002203011700002203033700002503055700002803080700002003108700002003128700002303148700002103171700002103192700002003213700002703233700002603260700002203286700001703308700001903325700002003344700001703364700001803381700002503399700002303424856003603447 2018 eng d a1945-719700aTrans-ethnic Evaluation Identifies Novel Low Frequency Loci Associated with 25-Hydroxyvitamin D Concentrations.0 aTransethnic Evaluation Identifies Novel Low Frequency Loci Assoc c2018 Jan 093 aContext: Vitamin D inadequacy is common in the adult population of the United States. While the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known in Hispanic or African ancestry populations.
Objective: The TRANSCEN-D (TRANS-ethniC Evaluation of vitamiN D GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D (25(OH)D) concentrations from the meta-analyses of European ancestry (SUNLIGHT) and to identify novel genetic variants related to vitamin D concentrations in African and Hispanic ancestries.
Design: Ancestry-specific (Hispanic and African) and trans-ethnic (Hispanic, African and European) meta-analyses were performed using the METAL software.
Patients or Other Participants: In total, 8,541 African-American and 3,485 Hispanic-American (from North America) participants from twelve cohorts, and 16,124 European participants from SUNLIGHT were included in the study.
Main Outcome Measure(s): Blood concentrations of 25(OH)D were measured for all participants.
Results: Ancestry-specific analyses in African and Hispanic Americans replicated SNPs in GC (2 and 4 SNPs, respectively). A potentially novel SNP (rs79666294) near the KIF4B gene was identified in the African-American cohort. Trans-ethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the trans-ethnic analyses revealed novel SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.
Conclusions: Ancestry-specific and trans-ethnic GWAS of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed novel findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism require further investigation.
1 aHong, Jaeyoung1 aHatchell, Kathryn, E1 aBradfield, Jonathan, P1 aAndrew, Bjonnes1 aAlessandra, Chesi1 aChao-Qiang, Lai1 aLangefeld, Carl, D1 aLu, Lingyi1 aLu, Yingchang1 aLutsey, Pamela, L1 aMusani, Solomon, K1 aNalls, Mike, A1 aRobinson-Cohen, Cassianne1 aRoizen, Jeffery, D1 aSaxena, Richa1 aTucker, Katherine, L1 aZiegler, Julie, T1 aArking, Dan, E1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBowden, Donald, W1 aGilsanz, Vincente1 aHouston, Denise, K1 aKalkwarf, Heidi, J1 aKelly, Andrea1 aLappe, Joan, M1 aLiu, Yongmei1 aMichos, Erin, D1 aOberfield, Sharon, E1 aPalmer, Nicholette, D1 aRotter, Jerome, I1 aSapkota, Bishwa1 aShepherd, John, A1 aWilson, James, G1 aBasu, Saonli1 ade Boer, Ian, H1 aDivers, Jasmin1 aFreedman, Barry, I1 aGrant, Struan, F A1 aHakanarson, Hakon1 aHarris, Tamara, B1 aKestenbaum, Bryan, R1 aKritchevsky, Stephen, B1 aLoos, Ruth, J F1 aNorris, Jill, M1 aNorwood, Arnita, F1 aOrdovas, Jose, M1 aPankow, James, S1 aPsaty, Bruce, M1 aSanhgera, Dharambir, K1 aWagenknecht, Lynne, E1 aZemel, Babette, S1 aMeigs, James1 aDupuis, Josée1 aFlorez, Jose, C1 aWang, Thomas1 aLiu, Ching-Ti1 aEngelman, Corinne, D1 aBillings, Liana, K uhttps://chs-nhlbi.org/node/768105481nas a2201285 4500008004100000022001400041245015800055210006900213260001600282520179200298100001902090700001702109700002102126700001702147700002902164700002102193700002402214700002002238700001302258700002002271700002102291700002102312700001302333700001502346700001902361700001602380700002202396700002102418700002302439700002302462700002502485700001902510700001902529700002102548700002502569700003002594700002302624700002702647700002002674700002302694700002202717700002202739700001802761700002802779700001902807700002402826700002202850700002102872700002002893700002402913700002002937700001902957700001602976700001802992700002003010700001803030700002203048700001903070700001803089700002003107700002003127700001903147700002003166700001803186700001903204700002003223700003103243700001903274700002003293700002003313700001903333700001903352700002203371700001903393700002003412700002103432700002003453700002103473700002203494700002103516700002503537700002003562700002403582700002503606700002303631700002203654700001703676700001903693700002303712700002003735700001903755700002003774700002403794700002603818700002003844700001903864700001503883700002103898700002403919700002403943700001903967700002003986700002804006700002004034700001704054700002004071700002304091710004504114856003604159 2018 eng d a1476-557800aWhole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.0 aWhole exome sequencing study identifies novel rare and common Al c2018 Aug 143 aThe Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
1 aBis, Joshua, C1 aJian, Xueqiu1 aKunkle, Brian, W1 aChen, Yuning1 aHamilton-Nelson, Kara, L1 aBush, William, S1 aSalerno, William, J1 aLancour, Daniel1 aMa, Yiyi1 aRenton, Alan, E1 aMarcora, Edoardo1 aFarrell, John, J1 aZhao, Yi1 aQu, Liming1 aAhmad, Shahzad1 aAmin, Najaf1 aAmouyel, Philippe1 aBeecham, Gary, W1 aBelow, Jennifer, E1 aCampion, Dominique1 aCharbonnier, Camille1 aChung, Jaeyoon1 aCrane, Paul, K1 aCruchaga, Carlos1 aCupples, Adrienne, L1 aDartigues, Jean-François1 aDebette, Stephanie1 aDeleuze, Jean-Francois1 aFulton, Lucinda1 aGabriel, Stacey, B1 aGenin, Emmanuelle1 aGibbs, Richard, A1 aGoate, Alison1 aGrenier-Boley, Benjamin1 aGupta, Namrata1 aHaines, Jonathan, L1 aHavulinna, Aki, S1 aHelisalmi, Seppo1 aHiltunen, Mikko1 aHowrigan, Daniel, P1 aIkram, Arfan, M1 aKaprio, Jaakko1 aKonrad, Jan1 aKuzma, Amanda1 aLander, Eric, S1 aLathrop, Mark1 aLehtimäki, Terho1 aLin, Honghuang1 aMattila, Kari1 aMayeux, Richard1 aMuzny, Donna, M1 aNasser, Waleed1 aNeale, Benjamin1 aNho, Kwangsik1 aNicolas, Gaël1 aPatel, Devanshi1 aPericak-Vance, Margaret, A1 aPerola, Markus1 aPsaty, Bruce, M1 aQuenez, Olivier1 aRajabli, Farid1 aRedon, Richard1 aReitz, Christiane1 aRemes, Anne, M1 aSalomaa, Veikko1 aSarnowski, Chloe1 aSchmidt, Helena1 aSchmidt, Michael1 aSchmidt, Reinhold1 aSoininen, Hilkka1 aThornton, Timothy, A1 aTosto, Giuseppe1 aTzourio, Christophe1 avan der Lee, Sven, J1 aDuijn, Cornelia, M1 aVardarajan, Badri1 aWang, Weixin1 aWijsman, Ellen1 aWilson, Richard, K1 aWitten, Daniela1 aWorley, Kim, C1 aZhang, Xiaoling1 aBellenguez, Céline1 aLambert, Jean-Charles1 aKurki, Mitja, I1 aPalotie, Aarno1 aDaly, Mark1 aBoerwinkle, Eric1 aLunetta, Kathryn, L1 aDeStefano, Anita, L1 aDupuis, Josée1 aMartin, Eden, R1 aSchellenberg, Gerard, D1 aSeshadri, Sudha1 aNaj, Adam, C1 aFornage, Myriam1 aFarrer, Lindsay, A1 aAlzheimer’s Disease Sequencing Project uhttps://chs-nhlbi.org/node/778502912nas a2200457 4500008004100000022001400041245009600055210006900151260001300220300001200233490000600245520159000251100002501841700001901866700002001885700002101905700002001926700002001946700002501966700002001991700002102011700001402032700002202046700002102068700001702089700001802106700001602124700001802140700002002158700001902178700002002197700002402217700002102241700002502262700001902287700003102306700002002337700001802357710004302375856003602418 2018 eng d a2328-950300aWhole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease.0 aWhole genome sequencing of Caribbean Hispanic families with late c2018 Apr a406-4170 v53 aObjective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families.
Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.
Results: A variant in p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07-30.9, = 0.041). In addition, missense mutations in and under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant ( < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including ( = 0.049), ( = 0.0098) and ( = 0.040).
Conclusions and Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
1 aVardarajan, Badri, N1 aBarral, Sandra1 aJaworski, James1 aBeecham, Gary, W1 aBlue, Elizabeth1 aTosto, Giuseppe1 aReyes-Dumeyer, Dolly1 aMedrano, Martin1 aLantigua, Rafael1 aNaj, Adam1 aThornton, Timothy1 aDeStefano, Anita1 aMartin, Eden1 aSan Wang, Li-1 aBrown, Lisa1 aBush, William1 aDuijn, Cornelia1 aGoate, Allison1 aFarrer, Lindsay1 aHaines, Jonathan, L1 aBoerwinkle, Eric1 aSchellenberg, Gerard1 aWijsman, Ellen1 aPericak-Vance, Margaret, A1 aMayeux, Richard1 aSan Wang, Li-1 aAlzheimer's Disease Sequencing Project uhttps://chs-nhlbi.org/node/766102737nas a2200301 4500008004100000022001400041245008700055210006900142260001300211300001200224490000600236520182600242100002202068700002202090700002002112700002302132700001902155700002102174700002302195700002802218700002102246700002002267700002502287700002402312700002002336710004302356856003602399 2018 eng d a2328-950300aWhole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease.0 aWholeexome sequencing in 20197 persons for rare variants in Alzh c2018 Jul a832-8420 v53 aObjective: The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals.
Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.
Results: We identified 19 cases carrying extremely rare loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( = 2.17 × 10; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including , and were among candidates for follow-up studies.
Interpretation: This study implicates ultra-rare, loss-of-function variants in as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.
1 aRaghavan, Neha, S1 aBrickman, Adam, M1 aAndrews, Howard1 aManly, Jennifer, J1 aSchupf, Nicole1 aLantigua, Rafael1 aWolock, Charles, J1 aKamalakaran, Sitharthan1 aPetrovski, Slave1 aTosto, Giuseppe1 aVardarajan, Badri, N1 aGoldstein, David, B1 aMayeux, Richard1 aAlzheimer's Disease Sequencing Project uhttps://chs-nhlbi.org/node/781002786nas a2200229 4500008004100000022001400041245010500055210006900160260001300229300001000242490000700252520207700259100002902336700001902365700002302384700002502407700002502432700001902457700002202476700002202498856003602520 2019 eng d a1532-541500aAbnormal Fasting Glucose Increases Risk of Unrecognized Myocardial Infarctions in an Elderly Cohort.0 aAbnormal Fasting Glucose Increases Risk of Unrecognized Myocardi c2019 Jan a43-490 v673 aOBJECTIVES: To investigate glucose levels as a risk factor for unrecognized myocardial infarctions (UMIs).
DESIGN: Cohort SETTING: Cardiovascular Health Study.
PARTICIPANTS: Individuals aged 65 and older with fasting glucose measurements (N=4,355; normal fasting glucose (NFG), n = 2,041; impaired fasting glucose (IFG), n = 1,706; DM: n = 608; 40% male, 84% white, mean age 72.4 ± 5.6).
MEASUREMENTS: The relationship between glucose levels and UMI was examined. Participants with prior coronary heart disease (CHD) or UMI on initial electrocardiography were excluded. Using Minnesota codes, UMI was identified according to the presence of pathological Q-waves or minor Q-waves with ST-T abnormalities. Crude and adjusted hazard ratios (HRs) were calculated. Analyses were adjusted for age, sex, body mass index (BMI), hypertension, antihypertensive and lipid-lowering medication use, total cholesterol, high-density lipoprotein cholesterol, and smoking status.
RESULTS: Over a mean follow-up of 6 years, there were 459 incident UMIs (NFG, n=202; IFG, n=183; DM, n=74). Participants with IFG were slightly more likely than those with NFG to experience a UMI (hazard ratio (HR)=1.11, 95% confidence interval (CI)=0.91-1.36, p = .30), and those with DM were more likely than those with NFG to experience a UMI (HR=1.65, 95% CI=1.25-2.13, p < .001). After adjustment HR for UMI in IFG those with IFG were no more likely than those with NFG to experience a UMI (HR=1.01, 95% CI=0.82-1.24, p = .93), whereas those with DM were more likely than those with NFG to experience a UMI (HR=1.37, 95% CI=1.02-1.81, p = .03). The 2-hour oral glucose tolerance test was not statistically significantly associated with UMI.
CONCLUSION: Fasting glucose status, particularly in the diabetic range, forecasted UMI during 6 years of follow-up in elderly adults. Further studies are needed to clarify the level of glucose at which risk is greater. J Am Geriatr Soc 67:43-49, 2019.
1 aStacey, Richard, Brandon1 aZgibor, Janice1 aLeaverton, Paul, E1 aSchocken, Douglas, D1 aPeregoy, Jennifer, A1 aLyles, Mary, F1 aBertoni, Alain, G1 aBurke, Gregory, L uhttps://chs-nhlbi.org/node/792502447nas a2200157 4500008004100000022001400041245008600055210006900141260001600210520194100226100002202167700002202189700002002211700002202231856003602253 2019 eng d a1525-149700aThe Accuracy of Cardiovascular Pooled Cohort Risk Estimates in U.S. Older Adults.0 aAccuracy of Cardiovascular Pooled Cohort Risk Estimates in US Ol c2019 Oct 303 aBACKGROUND: The ACC/AHA guidelines for primary prevention rely on the Pooled Cohort Risk Equations (PCE) risk estimates of atherosclerotic cardiovascular disease (ASCVD) to guide treatment decisions. In light of the PCE being derived in younger populations, their accuracy in older adults is uncertain.
OBJECTIVE: To evaluate the predictive accuracy and calibration of the PCE in older individuals.
DESIGN AND SETTING: We estimated CVD predicted and observed risk among individuals from four large prospective cohort studies: Cardiovascular Health Study, Multiethnic Study of Atherosclerosis, Framingham Original, and Framingham Offspring.
PARTICIPANTS: 12,527 overall individuals without ASCVD, including 9864 individuals aged 40-74 years and 2663 aged ≥75 years.
MEASUREMENTS: We examined the operating characteristics of the PCE to estimate 5-year risk of stroke, MI, and CHD death overall and by age and sex strata. The associations between individual components of the PCE and cardiovascular events by age group (≥75 vs 40-74 years) were also evaluated.
RESULTS: The PCE had low discrimination for 5-year ASCVD risk in older (≥75 years) (c-statistic = 0.62, 95% CI 0.60-0.65) vs. younger (40-74 years) adults (c-statistic = 0.75, 95% CI 0.73-0.76). Calibration of the PCE was suboptimal in both older and younger adults, overestimating risk in the highest risk groups. Performance of the PCE in older adults was similarly poor when stratified by sex and age ≥ 80 years.
LIMITATIONS: Since the PCE were derived from similar cohorts, though using different age groups and exams, this analysis likely overestimates the performance of the PCE.
CONCLUSION: The performance of the PCE for ASCVD risk estimation in older adults is suboptimal; new models to effectively risk-stratify older adults are needed.
1 aNanna, Michael, G1 aPeterson, Eric, D1 aWojdyla, Daniel1 aNavar, Ann, Marie uhttps://chs-nhlbi.org/node/820103584nas a2200649 4500008004100000022001400041245010200055210006900157260001500226300001200241490000700253520177200260100001702032700001902049700001702068700002002085700001402105700002402119700002302143700001802166700002502184700001902209700002302228700002402251700002102275700002002296700001702316700002002333700001302353700002002366700002002386700002202406700003002428700002502458700002002483700001802503700001902521700002002540700002302560700002002583700002002603700002102623700002402644700002102668700001402689700001902703700002202722700002302744700001702767700001602784700002202800700002102822700001802843700001902861700001802880856003602898 2019 eng d a1460-208300aAdmixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans.0 aAdmixture mapping identifies novel loci for obstructive sleep ap c2019 02 15 a675-6870 v283 aObstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.
1 aWang, Heming1 aCade, Brian, E1 aSofer, Tamar1 aSands, Scott, A1 aChen, Han1 aBrowning, Sharon, R1 aStilp, Adrienne, M1 aLouie, Tin, L1 aThornton, Timothy, A1 aJohnson, Craig1 aBelow, Jennifer, E1 aConomos, Matthew, P1 aEvans, Daniel, S1 aGharib, Sina, A1 aGuo, Xiuqing1 aWood, Alexis, C1 aMei, Hao1 aYaffe, Kristine1 aLoredo, Jose, S1 aRamos, Alberto, R1 aBarrett-Connor, Elizabeth1 aAncoli-Israel, Sonia1 aZee, Phyllis, C1 aArens, Raanan1 aShah, Neomi, A1 aTaylor, Kent, D1 aTranah, Gregory, J1 aStone, Katie, L1 aHanis, Craig, L1 aWilson, James, G1 aGottlieb, Daniel, J1 aPatel, Sanjay, R1 aRice, Ken1 aPost, Wendy, S1 aRotter, Jerome, I1 aSunyaev, Shamil, R1 aCai, Jianwen1 aLin, Xihong1 aPurcell, Shaun, M1 aLaurie, Cathy, C1 aSaxena, Richa1 aRedline, Susan1 aZhu, Xiaofeng uhttps://chs-nhlbi.org/node/804900640nas a2200205 4500008004100000022001400041245008700055210006900142260001500211300001400226490000700240100002000247700002300267700002200290700001900312700002100331700002200352700002400374856003600398 2019 eng d a1460-238500aAPOL1 gene variants and kidney disease in whites: the cardiovascular health study.0 aAPOL1 gene variants and kidney disease in whites the cardiovascu c2019 12 01 a2155-21560 v341 aDrury, Erika, R1 aFriedman, David, J1 aPollak, Martin, R1 aIx, Joachim, H1 aKuller, Lewis, H1 aTracy, Russell, P1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/851204940nas a2200661 4500008004100000022001400041245014200055210006900197260001600266520300700282100002403289700002203313700003003335700001903365700001903384700002303403700002003426700001903446700002303465700001703488700002203505700001803527700001903545700002203564700002203586700002303608700002103631700001803652700001803670700002103688700001803709700002403727700002003751700002103771700002003792700002003812700002003832700001503852700002003867700001903887700002403906700002203930700002103952700001803973700001903991700002104010700002204031700001604053700002204069700002204091700002404113700002204137700002004159700001504179700002504194700002304219856003604242 2019 eng d a2380-659100aAssessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study.0 aAssessment of the Relationship Between Genetic Determinants of T c2019 Jan 233 aImportance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.
Objective: To evaluate the potential direct involvement of thyroid traits on AF.
Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.
Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.
Main Outcomes and Measures: Prevalent and incident AF.
Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).
Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.
1 aEllervik, Christina1 aRoselli, Carolina1 aChristophersen, Ingrid, E1 aAlonso, Alvaro1 aPietzner, Maik1 aSitlani, Collen, M1 aTrompet, Stella1 aArking, Dan, E1 aGeelhoed, Bastiaan1 aGuo, Xiuqing1 aKleber, Marcus, E1 aLin, Henry, J1 aLin, Honghuang1 aMacfarlane, Peter1 aSelvin, Elizabeth1 aShaffer, Christian1 aSmith, Albert, V1 aVerweij, Niek1 aWeiss, Stefan1 aCappola, Anne, R1 aDörr, Marcus1 aGudnason, Vilmundur1 aHeckbert, Susan1 aMooijaart, Simon1 aMärz, Winfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRoden, Dan1 aStott, David, J1 aVölzke, Henry1 aBenjamin, Emelia, J1 aDelgado, Graciela1 aEllinor, Patrick1 aHomuth, Georg1 aKöttgen, Anna1 aJukema, Johan, W1 aLubitz, Steven, A1 aMora, Samia1 aRienstra, Michiel1 aRotter, Jerome, I1 aShoemaker, Benjamin1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aHarst, Pim1 aAlbert, Christine, M1 aChasman, Daniel, I uhttps://chs-nhlbi.org/node/797302241nas a2200217 4500008004100000022001400041245016500055210006900220260001300289300001300302490000700315520151200322100002601834700002301860700002001883700002201903700001901925700002001944700002301964856003601987 2019 eng d a1873-258500aThe association between physical function and proximity to death in older adults: a multilevel analysis of 4,150 decedents from the Cardiovascular Health Study.0 aassociation between physical function and proximity to death in c2019 Jul a59-65.e50 v353 aPURPOSE: When examining whether poor physical function is a risk factor for imminent death in older adults, one challenge is the lack of a meaningful time origin, a time point on which the estimate of time-to-death is anchored. In this study, we overcame this challenge by discarding the traditional-and flawed-approach of survival analysis with "time since beginning of follow up" as the time variable, and instead used a novel analytic approach that uses time-to-death as a covariate to examine its association with physical function.
METHODS: Physical function and other covariates were measured annually in the Cardiovascular Health Study on 4150 individuals followed up to their time of death. Using multilevel models, we estimated gait speed and grip strength in relation to two time axes: age and proximity to death.
RESULTS: As individuals approached death, both gait speed and grip strength decreased significantly. However, after adjustment for health and lifestyle covariates, there was significant variation in the level of physical function between individuals.
CONCLUSION: Although physical function was significantly associated with time-to-death, there was significant variation in level of physical function between individuals at comparable proximity to death. A better understanding of these variations is needed before measures of physical function are recommended as a clinical tool for identifying individuals at high risk of death.
1 aKarunananthan, Sathya1 aMoodie, Erica, E M1 aBergman, Howard1 aPayette, Hélène1 aWolfson, David1 aDiehr, Paula, H1 aWolfson, Christina uhttps://chs-nhlbi.org/node/810304015nas a2200685 4500008004100000245017200041210006900213260000700282300001400289490000800303520204200311100002202353700001702375700001402392700003102406700002002437700001502457700001402472700002102486700001502507700002402522700002802546700001902574700001902593700002102612700001602633700002202649700001802671700001802689700002002707700002002727700001702747700002102764700002202785700001602807700001802823700001802841700002202859700002302881700001202904700002402916700001802940700002502958700001702983700002503000700003003025700001903055700001903074700001903093700001703112700002103129700001803150700001303168700001803181700002003199700003203219700002503251700001703276856003603293 2019 eng d00a{Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals0 aAssociation of dietary folate and vitamin B12 intake with genome c08 a437–4500 v1103 aFolate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans.\ The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes.\ A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes.\ The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs.\ We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.1 aMandaviya, P., R.1 aJoehanes, R.1 aBrody, J.1 aCastillo-Fernandez, J., E.1 aDekkers, K., F.1 aDo, A., N.1 aGraff, M.1 aH?nninen, I., K.1 aTanaka, T.1 ade Jonge, E., A. L.1 ade Jong, J., C. Kiefte-1 aAbsher, D., M.1 aAslibekyan, S.1 ade Rijke, Y., B.1 aFornage, M.1 aHernandez, D., G.1 aHurme, M., A.1 aIkram, M., A.1 aJacques, P., F.1 aJustice, A., E.1 aKiel, D., P.1 aLemaitre, R., N.1 aMendelson, M., M.1 aMikkil?, V.1 aMoore, A., Z.1 aPallister, T.1 aRaitakari, O., T.1 aSchalkwijk, C., G.1 aSha, J.1 aSlagboom, E., P. E.1 aSmith, C., E.1 aStehouwer, C., D. A.1 aTsai, P., C.1 aUitterlinden, A., G.1 avan der Kallen, C., J. H.1 avan Heemst, D.1 aArnett, D., K.1 aBandinelli, S.1 aBell, J., T.1 aHeijmans, B., T.1 aLehtim?ki, T.1 aLevy, D.1 aNorth, K., E.1 aSotoodehnia, N.1 avan Greevenbroek, M., M. J.1 avan Meurs, J., B. J.1 aHeil, S., G. uhttps://chs-nhlbi.org/node/852103490nas a2200517 4500008004100000022001400041245012600055210006900181260001600250520197900266100001902245700002002264700002702284700002002311700001702331700001902348700001302367700001802380700002802398700001602426700002002442700001702462700002102479700001402500700003002514700001802544700002202562700002202584700002002606700002202626700002102648700001702669700002102686700001802707700002402725700002302749700002002772700002002792700002002812700002002832700002002852700001702872700002402889700002302913856003602936 2019 eng d a1460-215600aAssociation of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.0 aAssociation of variants in HTRA1 and NOTCH3 with MRIdefined extr c2019 Mar 113 aWe report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.
1 aMishra, Aniket1 aChauhan, Ganesh1 aViolleau, Marie-Helene1 aVojinovic, Dina1 aJian, Xueqiu1 aBis, Joshua, C1 aLi, Shuo1 aSaba, Yasaman1 aGrenier-Boley, Benjamin1 aYang, Qiong1 aBartz, Traci, M1 aHofer, Edith1 aSoumaré, Aïcha1 aPeng, Fen1 aDuperron, Marie-Gabrielle1 aFoglio, Mario1 aMosley, Thomas, H1 aSchmidt, Reinhold1 aPsaty, Bruce, M1 aLauner, Lenore, J1 aBoerwinkle, Eric1 aZhu, Yicheng1 aMazoyer, Bernard1 aLathrop, Mark1 aBellenguez, Céline1 aDuijn, Cornelia, M1 aIkram, Arfan, M1 aSchmidt, Helena1 aLongstreth, W T1 aFornage, Myriam1 aSeshadri, Sudha1 aJoutel, Anne1 aTzourio, Christophe1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/798915950nas a2205365 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2019 eng d a2041-172300aAssociations of autozygosity with a broad range of human phenotypes.0 aAssociations of autozygosity with a broad range of human phenoty c2019 Oct 31 a49570 v103 aIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
1 aClark, David, W1 aOkada, Yukinori1 aMoore, Kristjan, H S1 aMason, Dan1 aPirastu, Nicola1 aGandin, Ilaria1 aMattsson, Hannele1 aBarnes, Catriona, L K1 aLin, Kuang1 aZhao, Jing Hua1 aDeelen, Patrick1 aRohde, Rebecca1 aSchurmann, Claudia1 aGuo, Xiuqing1 aGiulianini, Franco1 aZhang, Weihua1 aMedina-Gómez, Carolina1 aKarlsson, Robert1 aBao, Yanchun1 aBartz, Traci, M1 aBaumbach, Clemens1 aBiino, Ginevra1 aBixley, Matthew, J1 aBrumat, Marco1 aChai, Jin-Fang1 aCorre, Tanguy1 aCousminer, Diana, L1 aDekker, Annelot, M1 aEccles, David, A1 avan Eijk, Kristel, R1 aFuchsberger, Christian1 aGao, He1 aGermain, Marine1 aGordon, Scott, D1 ade Haan, Hugoline, G1 aHarris, Sarah, E1 aHofer, Edith1 aHuerta-Chagoya, Alicia1 aIgartua, Catherine1 aJansen, Iris, E1 aJia, Yucheng1 aKacprowski, Tim1 aKarlsson, Torgny1 aKleber, Marcus, E1 aLi, Shengchao, Alfred1 aLi-Gao, Ruifang1 aMahajan, Anubha1 aMatsuda, Koichi1 aMeidtner, Karina1 aMeng, Weihua1 aMontasser, May, E1 avan der Most, Peter, J1 aMunz, Matthias1 aNutile, Teresa1 aPalviainen, Teemu1 aPrasad, Gauri1 aPrasad, Rashmi, B1 aPriyanka, Tallapragada, Divya Sri1 aRizzi, Federica1 aSalvi, Erika1 aSapkota, Bishwa, R1 aShriner, Daniel1 aSkotte, Line1 aSmart, Melissa, C1 aSmith, Albert, Vernon1 avan der Spek, Ashley1 aSpracklen, Cassandra, N1 aStrawbridge, Rona, J1 aTajuddin, Salman, M1 aTrompet, Stella1 aTurman, Constance1 aVerweij, Niek1 aViberti, Clara1 aWang, Lihua1 aWarren, Helen, R1 aWootton, Robyn, E1 aYanek, Lisa, R1 aYao, Jie1 aYousri, Noha, A1 aZhao, Wei1 aAdeyemo, Adebowale, A1 aAfaq, Saima1 aAguilar-Salinas, Carlos, Alberto1 aAkiyama, Masato1 aAlbert, Matthew, L1 aAllison, Matthew, A1 aAlver, Maris1 aAung, Tin1 aAzizi, Fereidoun1 aBentley, Amy, R1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBorja, Judith, B1 ade Borst, Gert, J1 aBottinger, Erwin, P1 aBroer, Linda1 aCampbell, Harry1 aChanock, Stephen1 aChee, Miao-Li1 aChen, Guanjie1 aChen, Yii-der, I1 aChen, Zhengming1 aChiu, Yen-Feng1 aCocca, Massimiliano1 aCollins, Francis, S1 aConcas, Maria, Pina1 aCorley, Janie1 aCugliari, Giovanni1 avan Dam, Rob, M1 aDamulina, Anna1 aDaneshpour, Maryam, S1 aDay, Felix, R1 aDelgado, Graciela, E1 aDhana, Klodian1 aDoney, Alexander, S F1 aDörr, Marcus1 aDoumatey, Ayo, P1 aDzimiri, Nduna1 aEbenesersdóttir, Sunna1 aElliott, Joshua1 aElliott, Paul1 aEwert, Ralf1 aFelix, Janine, F1 aFischer, Krista1 aFreedman, Barry, I1 aGirotto, Giorgia1 aGoel, Anuj1 aGögele, Martin1 aGoodarzi, Mark, O1 aGraff, Mariaelisa1 aGranot-Hershkovitz, Einat1 aGrodstein, Francine1 aGuarrera, Simonetta1 aGudbjartsson, Daniel, F1 aGuity, Kamran1 aGunnarsson, Bjarni1 aGuo, Yu1 aHagenaars, Saskia, P1 aHaiman, Christopher, A1 aHalevy, Avner1 aHarris, Tamara, B1 aHedayati, Mehdi1 avan Heel, David, A1 aHirata, Makoto1 aHöfer, Imo1 aHsiung, Chao, Agnes1 aHuang, Jinyan1 aHung, Yi-Jen1 aIkram, Arfan, M1 aJagadeesan, Anuradha1 aJousilahti, Pekka1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerrison, Nicola, D1 aKessler, Thorsten1 aKhaw, Kay-Tee1 aKhor, Chiea, Chuen1 ade Kleijn, Dominique, P V1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKraft, Peter1 aKrämer, Bernhard, K1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLawlor, Deborah, A1 aLee, I-Te1 aLee, Wen-Jane1 aLerch, Markus, M1 aLi, Liming1 aLiu, Jianjun1 aLoh, Marie1 aLondon, Stephanie, J1 aLoomis, Stephanie1 aLu, Yingchang1 aLuan, Jian'an1 aMägi, Reedik1 aManichaikul, Ani, W1 aManunta, Paolo1 aMásson, Gísli1 aMatoba, Nana1 aMei, Xue, W1 aMeisinger, Christa1 aMeitinger, Thomas1 aMezzavilla, Massimo1 aMilani, Lili1 aMillwood, Iona, Y1 aMomozawa, Yukihide1 aMoore, Amy1 aMorange, Pierre-Emmanuel1 aMoreno-Macias, Hortensia1 aMori, Trevor, A1 aMorrison, Alanna, C1 aMuka, Taulant1 aMurakami, Yoshinori1 aMurray, Alison, D1 ade Mutsert, Renée1 aMychaleckyj, Josyf, C1 aNalls, Mike, A1 aNauck, Matthias1 aNeville, Matt, J1 aNolte, Ilja, M1 aOng, Ken, K1 aOrozco, Lorena1 aPadmanabhan, Sandosh1 aPálsson, Gunnar1 aPankow, James, S1 aPattaro, Cristian1 aPattie, Alison1 aPolasek, Ozren1 aPoulter, Neil1 aPramstaller, Peter, P1 aQuintana-Murci, Lluis1 aRäikkönen, Katri1 aRalhan, Sarju1 aRao, Dabeeru, C1 avan Rheenen, Wouter1 aRich, Stephen, S1 aRidker, Paul, M1 aRietveld, Cornelius, A1 aRobino, Antonietta1 avan Rooij, Frank, J A1 aRuggiero, Daniela1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSabater-Lleal, Maria1 aSala, Cinzia, Felicita1 aSalomaa, Veikko1 aSandow, Kevin1 aSchmidt, Helena1 aScott, Laura, J1 aScott, William, R1 aSedaghati-Khayat, Bahareh1 aSennblad, Bengt1 avan Setten, Jessica1 aSever, Peter, J1 aSheu, Wayne, H-H1 aShi, Yuan1 aShrestha, Smeeta1 aShukla, Sharvari, Rahul1 aSigurdsson, Jon, K1 aSikka, Timo, Tonis1 aSingh, Jai, Rup1 aSmith, Blair, H1 aStančáková, Alena1 aStanton, Alice1 aStarr, John, M1 aStefansdottir, Lilja1 aStraker, Leon1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSwertz, Morris, A1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTerzikhan, Natalie1 aTham, Yih-Chung1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTillander, Annika1 aTracy, Russell, P1 aTusié-Luna, Teresa1 aTzoulaki, Ioanna1 aVaccargiu, Simona1 aVangipurapu, Jagadish1 aVeldink, Jan, H1 aVitart, Veronique1 aVölker, Uwe1 aVuoksimaa, Eero1 aWakil, Salma, M1 aWaldenberger, Melanie1 aWander, Gurpreet, S1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWild, Sarah1 aYajnik, Chittaranjan, S1 aYuan, Jian-Min1 aZeng, Lingyao1 aZhang, Liang1 aZhou, Jie1 aAmin, Najaf1 aAsselbergs, Folkert, W1 aBakker, Stephan, J L1 aBecker, Diane, M1 aLehne, Benjamin1 aBennett, David, A1 avan den Berg, Leonard, H1 aBerndt, Sonja, I1 aBharadwaj, Dwaipayan1 aBielak, Lawrence, F1 aBochud, Murielle1 aBoehnke, Mike1 aBouchard, Claude1 aBradfield, Jonathan, P1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarmi, Shai1 aCaulfield, Mark, J1 aCesarini, David1 aChambers, John, C1 aChandak, Giriraj, Ratan1 aCheng, Ching-Yu1 aCiullo, Marina1 aCornelis, Marilyn1 aCusi, Daniele1 aSmith, George Davey1 aDeary, Ian, J1 aDorajoo, Rajkumar1 aDuijn, Cornelia, M1 aEllinghaus, David1 aErdmann, Jeanette1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aEvans, Michele, K1 aFaul, Jessica, D1 aFeenstra, Bjarke1 aFeitosa, Mary1 aFoisy, Sylvain1 aFranke, Andre1 aFriedlander, Yechiel1 aGasparini, Paolo1 aGieger, Christian1 aGonzalez, Clicerio1 aGoyette, Philippe1 aGrant, Struan, F A1 aGriffiths, Lyn, R1 aGroop, Leif1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHakonarson, Hakon1 aHamsten, Anders1 aHarst, Pim1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHochner, Hagit1 aHuikuri, Heikki1 aHunt, Steven, C1 aJaddoe, Vincent, W V1 aDe Jager, Philip, L1 aJohannesson, Magnus1 aJohansson, Asa1 aJonas, Jost, B1 aJukema, Wouter1 aJunttila, Juhani1 aKaprio, Jaakko1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKumari, Meena1 aLaakso, Markku1 avan der Laan, Sander, W1 aLahti, Jari1 aLaudes, Matthias1 aLea, Rodney, A1 aLieb, Wolfgang1 aLumley, Thomas1 aMartin, Nicholas, G1 aMärz, Winfried1 aMatullo, Giuseppe1 aMcCarthy, Mark, I1 aMedland, Sarah, E1 aMerriman, Tony, R1 aMetspalu, Andres1 aMeyer, Brian, F1 aMohlke, Karen, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis1 aMunroe, Patricia, B1 aNorth, Kari, E1 aNyholt, Dale, R1 aO'Connell, Jeffery, R1 aOber, Carole1 aOldehinkel, Albertine, J1 aPalmas, Walter1 aPalmer, Colin1 aPasterkamp, Gerard, G1 aPatin, Etienne1 aPennell, Craig, E1 aPerusse, Louis1 aPeyser, Patricia, A1 aPirastu, Mario1 aPolderman, Tinca, J C1 aPorteous, David, J1 aPosthuma, Danielle1 aPsaty, Bruce, M1 aRioux, John, D1 aRivadeneira, Fernando1 aRotimi, Charles1 aRotter, Jerome, I1 aRudan, Igor1 aRuijter, Hester, M den1 aSanghera, Dharambir, K1 aSattar, Naveed1 aSchmidt, Reinhold1 aSchulze, Matthias, B1 aSchunkert, Heribert1 aScott, Robert, A1 aShuldiner, Alan, R1 aSim, Xueling1 aSmall, Neil1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aTai, E-Shyong1 aTeumer, Alexander1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTrégouët, David-Alexandre1 aTuomi, Tiinamaija1 aVollenweider, Peter1 aWang, Carol, A1 aWeir, David, R1 aWhitfield, John, B1 aWijmenga, Cisca1 aWong, Tien-Yin1 aWright, John1 aYang, Jingyun1 aYu, Lei1 aZemel, Babette, S1 aZonderman, Alan, B1 aPerola, Markus1 aMagnusson, Patrik, K E1 aUitterlinden, André, G1 aKooner, Jaspal, S1 aChasman, Daniel, I1 aLoos, Ruth, J F1 aFranceschini, Nora1 aFranke, Lude1 aHaley, Chris, S1 aHayward, Caroline1 aWalters, Robin, G1 aPerry, John, R B1 aEsko, Tõnu1 aHelgason, Agnar1 aStefansson, Kari1 aJoshi, Peter, K1 aKubo, Michiaki1 aWilson, James, F uhttps://chs-nhlbi.org/node/819804619nas a2201021 4500008004100000022001400041245012900055210006900184260001200253300001300265490000700278520172700285653001502012653001002027653000902037653002202046653003802068653002602106653003402132653001102166653002902177653002202206653003402228653001502262653001102277653001202288653004202300653000902342653001602351653002602367653005002393653001102443653001902454653003602473653002802509653002602537653001002563653002602573653001602599100001902615700001402634700002302648700001502671700002502686700001802711700002202729700002302751700001702774700002402791700002102815700002802836700002002864700002202884700002402906700002202930700001902952700002202971700001502993700002003008700001303028700002203041700002103063700001903084700002203103700002203125700002103147700001403168700001903182700001703201700002003218700002503238700001703263700002003280700002003300700002003320700002003340700002203360700002003382700002303402700002103425700002303446700002103469700001803490700001803508700001603526700001903542856003603561 2019 eng d a1553-740400aAssociations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.0 aAssociations of variants In the hexokinase 1 and interleukin 18 c2019 04 ae10077390 v153 aSleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCell Adhesion Molecules, Neuronal10aComputational Biology10aExtracellular Matrix Proteins10aFemale10aGene Regulatory Networks10aGenetic Variation10aGenome-Wide Association Study10aHexokinase10aHumans10aHypoxia10aInterleukin-18 Receptor alpha Subunit10aMale10aMiddle Aged10aNerve Tissue Proteins10aNLR Family, Pyrin Domain-Containing 3 Protein10aOxygen10aOxyhemoglobins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aSerine Endopeptidases10aSleep10aSleep Apnea Syndromes10aYoung Adult1 aCade, Brian, E1 aChen, Han1 aStilp, Adrienne, M1 aLouie, Tin1 aAncoli-Israel, Sonia1 aArens, Raanan1 aBarfield, Richard1 aBelow, Jennifer, E1 aCai, Jianwen1 aConomos, Matthew, P1 aEvans, Daniel, S1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aGleason, Kevin, J1 aGottlieb, Daniel, J1 aHillman, David, R1 aJohnson, Craig1 aLederer, David, J1 aLee, Jiwon1 aLoredo, Jose, S1 aMei, Hao1 aMukherjee, Sutapa1 aPatel, Sanjay, R1 aPost, Wendy, S1 aPurcell, Shaun, M1 aRamos, Alberto, R1 aReid, Kathryn, J1 aRice, Ken1 aShah, Neomi, A1 aSofer, Tamar1 aTaylor, Kent, D1 aThornton, Timothy, A1 aWang, Heming1 aYaffe, Kristine1 aZee, Phyllis, C1 aHanis, Craig, L1 aPalmer, Lyle, J1 aRotter, Jerome, I1 aStone, Katie, L1 aTranah, Gregory, J1 aWilson, James, G1 aSunyaev, Shamil, R1 aLaurie, Cathy, C1 aZhu, Xiaofeng1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/804405879nas a2201189 4500008004100000022001400041245009700055210006900152260001600221300001400237490000800251520248600259100002002745700001802765700002102783700002402804700001902828700002202847700001602869700001902885700002002904700002302924700001702947700002902964700002302993700002903016700002003045700002203065700002003087700002203107700001703129700002103146700002003167700002003187700001603207700001803223700001403241700001603255700002303271700002503294700001903319700002303338700002103361700001803382700001803400700002403418700002203442700002103464700002103485700002603506700001903532700001803551700002003569700002403589700001903613700002303632700002203655700002303677700001903700700001703719700002103736700002403757700001903781700001803800700001903818700001903837700001903856700001703875700001503892700001803907700001503925700002203940700001803962700002403980700001704004700002004021700001504041700002504056700002104081700003004102700002104132700002204153700001704175700001204192700002204204700002104226700002504247700002504272700002004297700002004317700002904337700001804366700002004384700001904404700001904423700001804442700002404460700002504484700001704509710012704526856003604653 2019 eng d a1524-453900aBiomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality.0 aBiomarkers of Dietary Omega6 Fatty Acids and Incident Cardiovasc c2019 May 21 a2422-24360 v1393 aBACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.
METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).
RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.
CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
1 aMarklund, Matti1 aH Y Wu, Jason1 aImamura, Fumiaki1 aDel Gobbo, Liana, C1 aFretts, Amanda1 ade Goede, Janette1 aShi, Peilin1 aTintle, Nathan1 aWennberg, Maria1 aAslibekyan, Stella1 aChen, Tzu-An1 aOtto, Marcia, C de Olive1 aHirakawa, Yoichiro1 aEriksen, Helle, Højmark1 aKröger, Janine1 aLaguzzi, Federica1 aLankinen, Maria1 aMurphy, Rachel, A1 aPrem, Kiesha1 aSamieri, Cecilia1 aVirtanen, Jyrki1 aWood, Alexis, C1 aWong, Kerry1 aYang, Wei-Sin1 aZhou, Xia1 aBaylin, Ana1 aBoer, Jolanda, M A1 aBrouwer, Ingeborg, A1 aCampos, Hannia1 aChaves, Paulo, H M1 aChien, Kuo-Liong1 ade Faire, Ulf1 aDjoussé, Luc1 aEiriksdottir, Gudny1 aEl-Abbadi, Naglaa1 aForouhi, Nita, G1 aGaziano, Michael1 aGeleijnse, Johanna, M1 aGigante, Bruna1 aGiles, Graham1 aGuallar, Eliseo1 aGudnason, Vilmundur1 aHarris, Tamara1 aHarris, William, S1 aHelmer, Catherine1 aHellenius, Mai-Lis1 aHodge, Allison1 aHu, Frank, B1 aJacques, Paul, F1 aJansson, Jan-Håkan1 aKalsbeek, Anya1 aKhaw, Kay-Tee1 aKoh, Woon-Puay1 aLaakso, Markku1 aLeander, Karin1 aLin, Hung-Ju1 aLind, Lars1 aLuben, Robert1 aLuo, Juhua1 aMcKnight, Barbara1 aMursu, Jaakko1 aNinomiya, Toshiharu1 aOvervad, Kim1 aPsaty, Bruce, M1 aRimm, Eric1 aSchulze, Matthias, B1 aSiscovick, David1 aNielsen, Michael, Skjelbo1 aSmith, Albert, V1 aSteffen, Brian, T1 aSteffen, Lyn1 aSun, Qi1 aSundström, Johan1 aTsai, Michael, Y1 aTunstall-Pedoe, Hugh1 aUusitupa, Matti, I J1 avan Dam, Rob, M1 aVeenstra, Jenna1 aVerschuren, W, M Monique1 aWareham, Nick1 aWillett, Walter1 aWoodward, Mark1 aYuan, Jian-Min1 aMicha, Renata1 aLemaitre, Rozenn, N1 aMozaffarian, Dariush1 aRiserus, Ulf1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE) uhttps://chs-nhlbi.org/node/804704760nas a2201057 4500008004100000022001400041245011000055210006900165260001500234300001200249490000800261520187700269653001002146653000902156653001902165653002102184653001602205653002002221653001102241653001102252653003402263653001102297653001402308653001502322653000902337653001602346653002602362653002202388653001402410653002402424653000902448653001802457100001802475700002602493700002802519700001902547700001902566700002002585700001902605700002302624700002202647700001802669700001902687700002002706700002402726700002002750700001902770700001702789700002202806700002102828700002002849700002302869700002102892700002502913700002402938700002002962700002202982700002003004700001203024700002003036700002203056700002003078700002203098700002203120700002203142700002003164700002003184700002003204700002103224700002003245700002103265700002003286700001603306700002503322700002103347700001903368700002203387700002003409700002403429700001603453700002003469700002203489700002203511700002003533700002003553700002903573700002103602700001703623700002603640856003603666 2019 eng d a1524-453900aBlood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.0 aBlood Leukocyte DNA Methylation Predicts Risk of Future Myocardi c2019 08 20 a645-6570 v1403 aBACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.
METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.
RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.
CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
10aAdult10aAged10aCohort Studies10aCoronary Disease10aCpG Islands10aDNA Methylation10aEurope10aFemale10aGenome-Wide Association Study10aHumans10aIncidence10aLeukocytes10aMale10aMiddle Aged10aMyocardial Infarction10aPopulation Groups10aPrognosis10aProspective Studies10aRisk10aUnited States1 aAgha, Golareh1 aMendelson, Michael, M1 aWard-Caviness, Cavin, K1 aJoehanes, Roby1 aHuan, Tianxiao1 aGondalia, Rahul1 aSalfati, Elias1 aBrody, Jennifer, A1 aFiorito, Giovanni1 aBressler, Jan1 aChen, Brian, H1 aLigthart, Symen1 aGuarrera, Simonetta1 aColicino, Elena1 aJust, Allan, C1 aWahl, Simone1 aGieger, Christian1 aVandiver, Amy, R1 aTanaka, Toshiko1 aHernandez, Dena, G1 aPilling, Luke, C1 aSingleton, Andrew, B1 aSacerdote, Carlotta1 aKrogh, Vittorio1 aPanico, Salvatore1 aTumino, Rosario1 aLi, Yun1 aZhang, Guosheng1 aStewart, James, D1 aFloyd, James, S1 aWiggins, Kerri, L1 aRotter, Jerome, I1 aMulthaup, Michael1 aBakulski, Kelly1 aHorvath, Steven1 aTsao, Philip, S1 aAbsher, Devin, M1 aVokonas, Pantel1 aHirschhorn, Joel1 aFallin, Daniele1 aLiu, Chunyu1 aBandinelli, Stefania1 aBoerwinkle, Eric1 aDehghan, Abbas1 aSchwartz, Joel, D1 aPsaty, Bruce, M1 aFeinberg, Andrew, P1 aHou, Lifang1 aFerrucci, Luigi1 aSotoodehnia, Nona1 aMatullo, Giuseppe1 aPeters, Annette1 aFornage, Myriam1 aAssimes, Themistocles, L1 aWhitsel, Eric, A1 aLevy, Daniel1 aBaccarelli, Andrea, A uhttps://chs-nhlbi.org/node/850713143nas a2204261 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2019 eng d a1546-171800aA catalog of genetic loci associated with kidney function from analyses of a million individuals.0 acatalog of genetic loci associated with kidney function from ana c2019 06 a957-9720 v513 aChronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aInheritance Patterns10aKidney Function Tests10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRenal Insufficiency, Chronic10aUromodulin1 aWuttke, Matthias1 aLi, Yong1 aLi, Man1 aSieber, Karsten, B1 aFeitosa, Mary, F1 aGorski, Mathias1 aTin, Adrienne1 aWang, Lihua1 aChu, Audrey, Y1 aHoppmann, Anselm1 aKirsten, Holger1 aGiri, Ayush1 aChai, Jin-Fang1 aSveinbjornsson, Gardar1 aTayo, Bamidele, O1 aNutile, Teresa1 aFuchsberger, Christian1 aMarten, Jonathan1 aCocca, Massimiliano1 aGhasemi, Sahar1 aXu, Yizhe1 aHorn, Katrin1 aNoce, Damia1 avan der Most, Peter, J1 aSedaghat, Sanaz1 aYu, Zhi1 aAkiyama, Masato1 aAfaq, Saima1 aAhluwalia, Tarunveer, S1 aAlmgren, Peter1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoissel, Mathilde1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrenner, Hermann1 aBrumat, Marco1 aBurkhardt, Ralph1 aButterworth, Adam, S1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCanouil, Mickaël1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aChee, Miao-Ling1 aChee, Miao-Li1 aChen, Xu1 aCheng, Ching-Yu1 aCheng, Yurong1 aChristensen, Kaare1 aCifkova, Renata1 aCiullo, Marina1 aConcas, Maria, Pina1 aCook, James, P1 aCoresh, Josef1 aCorre, Tanguy1 aSala, Cinzia, Felicita1 aCusi, Daniele1 aDanesh, John1 aDaw, Warwick1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDegenhardt, Frauke1 aDelgado, Graciela1 aDemirkan, Ayse1 aDi Angelantonio, Emanuele1 aDittrich, Katalin1 aDivers, Jasmin1 aDorajoo, Rajkumar1 aEckardt, Kai-Uwe1 aEhret, Georg1 aElliott, Paul1 aEndlich, Karlhans1 aEvans, Michele, K1 aFelix, Janine, F1 aFoo, Valencia, Hui Xian1 aFranco, Oscar, H1 aFranke, Andre1 aFreedman, Barry, I1 aFreitag-Wolf, Sandra1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGansevoort, Ron, T1 aGao, He1 aGasparini, Paolo1 aGaziano, Michael1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGiulianini, Franco1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHartman, Catharina, A1 aHayward, Caroline1 aHellwege, Jacklyn, N1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHofer, Edith1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aIndridason, Olafur, S1 aIngelsson, Erik1 aIsing, Marcus1 aJaddoe, Vincent, W V1 aJakobsdottir, Johanna1 aJonas, Jost, B1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKanai, Masahiro1 aKastarinen, Mika1 aKerr, Shona, M1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKörner, Antje1 aKovacs, Peter1 aKraja, Aldi, T1 aKrajcoviechova, Alena1 aKramer, Holly1 aKrämer, Bernhard, K1 aKronenberg, Florian1 aKubo, Michiaki1 aKuhnel, Brigitte1 aKuokkanen, Mikko1 aKuusisto, Johanna1 aLa Bianca, Martina1 aLaakso, Markku1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLee, Jeannette, Jen-Mai1 aLehne, Benjamin1 aLehtimäki, Terho1 aLieb, Wolfgang1 aLim, Su-Chi1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Jun1 aLiu, Jianjun1 aLoeffler, Markus1 aLoos, Ruth, J F1 aLucae, Susanne1 aLukas, Mary, Ann1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMahajan, Anubha1 aMartin, Nicholas, G1 aMartins, Jade1 aMärz, Winfried1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMeisinger, Christa1 aMeitinger, Thomas1 aMelander, Olle1 aMetspalu, Andres1 aMikaelsdottir, Evgenia, K1 aMilaneschi, Yuri1 aMiliku, Kozeta1 aMishra, Pashupati, P1 aMohlke, Karen, L1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMychaleckyj, Josyf, C1 aNadkarni, Girish, N1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey1 aO'Donoghue, Michelle, L1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aOrho-Melander, Marju1 aOuwehand, Willem, H1 aPadmanabhan, Sandosh1 aPalmer, Nicholette, D1 aPalsson, Runolfur1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPerola, Markus1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPodgornaia, Anna, I1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPramstaller, Peter, P1 aPreuss, Michael, H1 aPrins, Bram, P1 aProvince, Michael, A1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRizzi, Federica1 aRoberts, David, J1 aRobino, Antonietta1 aRossing, Peter1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSalvi, Erika1 aSaum, Kai-Uwe1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSchöttker, Ben1 aSchulz, Christina-Alexandra1 aSchupf, Nicole1 aShaffer, Christian, M1 aShi, Yuan1 aSmith, Albert, V1 aSmith, Blair, H1 aSoranzo, Nicole1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStringham, Heather, M1 aStumvoll, Michael1 aSvensson, Per, O1 aSzymczak, Silke1 aTai, E-Shyong1 aTajuddin, Salman, M1 aTan, Nicholas, Y Q1 aTaylor, Kent, D1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomsen, Hauke1 aThorleifsson, Gudmar1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aTzoulaki, Ioanna1 aUitterlinden, André, G1 aVaccargiu, Simona1 avan Dam, Rob, M1 aHarst, Pim1 aDuijn, Cornelia, M1 aEdward, Digna, R Velez1 aVerweij, Niek1 aVogelezang, Suzanne1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWallentin, Lars1 aWang, Ya, Xing1 aWang, Chaolong1 aWaterworth, Dawn, M1 aBin Wei, Wen1 aWhite, Harvey1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWojczynski, Mary, K1 aWong, Charlene1 aWong, Tien-Yin1 aXu, Liang1 aYang, Qiong1 aYasuda, Masayuki1 aYerges-Armstrong, Laura, M1 aZhang, Weihua1 aZonderman, Alan, B1 aRotter, Jerome, I1 aBochud, Murielle1 aPsaty, Bruce, M1 aVitart, Veronique1 aWilson, James, G1 aDehghan, Abbas1 aParsa, Afshin1 aChasman, Daniel, I1 aHo, Kevin1 aMorris, Andrew, P1 aDevuyst, Olivier1 aAkilesh, Shreeram1 aPendergrass, Sarah, A1 aSim, Xueling1 aBöger, Carsten, A1 aOkada, Yukinori1 aEdwards, Todd, L1 aSnieder, Harold1 aStefansson, Kari1 aHung, Adriana, M1 aHeid, Iris, M1 aScholz, Markus1 aTeumer, Alexander1 aKöttgen, Anna1 aPattaro, Cristian1 aLifeLines Cohort Study1 aV. A. Million Veteran Program uhttps://chs-nhlbi.org/node/810901454nas a2200493 4500008004100000022001400041245010500055210006900160260001300229300001200242490000700254100001800261700002200279700002300301700002300324700002300347700002200370700002200392700001800414700001600432700001500448700002300463700001700486700002400503700002200527700002200549700002000571700002400591700002100615700002000636700001900656700002000675700002200695700002000717700002500737700002200762700002200784700002000806700002800826700002200854700002400876700002400900856003600924 2019 eng d a2574-830000aCommon Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation.0 aCommon Genetic Variation in Relation to Brachial Vascular Dimens c2019 Feb ae0024090 v121 aDörr, Marcus1 aHamburg, Naomi, M1 aMüller, Christian1 aSmith, Nicholas, L1 aGustafsson, Stefan1 aLehtimäki, Terho1 aTeumer, Alexander1 aZeller, Tanja1 aLi, Xiaohui1 aLind, Lars1 aRaitakari, Olli, T1 aVölker, Uwe1 aBlankenberg, Stefan1 aMcKnight, Barbara1 aMorris, Andrew, P1 aKähönen, Mika1 aLemaitre, Rozenn, N1 aWild, Philipp, S1 aNauck, Matthias1 aVölzke, Henry1 aMünzel, Thomas1 aMitchell, Gary, F1 aPsaty, Bruce, M1 aLindgren, Cecilia, M1 aLarson, Martin, G1 aFelix, Stephan, B1 aIngelsson, Erik1 aLyytikäinen, Leo-Pekka1 aHerrington, David1 aBenjamin, Emelia, J1 aSchnabel, Renate, B uhttps://chs-nhlbi.org/node/797207560nas a2202017 4500008004100000022001400041245004500055210004400100260001600144300001200160490000800172520198400180100001902164700002502183700001902208700001802227700002302245700001602268700001902284700002202303700001802325700002102343700002302364700001702387700002102404700001802425700002002443700002702463700002002490700002202510700002202532700001502554700001602569700002102585700001802606700002402624700003102648700002502679700001702704700002102721700002202742700002402764700002102788700001902809700002302828700001902851700002102870700002102891700001202912700002202924700002102946700002402967700002202991700002203013700001903035700001803054700002003072700002003092700001803112700002003130700002003150700002303170700001803193700001903211700002203230700001603252700002103268700001803289700002803307700001803335700002703353700002203380700002203402700002203424700002503446700002103471700002103492700002203513700001903535700001603554700001703570700002303587700002103610700002103631700002003652700001503672700002203687700001703709700002203726700002103748700002003769700002303789700001803812700002103830700001603851700002303867700002803890700002203918700001903940700002003959700002303979700002504002700002204027700002004049700002104069700002004090700002604110700001904136700002004155700001904175700001904194700001904213700002004232700002304252700002004275700002304295700002304318700002004341700002604361700002104387700002204408700001604430700002004446700002504466700001904491700002004510700002104530700001904551700002004570700002404590700002504614700002104639700003504660700001904695700002704714700002604741700002204767700002304789700002404812700002504836700002804861700001904889700002304908700002804931700002304959700002704982700002405009700002405033700001905057700002605076700001705102700002505119700002105144700002305165700002205188700002105210700002705231700002105258700002205279700003105301700001205332700001805344700001905362700001705381700002305398700002205421700002305443700002105466700001905487856003605506 2019 eng d a1938-320700aDisentangling the genetics of lean mass.0 aDisentangling the genetics of lean mass c2019 Feb 01 a276-2870 v1093 aBackground: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.
Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.
Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).
Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.
Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
1 aKarasik, David1 aZillikens, Carola, M1 aHsu, Yi-Hsiang1 aAghdassi, Ali1 aÅkesson, Kristina1 aAmin, Najaf1 aBarroso, Inês1 aBennett, David, A1 aBertram, Lars1 aBochud, Murielle1 aBorecki, Ingrid, B1 aBroer, Linda1 aBuchman, Aron, S1 aByberg, Liisa1 aCampbell, Harry1 aCampos-Obando, Natalia1 aCauley, Jane, A1 aCawthon, Peggy, M1 aChambers, John, C1 aChen, Zhao1 aCho, Nam, H1 aChoi, Hyung, Jin1 aChou, Wen-Chi1 aCummings, Steven, R1 ade Groot, Lisette, C P G M1 aDe Jager, Phillip, L1 aDemuth, Ilja1 aDiatchenko, Luda1 aEcons, Michael, J1 aEiriksdottir, Gudny1 aEnneman, Anke, W1 aEriksson, Joel1 aEriksson, Johan, G1 aEstrada, Karol1 aEvans, Daniel, S1 aFeitosa, Mary, F1 aFu, Mao1 aGieger, Christian1 aGrallert, Harald1 aGudnason, Vilmundur1 aLenore, Launer, J1 aHayward, Caroline1 aHofman, Albert1 aHomuth, Georg1 aHuffman, Kim, M1 aHusted, Lise, B1 aIllig, Thomas1 aIngelsson, Erik1 aIttermann, Till1 aJansson, John-Olov1 aJohnson, Toby1 aBiffar, Reiner1 aJordan, Joanne, M1 aJula, Antti1 aKarlsson, Magnus1 aKhaw, Kay-Tee1 aKilpeläinen, Tuomas, O1 aKlopp, Norman1 aKloth, Jacqueline, S L1 aKoller, Daniel, L1 aKooner, Jaspal, S1 aKraus, William, E1 aKritchevsky, Stephen1 aKutalik, Zoltán1 aKuulasmaa, Teemu1 aKuusisto, Johanna1 aLaakso, Markku1 aLahti, Jari1 aLang, Thomas1 aLangdahl, Bente, L1 aLerch, Markus, M1 aLewis, Joshua, R1 aLill, Christina1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLivshits, Gregory1 aLjunggren, Osten1 aLoos, Ruth, J F1 aLorentzon, Mattias1 aLuan, Jian'an1 aLuben, Robert, N1 aMalkin, Ida1 aMcGuigan, Fiona, E1 aMedina-Gómez, Carolina1 aMeitinger, Thomas1 aMelhus, Håkan1 aMellström, Dan1 aMichaëlsson, Karl1 aMitchell, Braxton, D1 aMorris, Andrew, P1 aMosekilde, Leif1 aNethander, Maria1 aNewman, Anne, B1 aO'Connell, Jeffery, R1 aOostra, Ben, A1 aOrwoll, Eric, S1 aPalotie, Aarno1 aPeacock, Munro1 aPerola, Markus1 aPeters, Annette1 aPrince, Richard, L1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRalston, Stuart, H1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRobbins, John, A1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSatterfield, Suzanne1 aSchipf, Sabine1 aShin, Chan, Soo1 aSmith, Albert, V1 aSmith, Shad, B1 aSoranzo, Nicole1 aSpector, Timothy, D1 aStančáková, Alena1 aStefansson, Kari1 aSteinhagen-Thiessen, Elisabeth1 aStolk, Lisette1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aSwart, Karin, M A1 aThompson, Patricia1 aThomson, Cynthia, A1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTikkanen, Emmi1 aTranah, Gregory, J1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 avan Schoor, Natasja, M1 aVandenput, Liesbeth1 aVollenweider, Peter1 aVölzke, Henry1 aWactawski-Wende, Jean1 aWalker, Mark1 aWareham, Nicholas, J1 aWaterworth, Dawn1 aWeedon, Michael, N1 aWichmann, H-Erich1 aWiden, Elisabeth1 aWilliams, Frances, M K1 aWilson, James, F1 aWright, Nicole, C1 aYerges-Armstrong, Laura, M1 aYu, Lei1 aZhang, Weihua1 aZhao, Jing Hua1 aZhou, Yanhua1 aNielson, Carrie, M1 aHarris, Tamara, B1 aDemissie, Serkalem1 aKiel, Douglas, P1 aOhlsson, Claes uhttps://chs-nhlbi.org/node/797403011nas a2200361 4500008004100000022001400041245015500055210006900210260001600279520191700295100002202212700001702234700001702251700002302268700002102291700001602312700002002328700002202348700002102370700001902391700001402410700002102424700001802445700002002463700001902483700002202502700001802524700001902542700001602561700001902577700001702596856003602613 2019 eng d a1550-910900aEpigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations.0 aEpigenomewide association analysis of daytime sleepiness in the c2019 May 293 aSTUDY OBJECTIVES: Daytime sleepiness is a consequence of inadequate sleep, sleep-wake control disorder, or other medical conditions. Population variability in prevalence of daytime sleepiness is likely due to genetic and biological factors as well as social and environmental influences. DNA methylation (DNAm) potentially influences multiple health outcomes. Here, we explored the association between DNAm and daytime sleepiness quantified by the Epworth Sleepiness Scale (ESS).
METHODS: We performed multi-ethnic and ethnic-specific epigenome-wide association studies for DNAm and ESS in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 619) and the Cardiovascular Health Study (n = 483), with cross-study replication and meta-analysis. Genetic variants near ESS-associated DNAm were analyzed for methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank.
RESULTS: In MESA only, we detected four DNAm-ESS associations: one across all race/ethnic groups; three in African-Americans (AA) only. Two of the MESA AA associations, in genes KCTD5 and RXRA, nominally replicated in CHS (p-value < 0.05). In the AA meta-analysis, we detected 14 DNAm-ESS associations (FDR q-value < 0.05, top association p-value = 4.26 × 10-8). Three DNAm sites mapped to genes (CPLX3, GFAP, and C7orf50) with biological relevance. We also found evidence for associations with DNAm sites in RAI1, a gene associated with sleep and circadian phenotypes. UK Biobank follow-up analyses detected SNPs in RAI1, RXRA, and CPLX3 with nominal sleepiness associations.
CONCLUSIONS: We identified methylation sites in multiple genes possibly implicated in daytime sleepiness. Most significant DNAm-ESS associations were specific to AA. Future work is needed to identify mechanisms driving ancestry-specific methylation effects.
1 aBarfield, Richard1 aWang, Heming1 aLiu, Yongmei1 aBrody, Jennifer, A1 aSwenson, Brenton1 aLi, Ruitong1 aBartz, Traci, M1 aSotoodehnia, Nona1 aChen, Yii-der, I1 aCade, Brian, E1 aChen, Han1 aPatel, Sanjay, R1 aZhu, Xiaofeng1 aGharib, Sina, A1 aJohnson, Craig1 aRotter, Jerome, I1 aSaxena, Richa1 aPurcell, Shaun1 aLin, Xihong1 aRedline, Susan1 aSofer, Tamar uhttps://chs-nhlbi.org/node/809610274nas a2203361 4500008004100000245015200041210006900193260000700262300001400269490000700283520178000290100001702070700001602087700001302103700001702116700001302133700001402146700001602160700001602176700001502192700002102207700002702228700001502255700001702270700001702287700001602304700001602320700001602336700001702352700002502369700001802394700001902412700001602431700001902447700001802466700001302484700002002497700001802517700001902535700001502554700001502569700001802584700001702602700001702619700001902636700001802655700001802673700002302691700001602714700002002730700002102750700002002771700001902791700001902810700002102829700002102850700001702871700001802888700001402906700002002920700001802940700002002958700001702978700001702995700001903012700001803031700001503049700001703064700001503081700001503096700001803111700002803129700001903157700001703176700001303193700001903206700001603225700001903241700001803260700001903278700001403297700001403311700002003325700001603345700002003361700001503381700001603396700001703412700002303429700001403452700001803466700002003484700001703504700001703521700001303538700003103551700002103582700001503603700001403618700001803632700001703650700001503667700001803682700001503700700001603715700001903731700001703750700002303767700002103790700001503811700002403826700002003850700002003870700002003890700001903910700001403929700001903943700001903962700001703981700002103998700001904019700002004038700002004058700002404078700001604102700001504118700001404133700001804147700001404165700001904179700001804198700001804216700001704234700002304251700002004274700001604294700001804310700002004328700001904348700001704367700002304384700001904407700001604426700001804442700001604460700001504476700001704491700001504508700001504523700001404538700002504552700002604577700002004603700001704623700001804640700001704658700002104675700001704696700001604713700001804729700001704747700001804764700001704782700001604799700001804815700002104833700001904854700001904873700001504892700002304907700002004930700001604950700001404966700001504980700001304995700001505008700001805023700001505041700002205056700001605078700001805094700001905112700001905131700001605150700001405166700001705180700001705197700001705214700001205231700001805243700001605261700002505277700001305302700001705315700001205332700001805344700001605362700001905378700001305397700002205410700002005432700001505452700002005467700001805487700002005505700001605525700001705541700002005558700002305578700002605601700001505627700001305642700001805655700001505673700001805688700001905706700001605725700001905741700001905760700001705779700001505796700001605811700001305827700001705840700001205857700002005869700002205889700002205911700002005933700001905953700001605972700002205988700001606010700001606026700001606042700002006058700001806078700002706096700002006123700001506143700002106158700001706179700001606196700001706212700001706229700002106246700002406267700001406291700002506305700001906330700002406349700001306373700001506386700002306401700001506424700001906439700001406458700001406472700001806486700002006504700001206524700001506536700001706551700001706568700001406585700001706599700001806616700001906634700001906653700002006672700001706692700001606709700002006725700001406745700001606759700001306775700001906788700001306807700001506820700001906835700002206854856003606876 2019 eng d00a{Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies0 aEqualization of four cardiovascular risk algorithms after system c02 a621–6310 v403 aThere is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.\ Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.\ Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.1 aPennells, L.1 aKaptoge, S.1 aWood, A.1 aSweeting, M.1 aZhao, X.1 aWhite, I.1 aBurgess, S.1 aWilleit, P.1 aBolton, T.1 aMoons, K., G. M.1 avan der Schouw, Y., T.1 aSelmer, R.1 aKhaw, K., T.1 aGudnason, V.1 aAssmann, G.1 aAmouyel, P.1 aSalomaa, V.1 aKivimaki, M.1 aNordestgaard, B., G.1 aBlaha, M., J.1 aKuller, L., H.1 aBrenner, H.1 aGillum, R., F.1 aMeisinger, C.1 aFord, I.1 aKnuiman, M., W.1 aRosengren, A.1 aLawlor, D., A.1 aV?lzke, H.1 aCooper, C.1 aIba?ez, Mar?n1 aCasiglia, E.1 aKauhanen, J.1 aCooper, J., A.1 aRodriguez, B.1 aSundstr?m, J.1 aBarrett-Connor, E.1 aDankner, R.1 aNietert, P., J.1 aDavidson, K., W.1 aWallace, R., B.1 aBlazer, D., G.1 aBj?rkelund, C.1 aDonfrancesco, C.1 aKrumholz, H., M.1 aNissinen, A.1 aDavis, B., R.1 aCoady, S.1 aWhincup, P., H.1 aJ?rgensen, T.1 aDucimetiere, P.1 aTrevisan, M.1 aEngstr?m, G.1 aCrespo, C., J.1 aMeade, T., W.1 aVisser, M.1 aKromhout, D.1 aKiechl, S.1 aDaimon, M.1 aPrice, J., F.1 ade la C?mara, A., G?mez1 aJukema, Wouter1 aLamarche, B.1 aOnat, A.1 aSimons, L., A.1 aKavousi, M.1 aBen-Shlomo, Y.1 aGallacher, J.1 aDekker, J., M.1 aArima, H.1 aShara, N.1 aTipping, R., W.1 aRoussel, R.1 aBrunner, E., J.1 aKoenig, W.1 aSakurai, M.1 aPavlovic, J.1 aGansevoort, R., T.1 aNagel, D.1 aGoldbourt, U.1 aBarr, E., L. M.1 aPalmieri, L.1 aNj?lstad, I.1 aSato, S.1 aVerschuren, W., M. Monique1 aVarghese, C., V.1 aGraham, I.1 aOnuma, O.1 aGreenland, P.1 aWoodward, M.1 aEzzati, M.1 aPsaty, B., M.1 aSattar, N.1 aJackson, R.1 aRidker, P., M.1 aCook, N., R.1 aD'Agostino, R., B.1 aThompson, S., G.1 aDanesh, J.1 aDi Angelantonio, E.1 aTipping, R., W.1 aSimpson, L., M.1 aPressel, S., L.1 aCouper, D., J.1 aNambi, V.1 aMatsushita, K.1 aFolsom, A., R.1 aShaw, J., E.1 aMagliano, D., J.1 aZimmet, P., Z.1 aKnuiman, M., W.1 aWhincup, P., H.1 aWannamethee, S., G.1 aWilleit, J.1 aSanter, P.1 aEgger, G.1 aCasas, J., P.1 aAmuzu, A.1 aBen-Shlomo, Y.1 aGallacher, J.1 aTikhonoff, V.1 aCasiglia, E.1 aSutherland, S., E.1 aNietert, P., J.1 aCushman, M.1 aPsaty, B., M.1 aS?gaard, A., J.1 aH?heim, L., L.1 aAriansen, I.1 aTybj?rg-Hansen, A.1 aJensen, G., B.1 aSchnohr, P.1 aGiampaoli, S.1 aVanuzzo, D.1 aPanico, S.1 aPalmieri, L.1 aBalkau, B.1 aBonnet, F.1 aMarre, M.1 ade la C?mara, A., G.1 aHerrera, M., A. Rubio1 aFriedlander, Y.1 aMcCallum, J.1 aMcLachlan, S.1 aGuralnik, J.1 aPhillips, C., L.1 aKhaw, K., T.1 aWareham, N.1 aSch?ttker, B.1 aSaum, K., U.1 aHolleczek, B.1 aNissinen, A.1 aTolonen, H.1 aGiampaoli, S.1 aDonfrancesco, C.1 aVartiainen, E.1 aJousilahti, P.1 aHarald, K.1 aD?Agostino, R., B.1 aMassaro, J., M.1 aPencina, M.1 aVasan, R.1 aKayama, T.1 aKato, T.1 aOizumi, T.1 aJespersen, J.1 aM?ller, L.1 aBladbjerg, E., M.1 aChetrit, A.1 aRosengren, A.1 aWilhelmsen, L.1 aBj?rkelund, C.1 aLissner, L.1 aNagel, D.1 aDennison, E.1 aKiyohara, Y.1 aNinomiya, T.1 aDoi, Y.1 aRodriguez, B.1 aNijpels, G.1 aStehouwer, C., D. A.1 aSato, S.1 aKazumasa, Y.1 aIso, H.1 aGoldbourt, U.1 aSalomaa, V.1 aVartiainen, E.1 aKurl, S.1 aTuomainen, T., P.1 aSalonen, J., T.1 aVisser, M.1 aDeeg, D., J. H.1 aMeade, T., W.1 aNilsson, P., M.1 aHedblad, B.1 aMelander, O.1 aDe Boer, I., H.1 aDeFilippis, A., P.1 aVerschuren, W., M. M.1 aSattar, N.1 aWatt, G.1 aMeisinger, C.1 aKoenig, W.1 aRosengren, A.1 aKuller, L., H.1 aTverdal, A.1 aGillum, R., F.1 aCooper, J., A.1 aKirkland, S.1 aShimbo, D.1 aShaffer, J.1 aSato, S.1 aKazumasa, Y.1 aIso, H.1 aDucimetiere, P.1 aBakker, S., J. L.1 avan der Harst, P.1 aHillege, H., L.1 aCrespo, C., J.1 aAmouyel, P.1 aDallongeville, J.1 aAssmann, G.1 aSchulte, H.1 aTrompet, S.1 aSmit, R., A. J.1 aStott, D., J.1 avan der Schouw, Y., T.1 aDespr?s, J., P.1 aCantin, B.1 aDagenais, G., R.1 aLaughlin, G.1 aWingard, D.1 aTrevisan, M.1 aAspelund, T.1 aEiriksdottir, G.1 aGudmundsson, E., F.1 aIkram, A.1 avan Rooij, F., J. A.1 aFranco, O., H.1 aRueda-Ochoa, O., L.1 aMuka, T.1 aGlisic, M.1 aTunstall-Pedoe, H.1 aV?lzke, H.1 aHoward, B., V.1 aZhang, Y.1 aJolly, S.1 aGallacher, J.1 aDavey-Smith, G.1 aCan, G.1 aY?ksel, H.1 aNakagawa, H.1 aMorikawa, Y.1 aMiura, K.1 aNj?lstad, I.1 aIngelsson, M.1 aGiedraitis, V.1 aRidker, P., M.1 aGaziano, J., M.1 aKivimaki, M.1 aShipley, M.1 aBrunner, E., J.1 aArndt, V.1 aBrenner, H.1 aCook, N.1 aRidker, P., M.1 aFord, I.1 aSattar, N.1 aIba?ez, A., M.1 aGeleijnse, J., M. uhttps://chs-nhlbi.org/node/852606441nas a2202089 4500008004100000245007700041210006900118260000700187300001200194490000800206520116100214100001701375700002101392700002001413700001801433700001601451700001501467700002201482700001701504700001801521700002201539700002201561700001901583700001801602700002101620700001301641700001301654700002401667700001601691700001501707700001501722700002101737700001401758700001801772700001601790700001801806700001601824700002601840700002101866700001401887700001201901700002401913700002001937700002201957700001701979700001501996700001602011700002202027700001702049700001902066700001802085700001602103700001202119700001702131700002002148700001802168700003102186700002702217700001502244700002002259700002302279700001902302700002102321700001502342700001802357700002002375700001802395700001602413700001702429700001502446700001802461700001802479700001902497700001902516700002502535700002202560700001602582700001802598700001502616700001602631700002202647700001802669700001902687700001602706700001802722700001902740700001802759700002002777700001702797700001302814700001802827700001802845700001702863700001502880700001702895700001702912700002402929700001902953700002102972700001302993700001803006700001603024700002003040700002103060700001803081700001503099700001703114700002103131700001403152700001903166700001703185700001503202700001903217700001603236700002003252700001603272700001403288700001903302700001903321700002803340700001803368700001403386700001803400700002003418700001503438700001703453700002103470700001803491700001603509700002103525700001603546700001203562700002003574700001803594700001903612700002203631700002203653700001503675700001703690700001603707700001703723700001203740700001803752700001603770700001503786700001803801700002203819700001503841700001903856700001803875700001403893700001503907700001803922700001603940700001403956700001503970700001503985700001704000700001604017700001604033700001704049700001704066700001604083700001804099700001504117700001804132700001704150700001904167700001804186700001804204700001804222700001904240700001904259700002104278700001604299856003604315 2019 eng d00a{Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls0 aExome sequencing of 20791 cases of type 2 diabetes and 24440 con c06 a71–760 v5703 aProtein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.1 aFlannick, J.1 aMercader, J., M.1 aFuchsberger, C.1 aUdler, M., S.1 aMahajan, A.1 aWessel, J.1 aTeslovich, T., M.1 aCaulkins, L.1 aKoesterer, R.1 aBarajas-Olmos, F.1 aBlackwell, T., W.1 aBoerwinkle, E.1 aBrody, J., A.1 aCenteno-Cruz, F.1 aChen, L.1 aChen, S.1 aContreras-Cubas, C.1 aC?rdova, E.1 aCorrea, A.1 aCortes, M.1 aDeFronzo, R., A.1 aDolan, L.1 aDrews, K., L.1 aElliott, A.1 aFloyd, J., S.1 aGabriel, S.1 aGaray-Sevilla, M., E.1 aGarc?a-Ortiz, H.1 aGross, M.1 aHan, S.1 aHeard-Costa, N., L.1 aJackson, A., U.1 aJ?rgensen, M., E.1 aKang, H., M.1 aKelsey, M.1 aKim, B., J.1 aKoistinen, H., A.1 aKuusisto, J.1 aLeader, J., B.1 aLinneberg, A.1 aLiu, C., T.1 aLiu, J.1 aLyssenko, V.1 aManning, A., K.1 aMarcketta, A.1 aMalacara-Hernandez, J., M.1 aMart?nez-Hern?ndez, A.1 aMatsuo, K.1 aMayer-Davis, E.1 aMendoza-Caamal, E.1 aMohlke, K., L.1 aMorrison, A., C.1 aNdungu, A.1 aNg, M., C. Y.1 aO'Dushlaine, C.1 aPayne, A., J.1 aPihoker, C.1 aPost, W., S.1 aPreuss, M.1 aPsaty, B., M.1 aVasan, R., S.1 aRayner, N., W.1 aReiner, A., P.1 aRevilla-Monsalve, C.1 aRobertson, N., R.1 aSantoro, N.1 aSchurmann, C.1 aSo, W., Y.1 aSober?n, X.1 aStringham, H., M.1 aStrom, T., M.1 aTam, C., H. T.1 aThameem, F.1 aTomlinson, B.1 aTorres, J., M.1 aTracy, R., P.1 avan Dam, R., M.1 aVujkovic, M.1 aWang, S.1 aWelch, R., P.1 aWitte, D., R.1 aWong, T., Y.1 aAtzmon, G.1 aBarzilai, N.1 aBlangero, J.1 aBonnycastle, L., L.1 aBowden, D., W.1 aChambers, J., C.1 aChan, E.1 aCheng, C., Y.1 aCho, Y., S.1 aCollins, F., S.1 ade Vries, P., S.1 aDuggirala, R.1 aGlaser, B.1 aGonzalez, C.1 aGonzalez, M., E.1 aGroop, L.1 aKooner, J., S.1 aKwak, S., H.1 aLaakso, M.1 aLehman, D., M.1 aNilsson, P.1 aSpector, T., D.1 aTai, E., S.1 aTuomi, T.1 aTuomilehto, J.1 aWilson, J., G.1 aAguilar-Salinas, C., A.1 aBottinger, E.1 aBurke, B.1 aCarey, D., J.1 aChan, J., C. N.1 aDupuis, J.1 aFrossard, P.1 aHeckbert, S., R.1 aHwang, M., Y.1 aKim, Y., J.1 aKirchner, H., L.1 aLee, J., Y.1 aLee, J.1 aLoos, R., J. F.1 aMa, R., C. W.1 aMorris, A., D.1 aO'Donnell, C., J.1 aPalmer, C., N. A.1 aPankow, J.1 aPark, K., S.1 aRasheed, A.1 aSaleheen, D.1 aSim, X.1 aSmall, K., S.1 aTeo, Y., Y.1 aHaiman, C.1 aHanis, C., L.1 aHenderson, B., E.1 aOrozco, L.1 aTusi?-Luna, T.1 aDewey, F., E.1 aBaras, A.1 aGieger, C.1 aMeitinger, T.1 aStrauch, K.1 aLange, L.1 aGrarup, N.1 aHansen, T.1 aPedersen, O.1 aZeitler, P.1 aDabelea, D.1 aAbecasis, G.1 aBell, G., I.1 aCox, N., J.1 aSeielstad, M.1 aSladek, R.1 aMeigs, J., B.1 aRich, S., S.1 aRotter, J., I.1 aAltshuler, D.1 aBurtt, N., P.1 aScott, L., J.1 aMorris, A., P.1 aFlorez, J., C.1 aMcCarthy, M., I.1 aBoehnke, M. uhttps://chs-nhlbi.org/node/851503766nas a2201369 4500008004100000245008700041210006900128260000800197300001200205490000800217520032100225100002200546700001700568700001900585700001800604700001700622700001600639700001900655700001100674700002500685700001800710700001600728700001300744700001700757700001800774700001200792700001600804700001800820700002000838700001400858700002000872700001700892700002100909700001700930700002200947700002000969700001900989700001401008700001701022700001501039700001201054700001601066700001501082700001901097700002101116700001301137700001801150700001801168700001601186700001901202700001201221700001801233700001501251700001601266700001501282700001801297700001101315700001101326700001501337700001301352700001301365700001701378700001801395700001901413700001601432700001601448700001101464700002101475700001701496700002101513700001801534700001501552700002201567700001901589700001901608700001801627700002001645700001801665700002001683700002001703700002101723700002201744700002201766700001901788700001901807700001601826700001801842700001901860700001601879700001701895700002001912700002001932700001601952700001701968700001901985700001602004700001302020700002502033700001802058700001502076700001702091700001302108700002002121700002002141700002202161700001902183700001102202700001202213700001802225700001902243700002102262700001702283700002102300700002002321700001902341856003602360 2019 eng d00a{Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology0 aExomeDerived AdiponectinAssociated Variants Implicate Obesity an cJul a15–280 v1053 a) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.1 aSpracklen, C., N.1 aKaraderi, T.1 aYaghootkar, H.1 aSchurmann, C.1 aFine, R., S.1 aKutalik, Z.1 aPreuss, M., H.1 aLu, Y.1 aWittemans, L., B. L.1 aAdair, L., S.1 aAllison, M.1 aAmin, N.1 aAuer, P., L.1 aBartz, T., M.1 aher, M.1 aBoehnke, M.1 aBorja, J., B.1 aBork-Jensen, J.1 aBroer, L.1 aChasman, D., I.1 aChen, Y., I.1 aChirstofidou, P.1 aDemirkan, A.1 avan Duijn, C., M.1 aFeitosa, M., F.1 aGarcia, M., E.1 aGraff, M.1 aGrallert, H.1 aGrarup, N.1 aGuo, X.1 aHaesser, J.1 aHansen, T.1 aHarris, T., B.1 aHighland, H., M.1 aHong, J.1 aIkram, M., A.1 aIngelsson, E.1 aJackson, R.1 aJousilahti, P.1 anen, M.1 aKizer, J., R.1 aKovacs, P.1 aKriebel, J.1 aLaakso, M.1 aLange, L., A.1 aki, T.1 aLi, J.1 aLi-Gao, R.1 aLind, L.1 aLuan, J.1 ainen, L., P.1 aMacGregor, S.1 aMackey, D., A.1 aMahajan, A.1 aMangino, M.1 aö, S.1 aMcCarthy, M., I.1 aMcKnight, B.1 aMedina-Gomez, C.1 aMeigs, J., B.1 aMolnos, S.1 aMook-Kanamori, D.1 aMorris, A., P.1 ade Mutsert, R.1 aNalls, M., A.1 aNedeljkovic, I.1 aNorth, K., E.1 aPennell, C., E.1 aPradhan, A., D.1 aProvince, M., A.1 aRaitakari, O., T.1 aRaulerson, C., K.1 aReiner, A., P.1 aRidker, P., M.1 aRipatti, S.1 aRoberston, N.1 aRotter, J., I.1 aSalomaa, V.1 arate, A., A.1 aSitlani, C., M.1 aSpector, T., D.1 aStrauch, K.1 aStumvoll, M.1 aTaylor, K., D.1 aThuesen, B.1 anjes, A.1 aUitterlinden, A., G.1 aVenturini, C.1 aWalker, M.1 aWang, C., A.1 aWang, S.1 aWareham, N., J.1 aWillems, S., M.1 avan Dijk, Willems1 aWilson, J., G.1 aWu, Y.1 aYao, J.1 aYoung, K., L.1 aLangenberg, C.1 aFrayling, T., M.1 ainen, T., O.1 aLindgren, C., M.1 aLoos, R., J. F.1 aMohlke, K., L. uhttps://chs-nhlbi.org/node/937403435nas a2201357 4500008004100000245008700041210006900128260000800197300001400205490000800219100002200227700001700249700001900266700001800285700001700303700001600320700001900336700001100355700002500366700001800391700001600409700001300425700001700438700001800455700001200473700001600485700001800501700002000519700001400539700002000553700001700573700002100590700001700611700002200628700002000650700001900670700001400689700001700703700001500720700001200735700001600747700001500763700001900778700002100797700001300818700001800831700001800849700001600867700001900883700001200902700001800914700001500932700001600947700001500963700001800978700001100996700001101007700001501018700001301033700001301046700001701059700001801076700001901094700001601113700001601129700001101145700002101156700001701177700002101194700001801215700001501233700002201248700001901270700001901289700001801308700002001326700001801346700002001364700002001384700002101404700002201425700002201447700001901469700001901488700001601507700001801523700001901541700001601560700001701576700002001593700002001613700001601633700001701649700001901666700001601685700001301701700002501714700001801739700001501757700001701772700001301789700002001802700002001822700002201842700001901864700001101883700001201894700001801906700001901924700002101943700001701964700002101981700002002002700001902022856003602041 2019 eng d00a{Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology0 aExomeDerived AdiponectinAssociated Variants Implicate Obesity an cSep a670–6710 v1051 aSpracklen, C., N.1 aKaraderi, T.1 aYaghootkar, H.1 aSchurmann, C.1 aFine, R., S.1 aKutalik, Z.1 aPreuss, M., H.1 aLu, Y.1 aWittemans, L., B. L.1 aAdair, L., S.1 aAllison, M.1 aAmin, N.1 aAuer, P., L.1 aBartz, T., M.1 aher, M.1 aBoehnke, M.1 aBorja, J., B.1 aBork-Jensen, J.1 aBroer, L.1 aChasman, D., I.1 aChen, Y., I.1 aChirstofidou, P.1 aDemirkan, A.1 avan Duijn, C., M.1 aFeitosa, M., F.1 aGarcia, M., E.1 aGraff, M.1 aGrallert, H.1 aGrarup, N.1 aGuo, X.1 aHaesser, J.1 aHansen, T.1 aHarris, T., B.1 aHighland, H., M.1 aHong, J.1 aIkram, M., A.1 aIngelsson, E.1 aJackson, R.1 aJousilahti, P.1 anen, M.1 aKizer, J., R.1 aKovacs, P.1 aKriebel, J.1 aLaakso, M.1 aLange, L., A.1 aki, T.1 aLi, J.1 aLi-Gao, R.1 aLind, L.1 aLuan, J.1 ainen, L., P.1 aMacGregor, S.1 aMackey, D., A.1 aMahajan, A.1 aMangino, M.1 aö, S.1 aMcCarthy, M., I.1 aMcKnight, B.1 aMedina-Gomez, C.1 aMeigs, J., B.1 aMolnos, S.1 aMook-Kanamori, D.1 aMorris, A., P.1 ade Mutsert, R.1 aNalls, M., A.1 aNedeljkovic, I.1 aNorth, K., E.1 aPennell, C., E.1 aPradhan, A., D.1 aProvince, M., A.1 aRaitakari, O., T.1 aRaulerson, C., K.1 aReiner, A., P.1 aRidker, P., M.1 aRipatti, S.1 aRoberston, N.1 aRotter, J., I.1 aSalomaa, V.1 arate, A., A.1 aSitlani, C., M.1 aSpector, T., D.1 aStrauch, K.1 aStumvoll, M.1 aTaylor, K., D.1 aThuesen, B.1 anjes, A.1 aUitterlinden, A., G.1 aVenturini, C.1 aWalker, M.1 aWang, C., A.1 aWang, S.1 aWareham, N., J.1 aWillems, S., M.1 avan Dijk, Willems1 aWilson, J., G.1 aWu, Y.1 aYao, J.1 aYoung, K., L.1 aLangenberg, C.1 aFrayling, T., M.1 ainen, T., O.1 aLindgren, C., M.1 aLoos, R., J. F.1 aMohlke, K., L. uhttps://chs-nhlbi.org/node/939111242nas a2203601 4500008004100000022001400041245008000055210006900135260001300204300001400217490000700231520105900238100002601297700002201323700002101345700002201366700001901388700002001407700001901427700003301446700002001479700002801499700002101527700001901548700001701567700002201584700001701606700002201623700002501645700001801670700001901688700001601707700001301723700001501736700001701751700002001768700002601788700002901814700002001843700002301863700002501886700001701911700001701928700002501945700001601970700002101986700002302007700002202030700002202052700002102074700001802095700002202113700002002135700002102155700002202176700002002198700002002218700002902238700001902267700002102286700002102307700001602328700001802344700002102362700002002383700002302403700002202426700001902448700002002467700002102487700002402508700002202532700002102554700002202575700002502597700001802622700002902640700001602669700001702685700001802702700002902720700002802749700002102777700001602798700002202814700001702836700002302853700002102876700002302897700002602920700002302946700002102969700002602990700002003016700002303036700001903059700001903078700003303097700002203130700001503152700002303167700002003190700002103210700001603231700002103247700001903268700002203287700002203309700002103331700002003352700002703372700002003399700002303419700002003442700002503462700001703487700002503504700002303529700002303552700002203575700002203597700002003619700001703639700001903656700001703675700002703692700002203719700002403741700002303765700002203788700003403810700002103844700002203865700002403887700002203911700002203933700002403955700002703979700002004006700001304026700002404039700001904063700002304082700001904105700001904124700001704143700002504160700002804185700002604213700002404239700002104263700002404284700001904308700002604327700002404353700002104377700002004398700002304418700002104441700003304462700002404495700002304519700002104542700002004563700001804583700001904601700002604620700002004646700001904666700002804685700002104713700001904734700001904753700002504772700001804797700002004815700002004835700002504855700002304880700002304903700002404926700002004950700003004970700001705000700002705017700003405044700001605078700002005094700002105114700002605135700002205161700002905183700001905212700002205231700002405253700002605277700002205303700002205325700001305347700001905360700002005379700001905399700002405418700002505442700002205467700001705489700002205506700003005528700002005558700002205578700002805600700002605628700002005654700002005674700002505694700002105719700001805740700002405758700002705782700001805809700002305827700002405850700002505874700001805899700002205917700002705939700002105966700002305987700002206010700002106032700002106053700002306074700002006097700002106117700002006138700002106158700001806179700002206197700002806219700002306247700002106270700002206291700002306313700002206336700002006358700002306378700002206401700002006423700001806443700002406461700001706485700001806502700001906520700002406539700001706563700001806580700002306598700002006621700001906641700002406660700002406684700002306708700002006731700002206751700002506773700002606798700002406824700002806848700002106876700002106897700001906918700002206937700002106959700002906980700002607009700002407035700002407059700002307083700001907106700002407125700002107149700002007170700002207190700001907212700002307231700002207254700002307276700002007299700002007319700002307339700002207362700002107384700002407405700002107429700002307450700002407473700002207497700002307519700002207542700002007564700002007584856003607604 2019 eng d a1546-171800aGenetic architecture of subcortical brain structures in 38,851 individuals.0 aGenetic architecture of subcortical brain structures in 38851 in c2019 Nov a1624-16360 v513 aSubcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
1 aSatizabal, Claudia, L1 aAdams, Hieab, H H1 aHibar, Derrek, P1 aWhite, Charles, C1 aKnol, Maria, J1 aStein, Jason, L1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aJahanshad, Neda1 aRoshchupkin, Gennady, V1 aSmith, Albert, V1 aBis, Joshua, C1 aJian, Xueqiu1 aLuciano, Michelle1 aHofer, Edith1 aTeumer, Alexander1 avan der Lee, Sven, J1 aYang, Jingyun1 aYanek, Lisa, R1 aLee, Tom, V1 aLi, Shuo1 aHu, Yanhui1 aKoh, Jia, Yu1 aEicher, John, D1 aDesrivières, Sylvane1 aArias-Vasquez, Alejandro1 aChauhan, Ganesh1 aAthanasiu, Lavinia1 aRentería, Miguel, E1 aKim, Sungeun1 aHoehn, David1 aArmstrong, Nicola, J1 aChen, Qiang1 aHolmes, Avram, J1 aBraber, Anouk, den1 aKloszewska, Iwona1 aAndersson, Micael1 aEspeseth, Thomas1 aGrimm, Oliver1 aAbramovic, Lucija1 aAlhusaini, Saud1 aMilaneschi, Yuri1 aPapmeyer, Martina1 aAxelsson, Tomas1 aEhrlich, Stefan1 aRoiz-Santiañez, Roberto1 aKraemer, Bernd1 aHåberg, Asta, K1 aJones, Hannah, J1 aPike, Bruce1 aStein, Dan, J1 aStevens, Allison1 aBralten, Janita1 aVernooij, Meike, W1 aHarris, Tamara, B1 aFilippi, Irina1 aWitte, Veronica1 aGuadalupe, Tulio1 aWittfeld, Katharina1 aMosley, Thomas, H1 aBecker, James, T1 aDoan, Nhat, Trung1 aHagenaars, Saskia, P1 aSaba, Yasaman1 aCuellar-Partida, Gabriel1 aAmin, Najaf1 aHilal, Saima1 aNho, Kwangsik1 aMirza-Schreiber, Nazanin1 aArfanakis, Konstantinos1 aBecker, Diane, M1 aAmes, David1 aGoldman, Aaron, L1 aLee, Phil, H1 aBoomsma, Dorret, I1 aLovestone, Simon1 aGiddaluru, Sudheer1 aLe Hellard, Stephanie1 aMattheisen, Manuel1 aBohlken, Marc, M1 aKasperaviciute, Dalia1 aSchmaal, Lianne1 aLawrie, Stephen, M1 aAgartz, Ingrid1 aWalton, Esther1 aTordesillas-Gutierrez, Diana1 aDavies, Gareth, E1 aShin, Jean1 aIpser, Jonathan, C1 aVinke, Louis, N1 aHoogman, Martine1 aJia, Tianye1 aBurkhardt, Ralph1 aKlein, Marieke1 aCrivello, Fabrice1 aJanowitz, Deborah1 aCarmichael, Owen1 aHaukvik, Unn, K1 aAribisala, Benjamin, S1 aSchmidt, Helena1 aStrike, Lachlan, T1 aCheng, Ching-Yu1 aRisacher, Shannon, L1 aPütz, Benno1 aFleischman, Debra, A1 aAssareh, Amelia, A1 aMattay, Venkata, S1 aBuckner, Randy, L1 aMecocci, Patrizia1 aDale, Anders, M1 aCichon, Sven1 aBoks, Marco, P1 aMatarin, Mar1 aPenninx, Brenda, W J H1 aCalhoun, Vince, D1 aChakravarty, Mallar1 aMarquand, Andre, F1 aMacare, Christine1 aMasouleh, Shahrzad, Kharabian1 aOosterlaan, Jaap1 aAmouyel, Philippe1 aHegenscheid, Katrin1 aRotter, Jerome, I1 aSchork, Andrew, J1 aLiewald, David, C M1 ade Zubicaray, Greig, I1 aWong, Tien, Yin1 aShen, Li1 aSämann, Philipp, G1 aBrodaty, Henry1 aRoffman, Joshua, L1 aGeus, Eco, J C1 aTsolaki, Magda1 aErk, Susanne1 avan Eijk, Kristel, R1 aCavalleri, Gianpiero, L1 avan der Wee, Nic, J A1 aMcIntosh, Andrew, M1 aGollub, Randy, L1 aBulayeva, Kazima, B1 aBernard, Manon1 aRichards, Jennifer, S1 aHimali, Jayandra, J1 aLoeffler, Markus1 aRommelse, Nanda1 aHoffmann, Wolfgang1 aWestlye, Lars, T1 aHernández, Maria, C Valdés1 aHansell, Narelle, K1 avan Erp, Theo, G M1 aWolf, Christiane1 aKwok, John, B J1 aVellas, Bruno1 aHeinz, Andreas1 aLoohuis, Loes, M Olde1 aDelanty, Norman1 aHo, Beng-Choon1 aChing, Christopher, R K1 aShumskaya, Elena1 aSingh, Baljeet1 aHofman, Albert1 avan der Meer, Dennis1 aHomuth, Georg1 aPsaty, Bruce, M1 aBastin, Mark, E1 aMontgomery, Grant, W1 aForoud, Tatiana, M1 aReppermund, Simone1 aHottenga, Jouke-Jan1 aSimmons, Andrew1 aMeyer-Lindenberg, Andreas1 aCahn, Wiepke1 aWhelan, Christopher, D1 avan Donkelaar, Marjolein, M J1 aYang, Qiong1 aHosten, Norbert1 aGreen, Robert, C1 aThalamuthu, Anbupalam1 aMohnke, Sebastian1 aPol, Hilleke, E Hulshoff1 aLin, Honghuang1 aJack, Clifford, R1 aSchofield, Peter, R1 aMühleisen, Thomas, W1 aMaillard, Pauline1 aPotkin, Steven, G1 aWen, Wei1 aFletcher, Evan1 aToga, Arthur, W1 aGruber, Oliver1 aHuentelman, Matthew1 aSmith, George, Davey1 aLauner, Lenore, J1 aNyberg, Lars1 aJönsson, Erik, G1 aCrespo-Facorro, Benedicto1 aKoen, Nastassja1 aGreve, Douglas, N1 aUitterlinden, André, G1 aWeinberger, Daniel, R1 aSteen, Vidar, M1 aFedko, Iryna, O1 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2019 eng d a1546-171800aGenetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.0 aGenetic metaanalysis of diagnosed Alzheimers disease identifies c2019 Mar a414-4300 v513 aRisk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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Nick1 aLopez, Oscar, L1 aIngelsson, Martin1 aDeloukas, Panagiotis1 aCruchaga, Carlos1 aGraff, Caroline1 aGwilliam, Rhian1 aFornage, Myriam1 aGoate, Alison, M1 aSánchez-Juan, Pascual1 aKehoe, Patrick, G1 aAmin, Najaf1 aErtekin-Taner, Nilifur1 aBerr, Claudine1 aDebette, Stephanie1 aLove, Seth1 aLauner, Lenore, J1 aYounkin, Steven, G1 aDartigues, Jean-François1 aCorcoran, Chris1 aIkram, Arfan, M1 aDickson, Dennis, W1 aNicolas, Gaël1 aCampion, Dominique1 aTschanz, JoAnn1 aSchmidt, Helena1 aHakonarson, Hakon1 aClarimon, Jordi1 aMunger, Ron1 aSchmidt, Reinhold1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aO'Donovan, Michael, C1 aDeStefano, Anita, L1 aJones, Lesley1 aHaines, Jonathan, L1 aDeleuze, Jean-Francois1 aOwen, Michael, J1 aGudnason, Vilmundur1 aMayeux, Richard1 aEscott-Price, Valentina1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aRuiz, Agustin1 aDuijn, Cornelia, M1 aHolmans, Peter, A1 aSeshadri, Sudha1 aWilliams, Julie1 aAmouyel, Phillippe1 aSchellenberg, Gerard, D1 aLambert, Jean-Charles1 aPericak-Vance, Margaret, A1 aAlzheimer Disease Genetics Consortium (ADGC),1 aEuropean Alzheimer’s Disease Initiative (EADI),1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE),1 aGenetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), uhttps://chs-nhlbi.org/node/797707054nas a2202353 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2019 eng d00a{Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria0 aGenomewide association metaanalyses and finemapping elucidate pa c09 a41300 v103 aIncreased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.1 aTeumer, A.1 aLi, Y.1 aGhasemi, S.1 aPrins, B., P.1 aWuttke, M.1 aHermle, T.1 aGiri, A.1 aSieber, K., B.1 aQiu, C.1 aKirsten, H.1 aTin, A.1 aChu, A., Y.1 aBansal, N.1 aFeitosa, M., F.1 aWang, L.1 aChai, J., F.1 aCocca, M.1 aFuchsberger, C.1 aGorski, M.1 aHoppmann, A.1 aHorn, K.1 aLi, M.1 aMarten, J.1 aNoce, D.1 aNutile, T.1 aSedaghat, S.1 aSveinbjornsson, G.1 aTayo, B., O.1 avan der Most, P., J.1 aXu, Y.1 aYu, Z.1 aGerstner, L.1 arnl?v, J., ?1 aBakker, S., J. L.1 aBaptista, D.1 aBiggs, M., L.1 aBoerwinkle, E.1 aBrenner, H.1 aBurkhardt, R.1 aCarroll, R., J.1 aChee, M., L.1 aChee, M., L.1 aChen, M.1 aCheng, C., Y.1 aCook, J., P.1 aCoresh, J.1 aCorre, T.1 aDanesh, J.1 ade Borst, M., H.1 aDe Grandi, A.1 ade Mutsert, R.1 ade Vries, A., P. J.1 aDegenhardt, F.1 aDittrich, K.1 aDivers, J.1 aEckardt, K., U.1 aEhret, G.1 aEndlich, K.1 aFelix, J., F.1 aFranco, O., H.1 aFranke, A.1 aFreedman, B., I.1 aFreitag-Wolf, S.1 aGansevoort, R., T.1 aGiedraitis, V.1 aG?gele, M.1 aGrundner-Culemann, F.1 aGudbjartsson, D., F.1 aGudnason, V.1 aHamet, P.1 aHarris, T., B.1 aHicks, A., A.1 aHolm, H.1 aFoo, V., H. X.1 aHwang, S., J.1 aIkram, M., A.1 aIngelsson, E.1 aJaddoe, V., W. V.1 aJakobsdottir, J.1 aJosyula, N., S.1 aJung, B.1 aK?h?nen, M.1 aKhor, C., C.1 aKiess, W.1 aKoenig, W.1 aK?rner, A.1 aKovacs, P.1 aKramer, H.1 aKr?mer, B., K.1 aKronenberg, F.1 aLange, L., A.1 aLangefeld, C., D.1 aLee, J., J.1 aLehtim?ki, T.1 aLieb, W.1 aLim, S., C.1 aLind, L.1 aLindgren, C., M.1 aLiu, J.1 aLoeffler, M.1 aLyytik?inen, L., P.1 aMahajan, A.1 aMaranville, J., C.1 aMascalzoni, D.1 aMcMullen, B.1 aMeisinger, C.1 aMeitinger, T.1 aMiliku, K.1 aMook-Kanamori, D., O.1 aM?ller-Nurasyid, M.1 aMychaleckyj, J., C.1 aNauck, M.1 aNikus, K.1 aNing, B.1 aNoordam, R.1 aConnell, J., O.1 aOlafsson, I.1 aPalmer, N., D.1 aPeters, A.1 aPodgornaia, A., I.1 aPonte, B.1 aPoulain, T.1 aPramstaller, P., P.1 aRabelink, T., J.1 aRaffield, L., M.1 aReilly, D., F.1 aRettig, R.1 aRheinberger, M.1 aRice, K., M.1 aRivadeneira, F.1 aRunz, H.1 aRyan, K., A.1 aSabanayagam, C.1 aSaum, K., U.1 aSch?ttker, B.1 aShaffer, C., M.1 aShi, Y.1 aSmith, A., V.1 aStrauch, K.1 aStumvoll, M.1 aSun, B., B.1 aSzymczak, S.1 aTai, E., S.1 aTan, N., Y. Q.1 aTaylor, K., D.1 aTeren, A.1 aTham, Y., C.1 aThiery, J.1 aThio, C., H. L.1 aThomsen, H.1 aThorsteinsdottir, U.1 aT?njes, A.1 aTremblay, J.1 aUitterlinden, A., G.1 avan der Harst, P.1 aVerweij, N.1 aVogelezang, S.1 aV?lker, U.1 aWaldenberger, M.1 aWang, C.1 aWilson, O., D.1 aWong, C.1 aWong, T., Y.1 aYang, Q.1 aYasuda, M.1 aAkilesh, S.1 aBochud, M.1 aB?ger, C., A.1 aDevuyst, O.1 aEdwards, T., L.1 aHo, K.1 aMorris, A., P.1 aParsa, A.1 aPendergrass, S., A.1 aPsaty, B., M.1 aRotter, J., I.1 aStefansson, K.1 aWilson, J., G.1 aSusztak, K.1 aSnieder, H.1 aHeid, I., M.1 aScholz, M.1 aButterworth, A., S.1 aHung, A., M.1 aPattaro, C.1 aK?ttgen, A. uhttps://chs-nhlbi.org/node/853003329nas a2200853 4500008004100000245010600041210006900147300000800216490000600224520111000230100002401340700001701364700001601381700002201397700001801419700001401437700001601451700001801467700001401485700002601499700001801525700001601543700001801559700001301577700001701590700001901607700001901626700001301645700001801658700001101676700002201687700001101709700001301720700002401733700001601757700001801773700001901791700001301810700002001823700001901843700001601862700001301878700001801891700001701909700001901926700001701945700002001962700001901982700001602001700001302017700002002030700001302050700001902063700001802082700001802100700002102118700001602139700001602155700001902171700002102190700002102211700002202232700002002254700002102274700001602295700002302311700001802334700001702352700001602369700001702385700002102402700001602423856003602439 2019 eng d00a{A genome-wide association study identifies genetic loci associated with specific lobar brain volumes0 agenomewide association study identifies genetic loci associated a2850 v23 aBrain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.1 avan der Lee, S., J.1 aKnol, M., J.1 aChauhan, G.1 aSatizabal, C., L.1 aSmith, A., V.1 aHofer, E.1 aBis, J., C.1 aHibar, D., P.1 aHilal, S.1 avan den Akker, E., B.1 aArfanakis, K.1 aBernard, M.1 aYanek, L., R.1 aAmin, N.1 aCrivello, F.1 aCheung, J., W.1 aHarris, T., B.1 aSaba, Y.1 aLopez, O., L.1 aLi, S.1 avan der Grond, J.1 aYu, L.1 aPaus, T.1 aRoshchupkin, G., V.1 aAmouyel, P.1 aJahanshad, N.1 aTaylor, K., D.1 aYang, Q.1 aMathias, R., A.1 aBoehringer, S.1 aMazoyer, B.1 aRice, K.1 aCheng, C., Y.1 aMaillard, P.1 avan Heemst, D.1 aWong, T., Y.1 aNiessen, W., J.1 aBeiser, A., S.1 aBeekman, M.1 aZhao, W.1 aNyquist, P., A.1 aChen, C.1 aLauner, L., J.1 aPsaty, B., M.1 aIkram, M., K.1 aVernooij, M., W.1 aSchmidt, H.1 aPausova, Z.1 aBecker, D., M.1 aDe Jager, P., L.1 aThompson, P., M.1 avan Duijn, C., M.1 aBennett, D., A.1 aSlagboom, P., E.1 aSchmidt, R.1 aLongstreth, W., T.1 aIkram, M., A.1 aSeshadri, S.1 aDebette, S.1 aGudnason, V.1 aAdams, H., H. H.1 aDeCarli, C. uhttps://chs-nhlbi.org/node/853403820nas a2200697 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520168300286100002201969700002501991700002502016700002102041700001302062700002102075700002002096700002502116700002502141700002002166700002602186700002802212700002302240700002002263700002502283700002302308700001902331700002202350700002602372700002502398700001802423700002402441700002802465700003002493700002002523700002102543700002002564700002302584700001802607700002302625700002202648700002002670700002002690700003302710700002002743700002002763700002002783700002002803700002402823700002402847700001902871700002302890700002402913700003002937700002302967710002202990710007403012856003603086 2019 eng d a1528-002000aA genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.0 agenomewide association study identifies new loci for factor VII c2019 Feb 28 a967-9770 v1333 aFactor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.
1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 aMarten, Jonathan1 aSong, Ci1 aPankratz, Nathan1 aBartz, Traci, M1 ade Haan, Hugoline, G1 aDelgado, Graciela, E1 aEicher, John, D1 aMartinez-Perez, Angel1 aWard-Caviness, Cavin, K1 aBrody, Jennifer, A1 aChen, Ming-Huei1 ade Maat, Moniek, P M1 aFrånberg, Mattias1 aGill, Dipender1 aKleber, Marcus, E1 aRivadeneira, Fernando1 aSoria, José, Manuel1 aTang, Weihong1 aTofler, Geoffrey, H1 aUitterlinden, André, G1 aVlieg, Astrid, van Hylcka1 aSeshadri, Sudha1 aBoerwinkle, Eric1 aDavies, Neil, M1 aGiese, Anne-Katrin1 aIkram, Kamran1 aKittner, Steven, J1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aReiner, Alex, P1 aSargurupremraj, Muralidharan1 aTaylor, Kent, D1 aFornage, Myriam1 aHamsten, Anders1 aMärz, Winfried1 aRosendaal, Frits, R1 aSouto, Juan, Carlos1 aDehghan, Abbas1 aJohnson, Andrew, D1 aMorrison, Alanna, C1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aINVENT Consortium1 aMEGASTROKE Consortium of the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/798802292nas a2200649 4500008004100000245014800041210006900189260000700258300001600265490000700281520057000288100001800858700002000876700001800896700001800914700001600932700002000948700002000968700001600988700001601004700001701020700001201037700001601049700001101065700002001076700001901096700001601115700001401131700001901145700001901164700001601183700001901199700001201218700001101230700001201241700001401253700001901267700001401286700001501300700001801315700001301333700001901346700001701365700002601382700001601408700001501424700001901439700002101458700001301479700001801492700001701510700002001527700002201547700001901569700001801588856003601606 2019 eng d00a{Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group0 aGenomeWide Association Study of Apparent TreatmentResistant Hype c11 a1146–11530 v323 a{Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.\ We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 9311 aIrvin, M., R.1 aSitlani, C., M.1 aFloyd, J., S.1 aPsaty, B., M.1 aBis, J., C.1 aWiggins, K., L.1 aWhitsel, E., A.1 aSturmer, T.1 aStewart, J.1 aRaffield, L.1 aSun, F.1 aLiu, C., T.1 aXu, H.1 aCupples, A., L.1 aTanner, R., M.1 aRossing, P.1 aSmith, A.1 aZilh?o, N., R.1 aLauner, L., J.1 aNoordam, R.1 aRotter, J., I.1 aYao, J.1 aLi, X.1 aGuo, X.1 aLimdi, N.1 aSundaresan, A.1 aLange, L.1 aCorrea, A.1 aStott, D., J.1 aFord, I.1 aJukema, J., W.1 aGudnason, V.1 aMook-Kanamori, D., O.1 aTrompet, S.1 aPalmas, W.1 aWarren, H., R.1 aHellwege, J., N.1 aGiri, A.1 aO'Donnell, C.1 aHung, A., M.1 aEdwards, T., L.1 aAhluwalia, T., S.1 aArnett, D., K.1 aAvery, C., L. uhttps://chs-nhlbi.org/node/851804831nas a2201009 4500008004100000022001400041245014800055210006900203260001600272300001400288490000700302520194700309653000902256653002802265653003002293653001902323653002502342653004102367653002902408653002502437653002002462653003502482653001102517653001102528653001702539653003402556653001102590653001702601653000902618653001602627653002402643653001802667653001802685653002102703653002902724653003602753653002002789653001702809653002602826653001802852653001702870100002502887700002402912700002002936700002002956700001902976700002202995700002103017700001803038700001903056700002003075700001603095700001803111700001503129700002503144700002103169700001903190700001803209700002103227700002203248700002103270700002203291700001303313700001603326700001703342700001603359700002603375700001803401700001903419700002003438700001403458700001903472700002403491700002903515700002003544700001903564700002103583700002503604700001603629700002703645700002103672700002103693700002803714700002103742700002203763856003603785 2019 eng d a1941-722500aGenome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.0 aGenomeWide Association Study of Apparent TreatmentResistant Hype c2019 Nov 15 a1146-11530 v323 aBACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.
METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.
RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.
CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
10aAged10aAntihypertensive Agents10aBlack or African American10aBlood Pressure10aCase-Control Studies10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methyltransferase 3A10aDNA-Binding Proteins10aDrug Resistance10aDystrophin-Associated Proteins10aEurope10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMiddle Aged10aMyosin Heavy Chains10aMyosin Type V10aNeuropeptides10aPharmacogenetics10aPharmacogenomic Variants10aPolymorphism, Single Nucleotide10aRisk Assessment10aRisk Factors10aTranscription Factors10aUnited States10aWhite People1 aIrvin, Marguerite, R1 aSitlani, Colleen, M1 aFloyd, James, S1 aPsaty, Bruce, M1 aBis, Joshua, C1 aWiggins, Kerri, L1 aWhitsel, Eric, A1 aStürmer, Til1 aStewart, James1 aRaffield, Laura1 aSun, Fangui1 aLiu, Ching-Ti1 aXu, Hanfei1 aCupples, Adrienne, L1 aTanner, Rikki, M1 aRossing, Peter1 aSmith, Albert1 aZilhão, Nuno, R1 aLauner, Lenore, J1 aNoordam, Raymond1 aRotter, Jerome, I1 aYao, Jie1 aLi, Xiaohui1 aGuo, Xiuqing1 aLimdi, Nita1 aSundaresan, Aishwarya1 aLange, Leslie1 aCorrea, Adolfo1 aStott, David, J1 aFord, Ian1 aJukema, Wouter1 aGudnason, Vilmundur1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aPalmas, Walter1 aWarren, Helen, R1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aO'donnell, Christopher1 aHung, Adriana, M1 aEdwards, Todd, L1 aAhluwalia, Tarunveer, S1 aArnett, Donna, K1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/937203656nas a2200433 4500008004100000022001400041245009700055210006900152260001600221520237300237100002202610700001802632700002402650700001702674700002002691700002002711700002302731700002102754700002002775700002002795700002002815700001702835700002302852700002402875700002402899700002302923700001902946700001102965700002402976700002003000700002903020700002703049700002503076700002503101700002203126700002003148700001803168856003603186 2019 eng d a1938-320700aGenome-wide association study of breakfast skipping links clock regulation with food timing.0 aGenomewide association study of breakfast skipping links clock r c2019 Jun 133 aBACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits.
OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait.
METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963).
RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095).
CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.
1 aDashti, Hassan, S1 aMerino, Jordi1 aLane, Jacqueline, M1 aSong, Yanwei1 aSmith, Caren, E1 aTanaka, Toshiko1 aMcKeown, Nicola, M1 aTucker, Chandler1 aSun, Dianjianyi1 aBartz, Traci, M1 aLi-Gao, Ruifang1 aNisa, Hoirun1 aReutrakul, Sirimon1 aLemaitre, Rozenn, N1 aAlshehri, Tahani, M1 ade Mutsert, Renée1 aBazzano, Lydia1 aQi, Lu1 aKnutson, Kristen, L1 aPsaty, Bruce, M1 aMook-Kanamori, Dennis, O1 aPerica, Vesna, Boraska1 aNeuhouser, Marian, L1 aScheer, Frank, A J L1 aRutter, Martin, K1 aGaraulet, Marta1 aSaxena, Richa uhttps://chs-nhlbi.org/node/809902874nas a2200505 4500008004100000022001400041245013200055210006900187260001200256300001400268490000800282520125100290653004401541653002501585653002301610653003801633653003401671653001101705653005101716653004701767653002201814653002901836653003601865653003101901653001701932653003001949653001901979100002001998700001702018700002502035700001802060700001902078700002302097700001902120700002302139700002002162700002002182700002102202700002702223700002002250700001902270700002102289700002202310856003602332 2019 eng d a1532-653500aGenomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink.0 aGenomewide Association Study of StatinInduced Myopathy in Patien c2019 12 a1353-13610 v1063 aStatins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.
10aAdverse Drug Reaction Reporting Systems10aCase-Control Studies10aDatabases, Factual10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aLiver-Specific Organic Anion Transporter 110aMuscular Diseases10aPharmacogenomic Variants10aPolymorphism, Single Nucleotide10aReproducibility of Results10aRisk Factors10aSeverity of Illness Index10aUnited Kingdom1 aCarr, Daniel, F1 aFrancis, Ben1 aJorgensen, Andrea, L1 aZhang, Eunice1 aChinoy, Hector1 aHeckbert, Susan, R1 aBis, Joshua, C1 aBrody, Jennifer, A1 aFloyd, James, S1 aPsaty, Bruce, M1 aMolokhia, Mariam1 aLapeyre-Mestre, Maryse1 aConforti, Anita1 aAlfirevic, Ana1 avan Staa, Tjeerd1 aPirmohamed, Munir uhttps://chs-nhlbi.org/node/850804590nas a2201033 4500008004100000245016000041210006900201260000700270300001400277490000800291520182400299100002202123700002002145700002102165700001502186700002402201700001302225700001702238700002602255700001802281700001602299700002002315700001202335700001802347700002302365700001602388700002002404700001702424700001602441700001802457700001902475700001902494700001302513700001902526700001802545700001902563700001902582700001902601700002302620700001902643700001402662700001802676700001702694700001502711700001802726700001502744700002502759700001802784700001502802700001802817700001902835700001902854700001702873700001402890700001902904700001502923700002002938700002502958700001502983700001902998700001603017700001803033700002003051700001703071700001803088700002603106700001503132700001703147700001703164700001903181700001603200700001703216700001603233700002203249700001803271700001903289700001803308700001303326700001903339700001603358700002103374700002103395700002003416700002203436700002103458700002303479700001803502856003603520 2019 eng d00a{Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels0 aGenomeWide Association Transethnic MetaAnalyses Identifies Novel c01 a620–6350 v1393 aFactor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.\ We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.\ We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.\ The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.1 aSabater-Lleal, M.1 aHuffman, J., E.1 ade Vries, P., S.1 aMarten, J.1 aMastrangelo, M., A.1 aSong, C.1 aPankratz, N.1 aWard-Caviness, C., K.1 aYanek, L., R.1 aTrompet, S.1 aDelgado, G., E.1 aGuo, X.1 aBartz, T., M.1 aMartinez-Perez, A.1 aGermain, M.1 ade Haan, H., G.1 aOzel, A., B.1 aPolasek, O.1 aSmith, A., V.1 aEicher, J., D.1 aReiner, A., P.1 aTang, W.1 aDavies, N., M.1 aStott, D., J.1 aRotter, J., I.1 aTofler, G., H.1 aBoerwinkle, E.1 ade Maat, M., P. M.1 aKleber, M., E.1 aWelsh, P.1 aBrody, J., A.1 aChen, M., H.1 aVaidya, D.1 aSoria, J., M.1 aSuchon, P.1 aVlieg, van, Hylckama1 aDesch, K., C.1 aKolcic, I.1 aJoshi, P., K.1 aLauner, L., J.1 aHarris, T., B.1 aCampbell, H.1 aRudan, I.1 aBecker, D., M.1 aLi, J., Z.1 aRivadeneira, F.1 aUitterlinden, A., G.1 aHofman, A.1 aFranco, O., H.1 aCushman, M.1 aPsaty, B., M.1 aMorange, P., E.1 aMcKnight, B.1 aChong, M., R.1 aFernandez-Cadenas, I.1 aRosand, J.1 aLindgren, A.1 aGudnason, V.1 aWilson, J., F.1 aHayward, C.1 aGinsburg, D.1 aFornage, M.1 aRosendaal, F., R.1 aSouto, J., C.1 aBecker, L., C.1 aJenny, N., S.1 aM?rz, W.1 aJukema, J., W.1 aDehghan, A.1 aTr?gou?t, D., A.1 aMorrison, A., C.1 aJohnson, A., D.1 aO'Donnell, C., J.1 aStrachan, D., P.1 aLowenstein, C., J.1 aSmith, N., L. uhttps://chs-nhlbi.org/node/852703604nas a2200553 4500008004100000022001400041245013100055210006900186260001200255300001100267490000600278520187600284653002202160653004502182653002802227653002902255653001102284653003502295653002902330653003602359653004102395653003402436100001502470700001402485700002602499700002302525700002202548700002002570700002302590700002202613700001602635700001502651700002402666700002002690700002002710700002202730700002302752700003102775700002402806700002102830700002102851700002302872700002402895700002202919700002702941700002102968700002502989856003603014 2019 eng d a2324-926900aGenome-wide meta-analysis of SNP and antihypertensive medication interactions on left ventricular traits in African Americans.0 aGenomewide metaanalysis of SNP and antihypertensive medication i c2019 10 ae007880 v73 aBACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography.
METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates.
RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population.
CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.
10aAfrican Americans10aAngiotensin-Converting Enzyme Inhibitors10aAntihypertensive Agents10aCalcium Channel Blockers10aHumans10aObservational Studies as Topic10aPharmacogenomic Variants10aPolymorphism, Single Nucleotide10aSodium Chloride Symporter Inhibitors10aVentricular Dysfunction, Left1 aDo, Anh, N1 aZhao, Wei1 aBaldridge, Abigail, S1 aRaffield, Laura, M1 aWiggins, Kerri, L1 aShah, Sanjiv, J1 aAslibekyan, Stella1 aTiwari, Hemant, K1 aLimdi, Nita1 aZhi, Degui1 aSitlani, Colleen, M1 aTaylor, Kent, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aBrody, Jennifer, A1 aRasmussen-Torvik, Laura, J1 aLloyd-Jones, Donald1 aLange, Leslie, A1 aWilson, James, G1 aSmith, Jennifer, A1 aKardia, Sharon, L R1 aMosley, Thomas, H1 aVasan, Ramachandran, S1 aArnett, Donna, K1 aIrvin, Marguerite, R uhttps://chs-nhlbi.org/node/851103476nas a2200709 4500008004100000022001400041245014100055210006900196260001600265520166300281100002101944700001501965700001801980700001601998700001602014700001702030700001602047700001002063700001702073700001402090700001502104700001102119700001502130700001002145700001602155700001302171700001602184700001602200700001702216700001402233700001902247700001602266700001202282700001102294700001602305700001602321700001302337700001602350700001702366700001702383700001502400700001902415700001802434700001602452700001602468700001702484700002002501700001502521700001802536700001802554700001602572700001802588700001702606700001102623700001502634700001402649700001602663700001602679700001702695700001802712856003602730 2019 eng d a1473-115000aGenome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.0 aGenomewide metaanalysis of variantbydiuretic interactions as mod c2019 Dec 063 aHypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.
1 aFuentes, de, Las1 aSung, Y, J1 aSitlani, C, M1 aAvery, C, L1 aBartz, T, M1 ade Keyser, C1 aEvans, D, S1 aLi, X1 aMusani, S, K1 aRuiter, R1 aSmith, A V1 aSun, F1 aTrompet, S1 aXu, H1 aArnett, D K1 aBis, J C1 aBroeckel, U1 aBusch, E, L1 aChen, Y-D, I1 aCorrea, A1 aCummings, S, R1 aFloyd, J, S1 aFord, I1 aGuo, X1 aHarris, T B1 aIkram, M, A1 aLange, L1 aLauner, L J1 aReiner, A, P1 aSchwander, K1 aSmith, N L1 aSotoodehnia, N1 aStewart, J, D1 aStott, D, J1 aStürmer, T1 aTaylor, K, D1 aUitterlinden, A1 aVasan, R S1 aWiggins, K, L1 aCupples, L, A1 aGudnason, V1 aHeckbert, S R1 aJukema, J, W1 aLiu, Y1 aPsaty, B M1 aRao, D, C1 aRotter, J I1 aStricker, B1 aWilson, J, G1 aWhitsel, E, A uhttps://chs-nhlbi.org/node/826004216nas a2200841 4500008004100000022001400041245011700055210006900172260001600241300001400257490000800271520173700279100002102016700001302037700001902050700002002069700003002089700002302119700002302142700002002165700002202185700002102207700002302228700001902251700002002270700002202290700002002312700002202332700002102354700002402375700002502399700002102424700002402445700002202469700002302491700002302514700001902537700002302556700002302579700002302602700001802625700002202643700002502665700002502690700002102715700002102736700002302757700001702780700002102797700002502818700002602843700002702869700002402896700001502920700002202935700001702957700002402974700002402998700001803022700002003040700001803060700002403078700002003102700002003122700002903142700002303171700002503194700003203219700002303251710002803274710003603302856003603338 2019 eng d a1528-002000aGenomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.0 aGenomic and transcriptomic association studies identify 16 novel c2019 Nov 07 a1645-16570 v1343 aVenous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
1 aLindström, Sara1 aWang, Lu1 aSmith, Erin, N1 aGordon, William1 aVlieg, Astrid, van Hylcka1 ade Andrade, Mariza1 aBrody, Jennifer, A1 aPattee, Jack, W1 aHaessler, Jeffrey1 aBrumpton, Ben, M1 aChasman, Daniel, I1 aSuchon, Pierre1 aChen, Ming-Huei1 aTurman, Constance1 aGermain, Marine1 aWiggins, Kerri, L1 aMacDonald, James1 aBraekkan, Sigrid, K1 aArmasu, Sebastian, M1 aPankratz, Nathan1 aJackson, Rebecca, D1 aNielsen, Jonas, B1 aGiulianini, Franco1 aPuurunen, Marja, K1 aIbrahim, Manal1 aHeckbert, Susan, R1 aDamrauer, Scott, M1 aNatarajan, Pradeep1 aKlarin, Derek1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 aBammler, Theo, K1 aFrazer, Kelly, A1 aMcCauley, Bryan, M1 aTaylor, Kent1 aPankow, James, S1 aReiner, Alexander, P1 aGabrielsen, Maiken, E1 aDeleuze, Jean-Francois1 aO'Donnell, Chris, J1 aKim, Jihye1 aMcKnight, Barbara1 aKraft, Peter1 aHansen, John-Bjarne1 aRosendaal, Frits, R1 aHeit, John, A1 aPsaty, Bruce, M1 aTang, Weihong1 aKooperberg, Charles1 aHveem, Kristian1 aRidker, Paul, M1 aMorange, Pierre-Emmanuel1 aJohnson, Andrew, D1 aKabrhel, Christopher1 aTrégouët, David-Alexandre1 aSmith, Nicholas, L1 aMillion Veteran Program1 aCHARGE Hemostasis Working Group uhttps://chs-nhlbi.org/node/820005901nas a2201993 4500008004100000022001400041245012500055210006900180260001600249490000600265520115800271100002301429700001901452700001801471700002001489700001601509700001501525700002601540700002001566700001501586700001301601700001301614700001701627700001601644700001401660700001701674700001501691700002001706700002001726700001401746700001801760700001201778700001301790700001401803700001601817700001701833700001401850700001401864700001401878700001901892700001401911700001601925700001101941700001501952700001401967700001301981700002301994700001802017700001502035700001702050700001102067700001802078700001602096700001702112700001602129700001702145700001402162700002402176700001302200700001402213700001502227700001402242700001802256700001402274700001402288700001602302700001502318700001702333700001202350700001502362700001702377700001502394700001202409700001402421700001502435700001702450700001602467700001602483700001402499700001402513700001202527700001502539700001502554700001902569700001302588700001502601700001802616700001202634700001202646700001302658700001502671700001302686700001302699700001702712700001602729700001402745700001702759700001502776700002002791700002002811700001402831700001802845700001202863700001302875700001402888700001602902700001702918700001402935700001402949700001402963700001902977700001402996700001603010700001103026700001503037700001403052700001303066700002303079700001803102700001503120700001703135700001103152700001803163700001603181700001703197700001603214700001703230700001403247700002403261700001303285700001403298700001503312700001403327700001803341700001403359700001403373700001603387700001503403700001703418700001203435700001503447700001703462700001503479700001203494700001403506700001503520700001703535700001603552700001603568700001403584700001403598700001203612700001503624700001503639700001903654700001303673700001503686700001803701700001203719700001203731700001303743700001403756700001603770700002103786700002103807700002003828710002303848856003603871 2019 eng d a2050-084X00aGenomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances.0 aGenomics of 1 million parent lifespans implicates novel pathways c2019 Jan 150 v83 aWe use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near , , , , , and 13q21.31, and identify and replicate novel findings near , , and . We also validate previous findings near 5q33.3/ and , whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.
Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
1 aTimmers, Paul, Rhj1 aMounier, Ninon1 aLäll, Kristi1 aFischer, Krista1 aNing, Zheng1 aFeng, Xiao1 aBretherick, Andrew, D1 aClark, David, W1 aAgbessi, M1 aAhsan, H1 aAlves, I1 aAndiappan, A1 aAwadalla, P1 aBattle, A1 aBonder, M, J1 aBoomsma, D1 aChristiansen, M1 aClaringbould, A1 aDeelen, P1 avan Dongen, J1 aEsko, T1 aFavé, M1 aFranke, L1 aFrayling, T1 aGharib, S, A1 aGibson, G1 aHemani, G1 aJansen, R1 aKalnapenkis, A1 aKasela, S1 aKettunen, J1 aKim, Y1 aKirsten, H1 aKovacs, P1 aKrohn, K1 aKronberg-Guzman, J1 aKukushkina, V1 aKutalik, Z1 aKähönen, M1 aLee, B1 aLehtimäki, T1 aLoeffler, M1 aMarigorta, U1 aMetspalu, A1 avan Meurs, J1 aMilani, L1 aMüller-Nurasyid, M1 aNauck, M1 aNivard, M1 aPenninx, B1 aPerola, M1 aPervjakova, N1 aPierce, B1 aPowell, J1 aProkisch, H1 aPsaty, B M1 aRaitakari, O1 aRing, S1 aRipatti, S1 aRotzschke, O1 aRuëger, S1 aSaha, A1 aScholz, M1 aSchramm, K1 aSeppälä, I1 aStumvoll, M1 aSullivan, P1 aTeumer, A1 aThiery, J1 aTong, L1 aTönjes, A1 aVerlouw, J1 aVisscher, P, M1 aVõsa, U1 aVölker, U1 aYaghootkar, H1 aYang, J1 aZeng, B1 aZhang, F1 aAgbessi, M1 aAhsan, H1 aAlves, I1 aAndiappan, A1 aAwadalla, P1 aBattle, A1 aBonder, M, J1 aBoomsma, D1 aChristiansen, M1 aClaringbould, A1 aDeelen, P1 avan Dongen, J1 aEsko, T1 aFavé, M1 aFranke, L1 aFrayling, T1 aGharib, S, A1 aGibson, G1 aHemani, G1 aJansen, R1 aKalnapenkis, A1 aKasela, S1 aKettunen, J1 aKim, Y1 aKirsten, H1 aKovacs, P1 aKrohn, K1 aKronberg-Guzman, J1 aKukushkina, V1 aKutalik, Z1 aKähönen, M1 aLee, B1 aLehtimäki, T1 aLoeffler, M1 aMarigorta, U1 aMetspalu, A1 avan Meurs, J1 aMilani, L1 aMüller-Nurasyid, M1 aNauck, M1 aNivard, M1 aPenninx, B1 aPerola, M1 aPervjakova, N1 aPierce, B1 aPowell, J1 aProkisch, H1 aPsaty, B M1 aRaitakari, O1 aRing, S1 aRipatti, S1 aRotzschke, O1 aRuëger, S1 aSaha, A1 aScholz, M1 aSchramm, K1 aSeppälä, I1 aStumvoll, M1 aSullivan, P1 aTeumer, A1 aThiery, J1 aTong, L1 aTönjes, A1 aVerlouw, J1 aVisscher, P, M1 aVõsa, U1 aVölker, U1 aYaghootkar, H1 aYang, J1 aZeng, B1 aZhang, F1 aShen, Xia1 aEsko, Tõnu1 aKutalik, Zoltán1 aWilson, James, F1 aJoshi, Peter, K1 aeQTLGen Consortium uhttps://chs-nhlbi.org/node/798102119nas a2200265 4500008004100000022001400041245012000055210006900175260001600244520128100260100002301541700002501564700002101589700001701610700002401627700002901651700002201680700002001702700001401722700001801736700002001754700002001774700002301794856003601817 2019 eng d a1476-625600aHeterogeneous Exposure Associations in Observational Cohort Studies: The Example of Blood Pressure in Older Adults.0 aHeterogeneous Exposure Associations in Observational Cohort Stud c2019 Oct 083 aHeterogeneous exposure associations (HEAs) can be defined as differences in the association of a exposure with an outcome among subgroups that differ by a set of characteristics. This manuscript intends to foster discussion of HEAs in the epidemiological literature, and present a variant of the random forest algorithm that can be used to identify HEAs. We demonstrate the use of this algorithm in the setting of the association of systolic blood pressure and death in older adults. The training set included pooled data from the baseline examination of the Cardiovascular Health Study (1989-1993), the Health, Aging, and Body Composition study (1997-1998), and the Sacramento Area Latino Study on Aging (1998-1999). The test set included data from the National Health and Nutrition Examination Survey (1999-2002). The hazard ratios ranged from 1.25 (95% CI: 1.13, 1.37) per 10 mmHg higher systolic blood pressure in men aged ≤67 years with diastolic blood pressure >80 mmHg, to 1.00 (0.96, 1.03) in women with creatinine <0.7 mg/dL and a history of hypertension. HEAs have the potential to improve our understanding of disease mechanisms in diverse populations, and guide the design of randomized controlled trials to control exposures in heterogeneous populations.
1 aOdden, Michelle, C1 aRawlings, Andreea, M1 aKhodadadi, Abtin1 aFern, Xiaoli1 aShlipak, Michael, G1 aBibbins-Domingo, Kirsten1 aCovinsky, Kenneth1 aKanaya, Alka, M1 aLee, Anne1 aHaan, Mary, N1 aNewman, Anne, B1 aPsaty, Bruce, M1 aPeralta, Carmen, A uhttps://chs-nhlbi.org/node/827803078nas a2200325 4500008004100000245012300041210006900164300001300233490000700246520214700253100002002400700001302420700001802433700002102451700001102472700001802483700001602501700001902517700001802536700001902554700001702573700001802590700001502608700001802623700001902641700002202660700001702682700001702699856003602716 2019 eng d00a{The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE)0 aimpact of APOE genotype on survival Results of 38537 participant ae02196680 v143 aApolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-ε4 allele has long been associated with increased risks of Alzheimer's disease and mortality, but the effect of the less prevalent APOE-ε2 allele on diseases in the elderly and survival remains elusive.\ We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6% women) from six population-based cohort studies (Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study, Health-ABC Study, and the family-based Framingham Heart Study and Long Life Family Study) to determine the association of APOE, and in particular APOE-ε2, with survival in the population.\ During a mean follow-up of 11.7 years, 17,021 individuals died. Compared with homozygous APOE-ε3 carriers, APOE-ε2 carriers were at lower risk of death (hazard ratio,95% confidence interval: 0.94,0.90-0.99; P = 1.1*10-2), whereas APOE-ε4 carriers were at increased risk of death (HR 1.17,1.12-1.21; P = 2.8*10-16). APOE was associated with mortality risk in a dose-dependent manner, with risk estimates lowest for homozygous APOE-ε2 (HR 0.89,0.74-1.08), and highest for homozygous APOE-ε4 (HR 1.52,1.37-1.70). After censoring for dementia, effect estimates remained similar for APOE-ε2 (HR 0.95,0.90-1.01), but attenuated for APOE-ε4 (HR 1.07,1.01-1.12). Results were broadly similar across cohorts, and did not differ by age or sex. APOE genotype was associated with baseline lipid fractions (e.g. mean difference(95%CI) in LDL(mg/dL) for ε2 versus ε33: -17.1(-18.1-16.0), and ε4 versus ε33: +5.7(4.8;6.5)), but the association between APOE and mortality was unaltered after adjustment for baseline LDL or cardiovascular disease. Given the European ancestry of the study population, results may not apply to other ethnicities.\ Compared with APOE-ε3, APOE-ε2 is associated with prolonged survival, whereas mortality risk is increased for APOE-ε4 carriers. Further collaborative efforts are needed to unravel the role of APOE and in particular APOE-ε2 in health and disease.1 aWolters, F., J.1 aYang, Q.1 aBiggs, M., L.1 aJakobsdottir, J.1 aLi, S.1 aEvans, D., S.1 aBis, J., C.1 aHarris, T., B.1 aVasan, R., S.1 aZilhao, N., R.1 aGhanbari, M.1 aIkram, M., A.1 aLauner, L.1 aPsaty, B., M.1 aTranah, G., J.1 aKulminski, A., M.1 aGudnason, V.1 aSeshadri, S. uhttps://chs-nhlbi.org/node/853104013nas a2200685 4500008004100000022001400041245016200055210006900217260001600286300001200302490000800314520192200322100002102244700001702265700002302282700001502305700002202320700002002342700001702362700001602379700001702395700001802412700001202430700002302442700002202465700002302487700002502510700001702535700001802552700001902570700002602589700002002615700002402635700002202659700002102681700002002702700002202722700002102744700001902765700002402784700002002808700002302828700002502851700002502876700002502901700002702926700001902953700002402972700002102996700002203017700002103039700002203060700001903082700002003101710003403121710003603155710003603191710006403227856003603291 2019 eng d a1537-660500aImpact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.0 aImpact of Rare and Common Genetic Variants on Diabetes Diagnosis c2019 Oct 03 a706-7180 v1053 aHemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
1 aSarnowski, Chloe1 aLeong, Aaron1 aRaffield, Laura, M1 aWu, Peitao1 ade Vries, Paul, S1 aDiCorpo, Daniel1 aGuo, Xiuqing1 aXu, Huichun1 aLiu, Yongmei1 aZheng, Xiuwen1 aHu, Yao1 aBrody, Jennifer, A1 aGoodarzi, Mark, O1 aHidalgo, Bertha, A1 aHighland, Heather, M1 aJain, Deepti1 aLiu, Ching-Ti1 aNaik, Rakhi, P1 aO'Connell, Jeffrey, R1 aPerry, James, A1 aPorneala, Bianca, C1 aSelvin, Elizabeth1 aWessel, Jennifer1 aPsaty, Bruce, M1 aCurran, Joanne, E1 aPeralta, Juan, M1 aBlangero, John1 aKooperberg, Charles1 aMathias, Rasika1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aMitchell, Braxton, D1 aCupples, Adrienne, L1 aVasan, Ramachandran, S1 aCorrea, Adolfo1 aMorrison, Alanna, C1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aRich, Stephen, S1 aManning, Alisa, K1 aDupuis, Josée1 aMeigs, James, B1 aTOPMed Diabetes Working Group1 aTOPMed Hematology Working Group1 aTOPMed Hemostasis Working Group1 aNational Heart, Lung, and Blood Institute TOPMed Consortium uhttps://chs-nhlbi.org/node/820502918nas a2200589 4500008004100000022001400041245006600055210006200121260001600183520123400199100002101433700002301454700002201477700002001499700002001519700001901539700002001558700002001578700002001598700002101618700002101639700001701660700001701677700001801694700001901712700002601731700001801757700002101775700002401796700002201820700002701842700002901869700001901898700002101917700002001938700002201958700001701980700002501997700002302022700002402045700001702069700002402086700001802110700002302128700002902151700002502180700001702205700002302222700002502245710002202270856003602292 2019 eng d a1098-227200aA large-scale exome array analysis of venous thromboembolism.0 alargescale exome array analysis of venous thromboembolism c2019 Jan 193 aAlthough recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.
1 aLindström, Sara1 aBrody, Jennifer, A1 aTurman, Constance1 aGermain, Marine1 aBartz, Traci, M1 aSmith, Erin, N1 aChen, Ming-Huei1 aPuurunen, Marja1 aChasman, Daniel1 aHassler, Jeffrey1 aPankratz, Nathan1 aBasu, Saonli1 aGuan, Weihua1 aGyorgy, Beata1 aIbrahim, Manal1 aEmpana, Jean-Philippe1 aOlaso, Robert1 aJackson, Rebecca1 aBraekkan, Sigrid, K1 aMcKnight, Barbara1 aDeleuze, Jean-Francois1 aO'Donnell, Cristopher, J1 aJouven, Xavier1 aFrazer, Kelly, A1 aPsaty, Bruce, M1 aWiggins, Kerri, L1 aTaylor, Kent1 aReiner, Alexander, P1 aHeckbert, Susan, R1 aKooperberg, Charles1 aRidker, Paul1 aHansen, John-Bjarne1 aTang, Weihong1 aJohnson, Andrew, D1 aMorange, Pierre-Emmanuel1 aTrégouët, David, A1 aKraft, Peter1 aSmith, Nicholas, L1 aKabrhel, Christopher1 aINVENT Consortium uhttps://chs-nhlbi.org/node/797903358nas a2200589 4500008004100000245009600041210006900137260000700206300001400213490000700227520177900234100002002013700001902033700002002052700001902072700002002091700001802111700001802129700001902147700001302166700001602179700001702195700001802212700002002230700001402250700001902264700002402283700001602307700001602323700001702339700001702356700001702373700002402390700002202414700001902436700002002455700001802475700002002493700001902513700001502532700001802547700001602565700001902581700002202600700001702622700001502639700001902654700001602673700001802689700002502707856003602732 2019 eng d00a{Low thyroid function is not associated with an accelerated deterioration in renal function0 aLow thyroid function is not associated with an accelerated deter c04 a650–6590 v343 aChronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.\ Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.\ A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.\ Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.1 aMeuwese, C., L.1 avan Diepen, M.1 aCappola, A., R.1 aSarnak, M., J.1 aShlipak, M., G.1 aBauer, D., C.1 aFried, L., P.1 aIacoviello, M.1 aVaes, B.1 aDegryse, J.1 aKhaw, K., T.1 aLuben, R., N.1 asvold, B., O. ?1 aBj?ro, T.1 aVatten, L., J.1 ade Craen, A., J. M.1 aTrompet, S.1 aIervasi, G.1 aMolinaro, S.1 aCeresini, G.1 aFerrucci, L.1 aDullaart, R., P. F.1 aBakker, S., J. L.1 aJukema, J., W.1 aKearney, P., M.1 aStott, D., J.1 aPeeters, R., P.1 aFranco, O., H.1 aV?lzke, H.1 aWalsh, J., P.1 aBremner, A.1 aSgarbi, J., A.1 aMaciel, R., M. B.1 aImaizumi, M.1 aOhishi, W.1 aDekker, F., W.1 aRodondi, N.1 aGussekloo, J.1 aElzen, W., P. J. den uhttps://chs-nhlbi.org/node/852404639nas a2200829 4500008004100000022001400041245010700055210006900162260000900231300001300240490000700253520225600260100002802516700002202544700002202566700002502588700001902613700002402632700002302656700001702679700002202696700002002718700001802738700002202756700002502778700002502803700001702828700001902845700003002864700002402894700002102918700002602939700002202965700002102987700002103008700001803029700001603047700002303063700001303086700002503099700002803124700002103152700002303173700002203196700002203218700002003240700002303260700002103283700002403304700002303328700002603351700002003377700002003397700001303417700001903430700002203449700002003471700001903491700001903510700002103529700002403550700002203574700002003596700001803616700002303634700001903657700003003676700002303706700002003729700002403749856003603773 2019 eng d a1932-620300aMendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.0 aMendelian randomization evaluation of causal effects of fibrinog c2019 ae02162220 v143 aBACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.
METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.
CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
1 aWard-Caviness, Cavin, K1 ade Vries, Paul, S1 aWiggins, Kerri, L1 aHuffman, Jennifer, E1 aYanek, Lisa, R1 aBielak, Lawrence, F1 aGiulianini, Franco1 aGuo, Xiuqing1 aKleber, Marcus, E1 aKacprowski, Tim1 aGroß, Stefan1 aPetersman, Astrid1 aSmith, George, Davey1 aHartwig, Fernando, P1 aBowden, Jack1 aHemani, Gibran1 aMüller-Nuraysid, Martina1 aStrauch, Konstantin1 aKoenig, Wolfgang1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aPankratz, Nathan1 aBoerwinkle, Eric1 aTang, Weihong1 aFu, Yi-Ping1 aJohnson, Andrew, D1 aSong, Ci1 ade Maat, Moniek, P M1 aUitterlinden, André, G1 aFranco, Oscar, H1 aBrody, Jennifer, A1 aMcKnight, Barbara1 aChen, Yii-Der Ida1 aPsaty, Bruce, M1 aMathias, Rasika, A1 aBecker, Diane, M1 aPeyser, Patricia, A1 aSmith, Jennifer, A1 aBielinski, Suzette, J1 aRidker, Paul, M1 aTaylor, Kent, D1 aYao, Jie1 aTracy, Russell1 aDelgado, Graciela1 aTrompet, Stella1 aSattar, Naveed1 aJukema, Wouter1 aBecker, Lewis, C1 aKardia, Sharon, L R1 aRotter, Jerome, I1 aMärz, Winfried1 aDörr, Marcus1 aChasman, Daniel, I1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aPeters, Annette1 aMorrison, Alanna, C uhttps://chs-nhlbi.org/node/805003938nas a2201129 4500008004100000245009200041210006900133260000700202300000900209490000700218520104700225100001501272700001801287700001901305700001301324700001601337700001201353700002301365700001801388700002101406700001501427700001701442700001801459700001801477700001601495700002001511700001301531700001301544700001901557700001801576700001701594700001901611700001601630700001601646700002001662700002101682700002201703700001701725700002101742700001501763700001801778700002001796700001501816700001701831700001901848700001401867700001701881700001901898700001601917700001801933700001501951700001501966700001401981700001601995700001602011700002202027700001702049700002402066700001902090700001802109700001302127700002402140700002002164700001202184700001402196700001902210700001202229700001702241700001902258700001802277700002102295700001802316700002202334700002402356700001902380700001902399700001902418700001402437700002402451700001902475700002502494700002202519700002402541700002202565700001902587700001902606700001302625700001102638700001302649700001402662700001702676700001702693700002002710700002102730700002102751856003602772 2019 eng d00a{A meta-analysis of genome-wide association studies identifies multiple longevity genes0 ametaanalysis of genomewide association studies identifies multip c08 a36690 v103 aHuman longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.1 aDeelen, J.1 aEvans, D., S.1 aArking, D., E.1 aTesi, N.1 aNygaard, M.1 aLiu, X.1 aWojczynski, M., K.1 aBiggs, M., L.1 avan der Spek, A.1 aAtzmon, G.1 aWare, E., B.1 aSarnowski, C.1 aSmith, A., V.1 aSepp?l?, I.1 aCordell, H., J.1 aDose, J.1 aAmin, N.1 aArnold, A., M.1 aAyers, K., L.1 aBarzilai, N.1 aBecker, E., J.1 aBeekman, M.1 aBlanch?, H.1 aChristensen, K.1 aChristiansen, L.1 aCollerton, J., C.1 aCubaynes, S.1 aCummings, S., R.1 aDavies, K.1 aDebrabant, B.1 aDeleuze, J., F.1 aDuncan, R.1 aFaul, J., D.1 aFranceschi, C.1 aGalan, P.1 aGudnason, V.1 aHarris, T., B.1 aHuisman, M.1 aHurme, M., A.1 aJagger, C.1 aJansen, I.1 aJylh?, M.1 aK?h?nen, M.1 aKarasik, D.1 aKardia, S., L. R.1 aKingston, A.1 aKirkwood, T., B. L.1 aLauner, L., J.1 aLehtim?ki, T.1 aLieb, W.1 aLyytik?inen, L., P.1 aMartin-Ruiz, C.1 aMin, J.1 aNebel, A.1 aNewman, A., B.1 aNie, C.1 aNohr, E., A.1 aOrwoll, E., S.1 aPerls, T., T.1 aProvince, M., A.1 aPsaty, B., M.1 aRaitakari, O., T.1 aReinders, M., J. T.1 aRobine, J., M.1 aRotter, J., I.1 aSebastiani, P.1 aSmith, J.1 aS?rensen, T., I. A.1 aTaylor, K., D.1 aUitterlinden, A., G.1 avan der Flier, W.1 avan der Lee, S., J.1 avan Duijn, C., M.1 avan Heemst, D.1 aVaupel, J., W.1 aWeir, D.1 aYe, K.1 aZeng, Y.1 aZheng, W.1 aHolstege, H.1 aKiel, D., P.1 aLunetta, K., L.1 aSlagboom, P., E.1 aMurabito, J., M. uhttps://chs-nhlbi.org/node/851003281nas a2201129 4500008004100000245009200041210006900133260000800202300000900210490000700219520042200226100001500648700001800663700001900681700001300700700001600713700001200729700002300741700001800764700002100782700001500803700001700818700001800835700001800853700001100871700002000882700001300902700001300915700001900928700001800947700001700965700001900982700001601001700001101017700002001028700002101048700002201069700001701091700002101108700001501129700001801144700002001162700001501182700001701197700001901214700001401233700001701247700001901264700001601283700001801299700001501317700001501332700001101347700001201358700001601370700002201386700001701408700002401425700001901449700001101468700001301479700001701492700002001509700001201529700001401541700001901555700001201574700001701586700001901603700001801622700002101640700001801661700002201679700002401701700001901725700001901744700001901763700001401782700002201796700001901818700002501837700002201862700002401884700002201908700001901930700001901949700001301968700001101981700001301992700001402005700001702019700001702036700002002053700002102073700002102094856003602115 2019 eng d00a{A meta-analysis of genome-wide association studies identifies multiple longevity genes0 ametaanalysis of genomewide association studies identifies multip cAug a36690 v103 a2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.1 aDeelen, J.1 aEvans, D., S.1 aArking, D., E.1 aTesi, N.1 aNygaard, M.1 aLiu, X.1 aWojczynski, M., K.1 aBiggs, M., L.1 avan der Spek, A.1 aAtzmon, G.1 aWare, E., B.1 aSarnowski, C.1 aSmith, A., V.1 aä, I.1 aCordell, H., J.1 aDose, J.1 aAmin, N.1 aArnold, A., M.1 aAyers, K., L.1 aBarzilai, N.1 aBecker, E., J.1 aBeekman, M.1 aé, H.1 aChristensen, K.1 aChristiansen, L.1 aCollerton, J., C.1 aCubaynes, S.1 aCummings, S., R.1 aDavies, K.1 aDebrabant, B.1 aDeleuze, J., F.1 aDuncan, R.1 aFaul, J., D.1 aFranceschi, C.1 aGalan, P.1 aGudnason, V.1 aHarris, T., B.1 aHuisman, M.1 aHurme, M., A.1 aJagger, C.1 aJansen, I.1 aä, M.1 anen, M.1 aKarasik, D.1 aKardia, S., L. R.1 aKingston, A.1 aKirkwood, T., B. L.1 aLauner, L., J.1 aki, T.1 aLieb, W.1 ainen, L., P.1 aMartin-Ruiz, C.1 aMin, J.1 aNebel, A.1 aNewman, A., B.1 aNie, C.1 aNohr, E., A.1 aOrwoll, E., S.1 aPerls, T., T.1 aProvince, M., A.1 aPsaty, B., M.1 aRaitakari, O., T.1 aReinders, M., J. T.1 aRobine, J., M.1 aRotter, J., I.1 aSebastiani, P.1 aSmith, J.1 arensen, T., I. A.1 aTaylor, K., D.1 aUitterlinden, A., G.1 avan der Flier, W.1 avan der Lee, S., J.1 avan Duijn, C., M.1 avan Heemst, D.1 aVaupel, J., W.1 aWeir, D.1 aYe, K.1 aZeng, Y.1 aZheng, W.1 aHolstege, H.1 aKiel, D., P.1 aLunetta, K., L.1 aSlagboom, P., E.1 aMurabito, J., M. uhttps://chs-nhlbi.org/node/931003821nas a2200745 4500008004100000245010000041210006900141260000700210300001600217490000700233520189900240100001602139700001602155700001802171700002402189700001602213700001302229700001802242700001802260700001602278700001502294700001902309700002102328700001902349700001702368700001402385700001402399700001502413700001602428700001502444700001702459700001302476700001902489700001302508700001502521700001202536700001802548700001702566700002102583700001702604700001502621700001602636700001602652700001602668700001402684700002102698700001602719700001902735700002002754700001902774700001702793700002302810700001502833700001902848700002102867700001802888700001902906700002502925700001402950700002202964700002002986700001703006700001603023856003603039 2019 eng d00a{Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry0 aMetaAnalysis of Genomewide Association Studies Reveals Genetic V c07 a1284–12960 v343 aHip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research.1 aHsu, Y., H.1 aEstrada, K.1 aEvangelou, E.1 aAckert-Bicknell, C.1 aAkesson, K.1 aBeck, T.1 aBrown, S., J.1 aCapellini, T.1 aCarbone, L.1 aCauley, J.1 aCheung, C., L.1 aCummings, S., R.1 aCzerwinski, S.1 aDemissie, S.1 aEcons, M.1 aEvans, D.1 aFarber, C.1 aGautvik, K.1 aHarris, T.1 aKammerer, C.1 aKemp, J.1 aKoller, D., L.1 aKung, A.1 aLawlor, D.1 aLee, M.1 aLorentzon, M.1 aMcGuigan, F.1 aMedina-Gomez, C.1 aMitchell, B.1 aNewman, A.1 aNielson, C.1 aOhlsson, C.1 aPeacock, M.1 aReppe, S.1 aRichards, J., B.1 aRobbins, J.1 aSigurdsson, G.1 aSpector, T., D.1 aStefansson, K.1 aStreeten, E.1 aStyrkarsdottir, U.1 aTobias, J.1 aTrajanoska, K.1 aUitterlinden, A.1 aVandenput, L.1 aWilson, S., G.1 aYerges-Armstrong, L.1 aYoung, M.1 aZillikens, M., C.1 aRivadeneira, F.1 aKiel, D., P.1 aKarasik, D. uhttps://chs-nhlbi.org/node/851710550nas a2203325 4500008004100000022001400041245010600055210006900161260001600230520134200246100002201588700002201610700002001632700001701652700002301669700001901692700002101711700001901732700001701751700002301768700002001791700001701811700002001828700002501848700002301873700001701896700002101913700002401934700002101958700002001979700002001999700002402019700001502043700002202058700002002080700002202100700002002122700002102142700002402163700002502187700002202212700001702234700002202251700002002273700001302293700001902306700001902325700001502344700001502359700002302374700002102397700002502418700001402443700002802457700001802485700002102503700002902524700002202553700002102575700002202596700001902618700001802637700002802655700001702683700001902700700001902719700001902738700001902757700002102776700001702797700002502814700002302839700002202862700002702884700002002911700001702931700001802948700001702966700001902983700001803002700001903020700001603039700001603055700001903071700001903090700001403109700002503123700002103148700002103169700002103190700002203211700002803233700002203261700002103283700001803304700002603322700002303348700002103371700002003392700002403412700001503436700002203451700002203473700002103495700002103516700002403537700002103561700002503582700002103607700002303628700001903651700002003670700001603690700002203706700002003728700002003748700001903768700002103787700002303808700002003831700002103851700001903872700002303891700002503914700002203939700002303961700002803984700001904012700002504031700001804056700002404074700002104098700002604119700001904145700002204164700001904186700002304205700002404228700002204252700002004274700002404294700001304318700002004331700001704351700001504368700001504383700001504398700001804413700002404431700002304455700002204478700002104500700002104521700001704542700002104559700002204580700002404602700001904626700002004645700002704665700002204692700002304714700002604737700001704763700002304780700002004803700002404823700001904847700001804866700002204884700002304906700002004929700001904949700002104968700002304989700002605012700001905038700001605057700002405073700002505097700002205122700001705144700001405161700002005175700001605195700002005211700002305231700002005254700001905274700002405293700001805317700002005335700001905355700002105374700002805395700002205423700002205445700002605467700001605493700001605509700001405525700001705539700002405556700002005580700002405600700001305624700001305637700001705650700001905667700001405686700002305700700002105723700002105744700002205765700002205787700001805809700001605827700002005843700002005863700002305883700002205906700002105928700002205949700002305971700002305994700001906017700002206036700001906058700001906077700002206096700002706118700002006145700002606165700002106191700002206212700001706234700001706251700001506268700002606283700001906309700002506328700001806353700001906371700003006390700001506420700001806435700001906453700002106472700002206493700002406515700001806539700001706557700002006574700002006594700002006614700002406634700001806658700002306676700002906699700002006728700002106748700001806769700002206787700002306809700001906832700002006851700001706871700002206888700002106910700002506931700002406956700001806980700002306998700002507021700002007046700002407066710002407090710007407114856003607188 2019 eng d a1476-625600aMulti-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.0 aMultiAncestry GenomeWide Association Study of Lipid Levels Incor c2019 Jan 293 aAn individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
1 ade Vries, Paul, S1 aBrown, Michael, R1 aBentley, Amy, R1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aSchwander, Karen1 aKraja, Aldi, T1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDeng, Xuan1 aDorajoo, Rajkumar1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aEvangelou, Evangelos1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLee, Joseph, H1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aRiaz, Muhammad1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aConnell, John, M1 ade Faire, Ulf1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDing, Jingzhong1 aDominiczak, Anna, F1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGrabe, Hans, J1 aGrove, Megan, L1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJacobs, David, R1 aJohnson, Craig1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Steve, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLemaitre, Rozenn, N1 aLi, Yize1 aLiang, Jingjing1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMukamal, Kenneth, J1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRice, Treva, K1 aRich, Stephen, S1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTan, Nicholas1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 avan Heemst, Diana1 aVuckovic, Dragana1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Yujie1 aWang, Zhe1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aPenninx, Brenda1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aZheng, Wei1 aElliott, Paul1 aNorth, Kari, E1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aLiu, Ching-Ti1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aKardia, Sharon, L R1 aZhu, Xiaofeng1 aRotimi, Charles, N1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLiu, Jingmin1 aRotter, Jerome, I1 aGauderman, James1 aProvince, Michael, A1 aMunroe, Patricia, B1 aRice, Kenneth1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aMorrison, Alanna, C1 aInterAct Consortium1 aLifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study) uhttps://chs-nhlbi.org/node/797011178nas a2203793 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2019 eng d a1546-171800aMulti-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.0 aMultiancestry genomewide genesmoking interaction study of 387272 c2019 Apr a636-6480 v513 aThe concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
1 aBentley, Amy, R1 aSung, Yun, J1 aBrown, Michael, R1 aWinkler, Thomas, W1 aKraja, Aldi, T1 aNtalla, Ioanna1 aSchwander, Karen1 aChasman, Daniel, I1 aLim, Elise1 aDeng, Xuan1 aGuo, Xiuqing1 aLiu, Jingmin1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aBaker, Jenna1 aChen, Guanjie1 aAschard, Hugues1 aBartz, Traci, M1 aDing, Jingzhong1 aDorajoo, Rajkumar1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aZhao, Wei1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aHung, Yi-Jen1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLeander, Karin1 aLin, Keng-Hung1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aPrins, Bram1 aRiaz, Muhammad1 aRobino, Antonietta1 aSaid, Abdullah1 aSchupf, Nicole1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Tzung-Dau1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aXiang, Yong-Bing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAdeyemo, Adebowale1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aArzumanyan, Zorayr1 aAung, Tin1 aBallantyne, Christie1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBroeckel, Ulrich1 aBrown, Morris1 aCade, Brian, E1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aChristensen, Kaare1 aConcas, Maria, Pina1 aConnell, John, M1 aFuentes, Lisa, de Las1 ade Silva, Janaka1 ade Vries, Paul, S1 aDoumatey, Ayo1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFloyd, James, S1 aForouhi, Nita, G1 aForrester, Terrence1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGharib, Sina, A1 aGigante, Bruna1 aGiulianini, Franco1 aGrabe, Hans, J1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aIkram, Arfan, M1 aJia, Yucheng1 aJoehanes, Roby1 aJohnson, Craig1 aJonas, Jost, Bruno1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLiang, Jingjing1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLohman, Kurt, K1 aLouie, Tin1 aLuzzi, Anna1 aMägi, Reedik1 aMahajan, Anubha1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMurray, Alison, D1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRenstrom, Frida1 aRice, Treva, K1 aRich, Stephen, S1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTiemeier, Henning1 aTurner, Stephen, T1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Heming1 aWang, Lan1 aWang, Lihua1 aBin Wei, Wen1 aWilliams, Christine, A1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYoung, Kristin1 aYu, Caizheng1 aYuan, Jian-Min1 aZhou, Jie1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aCooper, Richard, S1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aJuang, Jyh-Ming, Jimmy1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLaurie, Cathy, C1 aLee, I-Te1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aRedline, Susan1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Jun-Sing1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZeggini, Eleftheria1 aZheng, Wei1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aProvince, Michael, A1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aFranceschini, Nora1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aCOGENT-Kidney Consortium1 aEPIC-InterAct Consortium1 aUnderstanding Society Scientific Group1 aLifelines Cohort uhttps://chs-nhlbi.org/node/800510388nas a2203469 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2019 eng d00a{A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure0 amultiancestry genomewide study incorporating genesmoking interac cApr3 aElevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.1 aSung, Y., J.1 aFuentes, de, Las1 aWinkler, T., W.1 aChasman, D., I.1 aBentley, A., R.1 aKraja, A., T.1 aNtalla, I.1 aWarren, H., R.1 aGuo, X.1 aSchwander, K.1 aManning, A., K.1 aBrown, M., R.1 aAschard, H.1 aFeitosa, M., F.1 aFranceschini, N.1 aLu, Y.1 aCheng, C., Y.1 aSim, X.1 aVojinovic, D.1 aMarten, J.1 aMusani, S., K.1 aKilpel?inen, T., O.1 aRichard, M., A.1 aAslibekyan, S.1 aBartz, T., M.1 aDorajoo, R.1 aLi, C.1 aLiu, Y.1 aRankinen, T.1 aSmith, A., V.1 aTajuddin, S., M.1 aTayo, B., O.1 aZhao, W.1 aZhou, Y.1 aMatoba, N.1 aSofer, T.1 aAlver, M.1 aAmini, M.1 aBoissel, M.1 aChai, J., F.1 aChen, X.1 aDivers, J.1 aGandin, I.1 aGao, C.1 aGiulianini, F.1 aGoel, A.1 aHarris, S., E.1 aHartwig, F., P.1 aHe, M.1 aHorimoto, A., R. V. R.1 aHsu, F., C.1 aJackson, A., U.1 aKammerer, C., M.1 aKasturiratne, A.1 aKomulainen, P.1 aK?hnel, B.1 aLeander, K.1 aLee, W., J.1 aLin, K., H.1 aLuan, J.1 aLyytik?inen, L., P.1 aMcKenzie, C., A.1 aNelson, C., P.1 aNoordam, R.1 aScott, R., A.1 aSheu, W., H. H.1 aStan??kov?, A.1 aTakeuchi, F.1 avan der Most, P., J.1 aVarga, T., V.1 aWaken, R., J.1 aWang, H.1 aWang, Y.1 aWare, E., B.1 aWeiss, S.1 aWen, W.1 aYanek, L., R.1 aZhang, W.1 aZhao, J., H.1 aAfaq, S.1 aAlfred, T.1 aAmin, N.1 aArking, D., E.1 aAung, T.1 aBarr, R., G.1 aBielak, L., F.1 aBoerwinkle, E.1 aBottinger, E., P.1 aBraund, P., S.1 aBrody, J., A.1 aBroeckel, U.1 aCade, B.1 aCampbell, A.1 aCanouil, M.1 aChakravarti, A.1 aCocca, M.1 aCollins, F., S.1 aConnell, J., M.1 ade Mutsert, R.1 ade Silva, H., J.1 aD?rr, M.1 aDuan, Q.1 aEaton, C., B.1 aEhret, G.1 aEvangelou, E.1 aFaul, J., D.1 aForouhi, N., G.1 aFranco, O., H.1 aFriedlander, Y.1 aGao, H.1 aGigante, B.1 aGu, C., C.1 aGupta, P.1 aHagenaars, S., P.1 aHarris, T., B.1 aHe, J.1 aHeikkinen, S.1 aHeng, C., K.1 aHofman, A.1 aHoward, B., V.1 aHunt, S., C.1 aIrvin, M., R.1 aJia, Y.1 aKatsuya, T.1 aKaufman, J.1 aKerrison, N., D.1 aKhor, C., C.1 aKoh, W., P.1 aKoistinen, H., A.1 aKooperberg, C., B.1 aKrieger, J., E.1 aKubo, M.1 aKutalik, Z.1 aKuusisto, J.1 aLakka, T., A.1 aLangefeld, C., D.1 aLangenberg, C.1 aLauner, L., J.1 aLee, J., H.1 aLehne, B.1 aLevy, D.1 aLewis, C., E.1 aLi, Y.1 aLim, S., H.1 aLiu, C., T.1 aLiu, J.1 aLiu, J.1 aLiu, Y.1 aLoh, M.1 aLohman, K., K.1 aLouie, T.1 aM?gi, R.1 aMatsuda, K.1 aMeitinger, T.1 aMetspalu, A.1 aMilani, L.1 aMomozawa, Y.1 aMosley, T., H.1 aNalls, M., A.1 aNasri, U.1 aO'Connell, J., R.1 aOgunniyi, A.1 aPalmas, W., R.1 aPalmer, N., D.1 aPankow, J., S.1 aPedersen, N., L.1 aPeters, A.1 aPeyser, P., A.1 aPolasek, O.1 aPorteous, D.1 aRaitakari, O., T.1 aRenstr?m, F.1 aRice, T., K.1 aRidker, P., M.1 aRobino, A.1 aRobinson, J., G.1 aRose, L., M.1 aRudan, I.1 aSabanayagam, C.1 aSalako, B., L.1 aSandow, K.1 aSchmidt, C., O.1 aSchreiner, P., J.1 aScott, W., R.1 aSever, P.1 aSims, M.1 aSitlani, C., M.1 aSmith, B., H.1 aSmith, J., A.1 aSnieder, H.1 aStarr, J., M.1 aStrauch, K.1 aTang, H.1 aTaylor, K., D.1 aTeo, Y., Y.1 aTham, Y., C.1 aUitterlinden, A., G.1 aWaldenberger, M.1 aWang, L.1 aWang, Y., X.1 aWei, W., B.1 aWilson, G.1 aWojczynski, M., K.1 aXiang, Y., B.1 aYao, J.1 aYuan, J., M.1 aZonderman, A., B.1 aBecker, D., M.1 aBoehnke, M.1 aBowden, D., W.1 aChambers, J., C.1 aChen, Y., I.1 aWeir, D., R.1 ade Faire, U.1 aDeary, I., J.1 aEsko, T.1 aFarrall, M.1 aForrester, T.1 aFreedman, B., I.1 aFroguel, P.1 aGasparini, P.1 aGieger, C.1 aHorta, B., L.1 aHung, Y., J.1 aJonas, J., B.1 aKato, N.1 aKooner, J., S.1 aLaakso, M.1 aLehtim?ki, T.1 aLiang, K., W.1 aMagnusson, P., K. E.1 aOldehinkel, A., J.1 aPereira, A., C.1 aPerls, T.1 aRauramaa, R.1 aRedline, S.1 aRettig, R.1 aSamani, N., J.1 aScott, J.1 aShu, X., O.1 avan der Harst, P.1 aWagenknecht, L., E.1 aWareham, N., J.1 aWatkins, H.1 aWickremasinghe, A., R.1 aWu, T.1 aKamatani, Y.1 aLaurie, C., C.1 aBouchard, C.1 aCooper, R., S.1 aEvans, M., K.1 aGudnason, V.1 aHixson, J.1 aKardia, S., L. R.1 aKritchevsky, S., B.1 aPsaty, B., M.1 avan Dam, R., M.1 aArnett, D., K.1 aMook-Kanamori, D., O.1 aFornage, M.1 aFox, E., R.1 aHayward, C.1 avan Duijn, C., M.1 aTai, E., S.1 aWong, T., Y.1 aLoos, R., J. F.1 aReiner, A., P.1 aRotimi, C., N.1 aBierut, L., J.1 aZhu, X.1 aCupples, L., A.1 aProvince, M., A.1 aRotter, J., I.1 aFranks, P., W.1 aRice, K.1 aElliott, P.1 aCaulfield, M., J.1 aGauderman, W., J.1 aMunroe, P., B.1 aRao, D., C.1 aMorrison, A., C. uhttps://chs-nhlbi.org/node/828106391nas a2201909 4500008004100000022001400041245012500055210006900180260001600249300000900265490000700274520109900281100002101380700001901401700001701420700002301437700002001460700002801480700002201508700001801530700002101548700001901569700001901588700002001607700002201627700001401649700002301663700002301686700002101709700002001730700002301750700002001773700002601793700001801819700002401837700001801861700001701879700001601896700001701912700001501929700001701944700002901961700002001990700002402010700002502034700001402059700002102073700002102094700001702115700002502132700002002157700001402177700002102191700002802212700002502240700001902265700002602284700002102310700001702331700002002348700001802368700001702386700001902403700001902422700002502441700001802466700002402484700002102508700001602529700002402545700001502569700002002584700002402604700002202628700002202650700002002672700002102692700002102713700001802734700002002752700002202772700002102794700001502815700001702830700002002847700002302867700001802890700002002908700002202928700002102950700002102971700001902992700002003011700002003031700002103051700002303072700002003095700002503115700001903140700002103159700002103180700002203201700002503223700001903248700002303267700001603290700002403306700001703330700002403347700002203371700002003393700002803413700002303441700001903464700002603483700002403509700002103533700001703554700002303571700002103594700001803615700001603633700002203649700001903671700001903690700002203709700001903731700002703750700002403777700002603801700001703827700002103844700001503865700002103880700002103901700002203922700002403944700001903968700002103987700002804008700002004036700002604056700001904082700002004101700002004121700001804141700001604159700002504175700002004200700001804220700001704238700002104255700001804276700002404294700002404318700001804342700002404360700002004384700002204404700001904426856003604445 2019 eng d a2041-172300aMulti-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.0 aMultiancestry sleepbySNP interaction analysis in 126926 individu c2019 Nov 12 a51210 v103 aBoth short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
1 aNoordam, Raymond1 aBos, Maxime, M1 aWang, Heming1 aWinkler, Thomas, W1 aBentley, Amy, R1 aKilpeläinen, Tuomas, O1 ade Vries, Paul, S1 aSung, Yun, Ju1 aSchwander, Karen1 aCade, Brian, E1 aManning, Alisa1 aAschard, Hugues1 aBrown, Michael, R1 aChen, Han1 aFranceschini, Nora1 aMusani, Solomon, K1 aRichard, Melissa1 aVojinovic, Dina1 aAslibekyan, Stella1 aBartz, Traci, M1 aFuentes, Lisa, de Las1 aFeitosa, Mary1 aHorimoto, Andrea, R1 aIlkov, Marjan1 aKho, Minjung1 aKraja, Aldi1 aLi, Changwei1 aLim, Elise1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aRankinen, Tuomo1 aTajuddin, Salman, M1 avan der Spek, Ashley1 aWang, Zhe1 aMarten, Jonathan1 aLaville, Vincent1 aAlver, Maris1 aEvangelou, Evangelos1 aGraff, Maria, E1 aHe, Meian1 aKuhnel, Brigitte1 aLyytikäinen, Leo-Pekka1 aMarques-Vidal, Pedro1 aNolte, Ilja, M1 aPalmer, Nicholette, D1 aRauramaa, Rainer1 aShu, Xiao-Ou1 aSnieder, Harold1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aAdolfo, Correa1 aBallantyne, Christie1 aBielak, Larry1 aBiermasz, Nienke, R1 aBoerwinkle, Eric1 aDimou, Niki1 aEiriksdottir, Gudny1 aGao, Chuan1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aHaba-Rubio, José1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeinzer, Raphael1 aHixson, James, E1 aHomuth, Georg1 aIkram, Arfan, M1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aLee, Jiwon1 aLiu, Jingmin1 aLohman, Kurt, K1 aLuik, Annemarie, I1 aMägi, Reedik1 aMartin, Lisa, W1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aNalls, Mike, A1 aO'Connell, Jeff1 aPeters, Annette1 aPeyser, Patricia1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRensen, Patrick, C N1 aRice, Treva, K1 aRich, Stephen, S1 aRoenneberg, Till1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aShikany, James1 aSidney, Stephen, S1 aSims, Mario1 aSitlani, Colleen, M1 aSofer, Tamar1 aStrauch, Konstantin1 aSwertz, Morris, A1 aTaylor, Kent, D1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aWaldenberger, Melanie1 aWallance, Robert, B1 aDijk, Ko Willems1 aYu, Caizheng1 aZonderman, Alan, B1 aBecker, Diane, M1 aElliott, Paul1 aEsko, Tõnu1 aGieger, Christian1 aGrabe, Hans, J1 aLakka, Timo, A1 aLehtimäki, Terho1 aNorth, Kari, E1 aPenninx, Brenda, W J H1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aXiang, Yong-Bing1 aZheng, Wei1 aArnett, Donna, K1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLoos, Ruth, J F1 aPereira, Alexandre, C1 aProvince, Mike1 aPsaty, Bruce, M1 aRotimi, Charles1 aZhu, Xiaofeng1 aAmin, Najaf1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, F1 aGuo, Xiuqing1 aGauderman, James1 aRice, Kenneth1 aKooperberg, Charles1 aMunroe, Patricia, B1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 avan Heemst, Diana1 aRedline, Susan uhttps://chs-nhlbi.org/node/820210097nas a2203265 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2019 eng d a2041-172300aMulti-ancestry study of blood lipid levels identifies four loci interacting with physical activity.0 aMultiancestry study of blood lipid levels identifies four loci i c2019 01 22 a3760 v103 aMany genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aBrazil10aCalcium-Binding Proteins10aCholesterol10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aExercise10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHispanic Americans10aHumans10aLIM-Homeodomain Proteins10aLipid Metabolism10aLipids10aMale10aMembrane Proteins10aMicrotubule-Associated Proteins10aMiddle Aged10aMuscle Proteins10aNerve Tissue Proteins10aTranscription Factors10aTriglycerides10aYoung Adult1 aKilpeläinen, Tuomas, O1 aBentley, Amy, R1 aNoordam, Raymond1 aSung, Yun, Ju1 aSchwander, Karen1 aWinkler, Thomas, W1 aJakupović, Hermina1 aChasman, Daniel, I1 aManning, Alisa1 aNtalla, Ioanna1 aAschard, Hugues1 aBrown, Michael, R1 aFuentes, Lisa, de Las1 aFranceschini, Nora1 aGuo, Xiuqing1 aVojinovic, Dina1 aAslibekyan, Stella1 aFeitosa, Mary, F1 aKho, Minjung1 aMusani, Solomon, K1 aRichard, Melissa1 aWang, Heming1 aWang, Zhe1 aBartz, Traci, M1 aBielak, Lawrence, F1 aCampbell, Archie1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLi, Changwei1 aLohman, Kurt, K1 aMarten, Jonathan1 aSim, Xueling1 aSmith, Albert, V1 aTajuddin, Salman, M1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGraff, Mariaelisa1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aZhao, Jing Hua1 aKraja, Aldi, T1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRobino, Antonietta1 aRueedi, Rico1 aStringham, Heather, M1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVerweij, Niek1 aWare, Erin, B1 aWen, Wanqing1 aLi, Xiaoyin1 aYanek, Lisa, R1 aAmin, Najaf1 aArnett, Donna, K1 aBoerwinkle, Eric1 aBrumat, Marco1 aCade, Brian1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aConcas, Maria, Pina1 aConnell, John1 ade Mutsert, Renée1 ade Silva, Janaka1 ade Vries, Paul, S1 aDemirkan, Ayse1 aDing, Jingzhong1 aEaton, Charles, B1 aFaul, Jessica, D1 aFriedlander, Yechiel1 aGabriel, Kelley, P1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGu, Chi, Charles1 aGu, Dongfeng1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHunt, Steven, C1 aIkram, Arfan, M1 aJonas, Jost, B1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLeander, Karin1 aLemaitre, Rozenn, N1 aLewis, Cora, E1 aLiang, Jingjing1 aLiu, Jianjun1 aMägi, Reedik1 aManichaikul, Ani1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMurray, Alison, D1 aNalls, Mike, A1 aNang, Ei-Ei, Khaing1 aNelson, Christopher, P1 aNona, Sotoodehnia1 aNorris, Jill, M1 aNwuba, Chiamaka, Vivian1 aO'Connell, Jeff1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPorteous, David, J1 aPoveda, Alaitz1 aRaitakari, Olli, T1 aRich, Stephen, S1 aRisch, Neil1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchreiner, Pamela, J1 aScott, Robert, A1 aSidney, Stephen, S1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aSofer, Tamar1 aStarr, John, M1 aSternfeld, Barbara1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTsai, Michael, Y1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 avan der Ende, Yldau1 avan Heemst, Diana1 aVoortman, Trudy1 aWaldenberger, Melanie1 aWennberg, Patrik1 aWilson, Gregory1 aXiang, Yong-Bing1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aKato, Norihiro1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aShu, Xiao-Ou1 aHarst, Pim1 avan Vliet-Ostaptchouk, Jana, V1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWang, Ya, X1 aWareham, Nicholas, J1 aWeir, David, R1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aEvans, Michele, K1 aFranks, Paul, W1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aLiu, Yongmei1 aNorth, Kari, E1 aPereira, Alexandre, C1 aRidker, Paul, M1 aTai, Shyong, E1 avan Dam, Rob, M1 aFox, Ervin, R1 aKardia, Sharon, L R1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aProvince, Michael, A1 aRedline, Susan1 aDuijn, Cornelia, M1 aRotter, Jerome, I1 aKooperberg, Charles, B1 aGauderman, James1 aPsaty, Bruce, M1 aRice, Kenneth1 aMunroe, Patricia, B1 aFornage, Myriam1 aCupples, Adrienne, L1 aRotimi, Charles, N1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aLoos, Ruth, J F1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/797604450nas a2201069 4500008004100000022001400041245015100055210006900206260001300275300001200288490000700300520139200307100002101699700001901720700002301739700002301762700001601785700002001801700001901821700002101840700002501861700002301886700002101909700001801930700002201948700001701970700002701987700002202014700001702036700002102053700002002074700002002094700001502114700001402129700001702143700001602160700001702176700001702193700002102210700001702231700001302248700002002261700002102281700001902302700002302321700001402344700002102358700001902379700002302398700001802421700001802439700003202457700002702489700001702516700002202533700001602555700001902571700002302590700002102613700001902634700002102653700002202674700001802696700002002714700002202734700001702756700002002773700001702793700001902810700002102829700001902850700002002869700001902889700002402908700002302932700001802955700002202973700002102995700002103016700002503037700001903062700002303081700001803104700002403122700001803146700002203164700002203186700002003208700001803228710009803246856003603344 2019 eng d a1939-327X00aMultiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.0 aMultiethnic GenomeWide Association Study of Diabetic Retinopathy c2019 Feb a441-4560 v683 aTo identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 × 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 × 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
1 aPollack, Samuela1 aIgo, Robert, P1 aJensen, Richard, A1 aChristiansen, Mark1 aLi, Xiaohui1 aCheng, Ching-Yu1 aC Y Ng, Maggie1 aSmith, Albert, V1 aRossin, Elizabeth, J1 aSegrè, Ayellet, V1 aDavoudi, Samaneh1 aTan, Gavin, S1 aChen, Yii-Der Ida1 aKuo, Jane, Z1 aDimitrov, Latchezar, M1 aStanwyck, Lynn, K1 aMeng, Weihua1 aHosseini, Mohsen1 aImamura, Minako1 aNousome, Darryl1 aKim, Jihye1 aHai, Yang1 aJia, Yucheng1 aAhn, Jeeyun1 aLeong, Aaron1 aShah, Kaanan1 aPark, Kyu, Hyung1 aGuo, Xiuqing1 aIpp, Eli1 aTaylor, Kent, D1 aAdler, Sharon, G1 aSedor, John, R1 aFreedman, Barry, I1 aLee, I-Te1 aSheu, Wayne, H-H1 aKubo, Michiaki1 aTakahashi, Atsushi1 aHadjadj, Samy1 aMarre, Michel1 aTrégouët, David-Alexandre1 aMcKean-Cowdin, Roberta1 aVarma, Rohit1 aMcCarthy, Mark, I1 aGroop, Leif1 aAhlqvist, Emma1 aLyssenko, Valeriya1 aAgardh, Elisabet1 aMorris, Andrew1 aDoney, Alex, S F1 aColhoun, Helen, M1 aToppila, Iiro1 aSandholm, Niina1 aGroop, Per-Henrik1 aMaeda, Shiro1 aHanis, Craig, L1 aPenman, Alan1 aChen, Ching, J1 aHancock, Heather1 aMitchell, Paul1 aCraig, Jamie, E1 aChew, Emily, Y1 aPaterson, Andrew, D1 aGrassi, Michael, A1 aPalmer, Colin1 aBowden, Donald, W1 aYaspan, Brian, L1 aSiscovick, David1 aCotch, Mary, Frances1 aWang, Jie, Jin1 aBurdon, Kathryn, P1 aWong, Tien, Y1 aKlein, Barbara, E K1 aKlein, Ronald1 aRotter, Jerome, I1 aIyengar, Sudha, K1 aPrice, Alkes, L1 aSobrin, Lucia1 aFamily Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group uhttps://chs-nhlbi.org/node/799004114nas a2201297 4500008004100000245009700041210006900138260000700207300001400214490000600228520082000234100001801054700001201072700001201084700001701096700001701113700001801130700001501148700001501163700001901178700002001197700001601217700001601233700001201249700002001261700001801281700002301299700001901322700001801341700001801359700001901377700001401396700001701410700001501427700002001442700002201462700001801484700002101502700001701523700002401540700001601564700001901580700001901599700001801618700001901636700001601655700001701671700002001688700001801708700001901726700001501745700001701760700001801777700002001795700002201815700001301837700001201850700001101862700001301873700001901886700001601905700001201921700001701933700001401950700001901964700001601983700001601999700002202015700001602037700001702053700001402070700002102084700001802105700001202123700002202135700002002157700001602177700001802193700002102211700001602232700002202248700001402270700001702284700001502301700001402316700001802330700002102348700001902369700002102388700001902409700002302428700002602451700001802477700002202495700001402517700001902531700001802550700002002568700001602588700001702604700001902621700001302640700001702653700001702670700002102687700001902708700002002727700001702747700001602764856003602780 2019 eng d00a{New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders0 aNew alcoholrelated genes suggest shared genetic mechanisms with c09 a950–9610 v33 aExcessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.1 aEvangelou, E.1 aGao, H.1 aChu, C.1 aNtritsos, G.1 aBlakeley, P.1 aButts, A., R.1 aPazoki, R.1 aSuzuki, H.1 aKoskeridis, F.1 aYiorkas, A., M.1 aKaraman, I.1 aElliott, J.1 aLuo, Q.1 aAeschbacher, S.1 aBartz, T., M.1 aBaumeister, S., E.1 aBraund, P., S.1 aBrown, M., R.1 aBrody, J., A.1 aClarke, T., K.1 aDimou, N.1 aFaul, J., D.1 aHomuth, G.1 aJackson, A., U.1 aKentistou, K., A.1 aJoshi, P., K.1 aLemaitre, R., N.1 aLind, P., A.1 aLyytik?inen, L., P.1 aMangino, M.1 aMilaneschi, Y.1 aNelson, C., P.1 aNolte, I., M.1 aPer?l?, M., M.1 aPolasek, O.1 aPorteous, D.1 aRatliff, S., M.1 aSmith, J., A.1 aStan??kov?, A.1 aTeumer, A.1 aTuominen, S.1 aTh?riault, S.1 aVangipurapu, J.1 aWhitfield, J., B.1 aWood, A.1 aYao, J.1 aYu, B.1 aZhao, W.1 aArking, D., E.1 aAuvinen, J.1 aLiu, C.1 aM?nnikk?, M.1 aRisch, L.1 aRotter, J., I.1 aSnieder, H.1 aVeijola, J.1 aBlakemore, A., I.1 aBoehnke, M.1 aCampbell, H.1 aConen, D.1 aEriksson, J., G.1 aGrabe, H., J.1 aGuo, X.1 avan der Harst, P.1 aHartman, C., A.1 aHayward, C.1 aHeath, A., C.1 aJarvelin, M., R.1 aK?h?nen, M.1 aKardia, S., L. R.1 aK?hne, M.1 aKuusisto, J.1 aLaakso, M.1 aLahti, J.1 aLehtim?ki, T.1 aMcIntosh, A., M.1 aMohlke, K., L.1 aMorrison, A., C.1 aMartin, N., G.1 aOldehinkel, A., J.1 aPenninx, B., W. J. H.1 aPsaty, B., M.1 aRaitakari, O., T.1 aRudan, I.1 aSamani, N., J.1 aScott, L., J.1 aSpector, T., D.1 aVerweij, N.1 aWeir, D., R.1 aWilson, J., F.1 aLevy, D.1 aTzoulaki, I.1 aBell, J., D.1 aMatthews, P., M.1 aRothenfluh, A.1 aDesrivi?res, S.1 aSchumann, G.1 aElliott, P. uhttps://chs-nhlbi.org/node/851402786nas a2200289 4500008004100000022001400041245010600055210006900161260001600230300001200246490000600258520191000264100002202174700002202196700003002218700002402248700001902272700002002291700002302311700002202334700001902356700002202375700001702397700002302414700002302437856003602460 2019 eng d a2047-998000aNT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure.0 aNT pro BNP as a Mediator of the Racial Difference in Incident At c2019 Apr 02 ae0108680 v83 aBackground Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40% higher than blacks; 95% CI , 29-53; ARIC : 39% higher; 95% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2%; 95% CI , 23.2-69.2%; ARIC : 24.6%; 95% CI , 14.8-39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed.
1 aWhitman, Isaac, R1 aVittinghoff, Eric1 adeFilippi, Christopher, R1 aGottdiener, John, S1 aAlonso, Alvaro1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aHoogeveen, Ron, C1 aArking, Dan, E1 aSelvin, Elizabeth1 aChen, Lin, Y1 aDewland, Thomas, A1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/800803751nas a2200721 4500008004100000245010600041210006900147260000700216300001400223490000800237520184500245100001102090700001902101700001802120700001202138700002402150700001702174700001802191700001202209700001802221700002102239700002002260700001302280700002002293700002202313700002102335700001302356700001702369700001402386700001902400700001802419700001902437700001902456700002102475700002102496700002002517700001802537700001802555700001802573700001702591700001902608700001702627700001802644700001702662700001702679700002502696700002202721700001102743700001902754700001602773700002202789700001902811700001702830700001502847700001902862700001702881700001702898700001802915700002002933700002002953700002002973856003602993 2019 eng d00a{Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal DPP10-Pulmonary Function Association0 aOmega3 Fatty Acids and GenomeWide Interaction Analyses Reveal DP c03 a631–6420 v1993 aOmega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.\ To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.\ Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs.\ DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; βSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; βSNP×DHA interaction = 36.2 ml).\ We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.1 aXu, J.1 aGaddis, N., C.1 aBartz, T., M.1 aHou, R.1 aManichaikul, A., W.1 aPankratz, N.1 aSmith, A., V.1 aSun, F.1 aTerzikhan, N.1 aMarkunas, C., A.1 aPatchen, B., K.1 aSchu, M.1 aBeydoun, M., A.1 aBrusselle, G., G.1 aEiriksdottir, G.1 aZhou, X.1 aWood, A., C.1 aGraff, M.1 aHarris, T., B.1 aIkram, M., A.1 aJacobs, D., R.1 aLauner, L., J.1 aLemaitre, R., N.1 aO'Connor, G., T.1 aOelsner, E., C.1 aPsaty, B., M.1 aVasan, R., S.1 aRohde, R., R.1 aRich, S., S.1 aRotter, J., I.1 aSeshadri, S.1 aSmith, L., J.1 aTiemeier, H.1 aTsai, M., Y.1 aUitterlinden, A., G.1 aVoruganti, V., S.1 aXu, H.1 aZilh?o, N., R.1 aFornage, M.1 aZillikens, M., C.1 aLondon, S., J.1 aBarr, R., G.1 aDupuis, J.1 aGharib, S., A.1 aGudnason, V.1 aLahousse, L.1 aNorth, K., E.1 aSteffen, L., M.1 aCassano, P., A.1 aHancock, D., B. uhttps://chs-nhlbi.org/node/853203488nas a2200637 4500008004100000022001400041245010900055210006900164260000900233300001300242490000700255520161700262100002001879700002401899700002301923700002301946700002501969700002101994700002002015700002102035700001802056700001902074700001702093700001402110700001902124700001802143700002702161700001902188700002202207700002402229700002002253700001902273700002302292700002702315700002302342700002502365700001902390700002202409700003102431700001902462700002102481700001902502700002002521700002102541700002402562700002102586700003902607700001802646700002202664700002202686700002302708700002002731700001902751710004402770856003602814 2019 eng d a1932-620300aPharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.0 aPharmacogenomics of statinrelated myopathy Metaanalysis of rare c2019 ae02181150 v143 aAIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.
METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.
CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.
1 aFloyd, James, S1 aBloch, Katarzyna, M1 aBrody, Jennifer, A1 aMaroteau, Cyrielle1 aSiddiqui, Moneeza, K1 aGregory, Richard1 aCarr, Daniel, F1 aMolokhia, Mariam1 aLiu, Xiaoming1 aBis, Joshua, C1 aAhmed, Ammar1 aLiu, Xuan1 aHallberg, Pär1 aYue, Qun-Ying1 aMagnusson, Patrik, K E1 aBrisson, Diane1 aWiggins, Kerri, L1 aMorrison, Alanna, C1 aKhoury, Etienne1 aMcKeigue, Paul1 aStricker, Bruno, H1 aLapeyre-Mestre, Maryse1 aHeckbert, Susan, R1 aGallagher, Arlene, M1 aChinoy, Hector1 aGibbs, Richard, A1 aBondon-Guitton, Emmanuelle1 aTracy, Russell1 aBoerwinkle, Eric1 aGaudet, Daniel1 aConforti, Anita1 avan Staa, Tjeerd1 aSitlani, Colleen, M1 aRice, Kenneth, M1 avan der Zee, Anke-Hilse, Maitland-1 aWadelius, Mia1 aMorris, Andrew, P1 aPirmohamed, Munir1 aPalmer, Colin, A N1 aPsaty, Bruce, M1 aAlfirevic, Ana1 aPREDICTION-ADR Consortium and EUDRAGENE uhttps://chs-nhlbi.org/node/810202888nas a2200265 4500008004100000022001400041245007500055210006900130260001300199300001200212490000700224520211200231100002402343700002002367700002202387700002202409700002202431700001902453700002402472700002002496700002302516700002502539700002202564856003602586 2019 eng d a1941-329700aPlasma Ceramides and Sphingomyelins in Relation to Heart Failure Risk.0 aPlasma Ceramides and Sphingomyelins in Relation to Heart Failure c2019 Jul ae0057080 v123 aBACKGROUND: Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the ceramide (Cer). However, the associations of different circulating Cer species, and their sphingomyelin (SM) precursors, with heart failure have received limited attention.
METHODS AND RESULTS: We studied the associations of plasma Cer and SM species with incident heart failure in the Cardiovascular Health Study. We examined 8 species: Cer and SM with palmitic acid (Cer-16 and SM-16), species with arachidic acid (Cer-20 and SM-20), species with behenic acid (Cer-22 and SM-22), and species with lignoceric acid (Cer-24 and SM-24). During a median follow-up of 9.4 years, we identified 1179 cases of incident heart failure among 4249 study participants. In Cox regression analyses adjusted for risk factors, higher levels of Cer-16 and SM-16 were associated with higher risk of incident heart failure (hazard ratio for one SD increase:1.25 [95% CI, 1.16-1.36] and 1.28 [1.18-1.40], respectively). In contrast, higher levels of Cer-22 were associated with lower risk of heart failure in multivariable analyses further adjusted for Cer-16 (hazard ratio, 0.85 [0.78-0.92]); and higher levels of SM-20, SM-22 and SM-24 were associated with lower risk of heart failure in analyses further adjusted for SM-16 (hazard ratios, 0.83 [0.77-0.90], 0.81 [0.75-0.88], and 0.83 [0.77-0.90], respectively). No statistically significant interactions with age, sex, black race, body mass index, or baseline coronary heart disease were detected. Similar associations were observed for heart failure with preserved (n=529) or reduced (n=348) ejection fraction.
CONCLUSIONS: This study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005133.
1 aLemaitre, Rozenn, N1 aJensen, Paul, N1 aHoofnagle, Andrew1 aMcKnight, Barbara1 aFretts, Amanda, M1 aKing, Irena, B1 aSiscovick, David, S1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMozaffarian, Dariush1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/810502966nas a2200277 4500008004100000022001400041245012200055210006900177260001600246300001400262490000700276520213400283100001802417700001602435700002202451700001802473700001902491700002102510700002002531700001902551700001902570700002702589700001802616700001802634856003602652 2019 eng d a1529-240100aPTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease.0 aPTCD1 Is Required for Mitochondrial OxidativePhosphorylation Pos c2019 Jun 12 a4636-46560 v393 aIn addition to amyloid-β plaques and tau tangles, mitochondrial dysfunction is implicated in the pathology of Alzheimer's disease (AD). Neurons heavily rely on mitochondrial function, and deficits in brain energy metabolism are detected early in AD; however, direct human genetic evidence for mitochondrial involvement in AD pathogenesis is limited. We analyzed whole-exome sequencing data of 4549 AD cases and 3332 age-matched controls and discovered that rare protein altering variants in the gene pentatricopeptide repeat-containing protein 1 () show a trend for enrichment in cases compared with controls. We show here that PTCD1 is required for normal mitochondrial rRNA levels, proper assembly of the mitochondrial ribosome and hence for mitochondrial translation and assembly of the electron transport chain. Loss of PTCD1 function impairs oxidative phosphorylation and forces cells to rely on glycolysis for energy production. Cells expressing the AD-linked variant of PTCD1 fail to sustain energy production under increased metabolic stress. In neurons, reduced PTCD1 expression leads to lower ATP levels and impacts spontaneous synaptic activity. Thus, our study uncovers a possible link between a protein required for mitochondrial function and energy metabolism and AD risk. Mitochondria are the main source of cellular energy and mitochondrial dysfunction is implicated in the pathology of Alzheimer's disease (AD) and other neurodegenerative disorders. Here, we identify a variant in the gene that is enriched in AD patients and demonstrate that PTCD1 is required for ATP generation through oxidative phosphorylation. PTCD1 regulates the level of 16S rRNA, the backbone of the mitoribosome, and is essential for mitochondrial translation and assembly of the electron transport chain. Cells expressing the AD-associated variant fail to maintain adequate ATP production during metabolic stress, and reduced PTCD1 activity disrupts neuronal energy homeostasis and dampens spontaneous transmission. Our work provides a mechanistic link between a protein required for mitochondrial function and genetic AD risk.
1 aFleck, Daniel1 aPhu, Lilian1 aVerschueren, Erik1 aHinkle, Trent1 aReichelt, Mike1 aBhangale, Tushar1 aHaley, Benjamin1 aWang, Yuanyuan1 aGraham, Robert1 aKirkpatrick, Donald, S1 aSheng, Morgan1 aBingol, Baris uhttps://chs-nhlbi.org/node/810103955nas a2200937 4500008004100000245010700041210006900148260000700217300001000224490000800234520155000242100001501792700002101807700001701828700001901845700001801864700001101882700001601893700001801909700001801927700002101945700002001966700001601986700002102002700001802023700002502041700001202066700001602078700001502094700001302109700001302122700001902135700001302154700001802167700001602185700001402201700001902215700001902234700001502253700001702268700001602285700001902301700001902320700001902339700001602358700001502374700001902389700001902408700001802427700001802445700001402463700002102477700001902498700002002517700001802537700001702555700001402572700001502586700001802601700002202619700001702641700001302658700001902671700001102690700002002701700002002721700002402741700002102765700001702786700001502803700001602818700001602834700001502850700002002865700001502885700001802900700002402918700002002942700001902962856003602981 2019 eng d00a{Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis0 aQuality of dietary fat and genetic risk of type 2 diabetes indiv c07 al42920 v3663 a{To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.\ Individual participant data meta-analysis.\ Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators.\ Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score.\ Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.751 aMerino, J.1 aGuasch-Ferr?, M.1 aEllervik, C.1 aDashti, H., S.1 aSharp, S., J.1 aWu, P.1 aOvervad, K.1 aSarnowski, C.1 aKuokkanen, M.1 aLemaitre, R., N.1 aJustice, A., E.1 aEricson, U.1 aBraun, K., V. E.1 aMahendran, Y.1 aFrazier-Wood, A., C.1 aSun, D.1 aChu, A., Y.1 aTanaka, T.1 aLuan, J.1 aHong, J.1 aTj?nneland, A.1 aDing, M.1 aLundqvist, A.1 aMukamal, K.1 aRohde, R.1 aSchulz, C., A.1 aFranco, O., H.1 aGrarup, N.1 aChen, Y., I.1 aBazzano, L.1 aFranks, P., W.1 aBuring, J., E.1 aLangenberg, C.1 aLiu, C., T.1 aHansen, T.1 aJensen, M., K.1 aS??ksj?rvi, K.1 aPsaty, B., M.1 aYoung, K., L.1 aHindy, G.1 aSandholt, C., H.1 aRidker, P., M.1 aOrdovas, J., M.1 aMeigs, J., B.1 aPedersen, O.1 aKraft, P.1 aPerola, M.1 aNorth, K., E.1 aOrho-Melander, M.1 aVoortman, T.1 aToft, U.1 aRotter, J., I.1 aQi, L.1 aForouhi, N., G.1 aMozaffarian, D.1 aS?rensen, T., I. A.1 aStampfer, M., J.1 aM?nnist?, S.1 aSelvin, E.1 aImamura, F.1 aSalomaa, V.1 aHu, F., B.1 aWareham, N., J.1 aDupuis, J.1 aSmith, C., E.1 aKilpel?inen, T., O.1 aChasman, D., I.1 aFlorez, J., C. uhttps://chs-nhlbi.org/node/852302046nas a2200289 4500008004100000022001400041245009700055210006900152260001600221520113600237100002001373700001801393700001801411700002501429700001301454700002001467700002101487700001901508700002001527700002401547700002801571700003101599700002401630700002301654710004301677856003601720 2019 eng d a1552-527900aA rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease.0 arare missense variant of CASP7 is associated with familial lateo c2019 Jan 033 aINTRODUCTION: The genetic architecture of Alzheimer's disease (AD) is only partially understood.
METHODS: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families.
RESULTS: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10).
DISCUSSION: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.
1 aZhang, Xiaoling1 aZhu, Congcong1 aBeecham, Gary1 aVardarajan, Badri, N1 aMa, Yiyi1 aLancour, Daniel1 aFarrell, John, J1 aChung, Jaeyoon1 aMayeux, Richard1 aHaines, Jonathan, L1 aSchellenberg, Gerard, D1 aPericak-Vance, Margaret, A1 aLunetta, Kathryn, L1 aFarrer, Lindsay, A1 aAlzheimer's Disease Sequencing Project uhttps://chs-nhlbi.org/node/793209233nas a2202929 4500008004100000245015900041210006900200260000700269300001400276490000700290520204400297100001802341700001802359700001802377700001502395700001602410700002002426700002302446700002202469700001502491700001802506700001702524700001602541700001902557700002002576700001402596700002102610700002002631700002102651700001902672700001702691700002002708700001402728700002302742700001902765700002002784700001702804700001402821700001402835700001402849700001502863700001302878700001702891700001702908700001402925700001702939700001602956700001802972700001102990700001703001700001503018700001903033700001403052700001303066700002103079700001603100700001503116700001403131700001703145700001403162700001203176700001303188700001303201700001303214700001903227700001403246700001503260700001403275700001703289700001303306700001403319700001503333700001503348700001503363700001403378700002003392700001503412700001403427700001303441700001303454700001303467700001603480700001503496700001303511700001703524700001203541700001803553700001603571700001503587700001703602700001703619700001503636700001703651700001403668700001603682700001703698700001603715700001603731700001603747700001803763700001703781700002103798700001203819700001803831700001603849700001903865700002203884700002003906700001403926700002103940700001803961700001103979700001203990700001704002700001704019700001504036700001604051700001304067700001804080700001704098700001304115700001504128700001704143700001604160700001304176700001204189700001604201700001504217700002304232700002404255700002304279700002204302700001504324700001404339700001604353700001704369700001304386700001504399700001904414700001804433700001304451700001504464700001704479700001704496700001804513700002104531700001804552700001704570700001304587700001604600700001604616700001404632700001504646700001604661700001604677700001404693700001504707700001404722700001604736700001504752700001504767700001604782700001804798700002004816700001804836700001504854700001604869700001504885700001504900700001704915700001904932700002004951700002304971700001904994700001205013700002505025700001805050700001405068700001705082700001605099700001905115700001805134700001505152700002305167700001605190700002305206700001505229700002205244700001605266700001605282700001805298700002505316700001705341700001605358700001705374700001805391700001805409700001605427700002005443700001805463700001905481700002005500700001705520700002005537700001805557700002405575700001405599700001805613700001705631700001405648700001505662700001205677700001605689700001605705700001705721700001705738700001705755700001405772700001705786700001705803700001705820700001605837700001705853700002005870700002305890700002705913700001805940700001805958700002305976700001805999700001506017700002006032700001806052700001906070700001506089700001706104700001906121700001306140700001506153700001806168700001306186700001906199700001306218700001906231700001706250856003606267 2019 eng d00a{Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium0 aRelationship of Estimated GFR and Albuminuria to Concurrent Labo c02 a206–2170 v733 aChronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.\ Cross-sectional individual participant-level analyses in a global consortium.\ 17 CKD and 38 general population and high-risk cohorts.\ Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.\ Data were obtained and analyzed between July 2015 and January 2018.\ We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.\ The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).\ Variations in study era, health care delivery system, typical diet, and laboratory assays.\ Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.1 aInker, L., A.1 aGrams, M., E.1 aLevey, A., S.1 aCoresh, J.1 aCirillo, M.1 aCollins, J., F.1 aGansevoort, R., T.1 aGutierrez, O., M.1 aHamano, T.1 aHeine, G., H.1 aIshikawa, S.1 aJee, S., H.1 aKronenberg, F.1 aLandray, M., J.1 aMiura, K.1 aNadkarni, G., N.1 aPeralta, C., A.1 aRothenbacher, D.1 aSchaeffner, E.1 aSedaghat, S.1 aShlipak, M., G.1 aZhang, L.1 avan Zuilen, A., D.1 aHallan, S., I.1 aKovesdy, C., P.1 aWoodward, M.1 aLevin, A.1 aAstor, B.1 aAppel, L.1 aGreene, T.1 aChen, T.1 aChalmers, J.1 aWoodward, M.1 aArima, H.1 aPerkovic, V.1 aYatsuya, H.1 aTamakoshi, K.1 aLi, Y.1 aHirakawa, Y.1 aCoresh, J.1 aMatsushita, K.1 aGrams, M.1 aSang, Y.1 aPolkinghorne, K.1 aChadban, S.1 aAtkins, R.1 aLevin, A.1 aDjurdjev, O.1 aZhang, L.1 aLiu, L.1 aZhao, M.1 aWang, F.1 aWang, J.1 aSchaeffner, E.1 aEbert, N.1 aMartus, P.1 aLevin, A.1 aDjurdjev, O.1 aTang, M.1 aHeine, G.1 aEmrich, I.1 aSeiler, S.1 aZawada, A.1 aNally, J.1 aNavaneethan, S.1 aSchold, J.1 aZhang, L.1 aZhao, M.1 aWang, F.1 aWang, J.1 aShlipak, M.1 aSarnak, M.1 aKatz, R.1 aHiramoto, J.1 aIso, H.1 aYamagishi, K.1 aUmesawa, M.1 aMuraki, I.1 aFukagawa, M.1 aMaruyama, S.1 aHamano, T.1 aHasegawa, T.1 aFujii, N.1 aWheeler, D.1 aEmberson, J.1 aTownend, J.1 aLandray, M.1 aBrenner, H.1 aSch?ttker, B.1 aSaum, K., U.1 aRothenbacher, D.1 aFox, C.1 aHwang, S., J.1 aK?ttgen, A.1 aKronenberg, F.1 aSchneider, M., P.1 aEckardt, K., U.1 aGreen, J.1 aKirchner, H., L.1 aChang, A., R.1 aHo, K.1 aIto, S.1 aMiyazaki, M.1 aNakayama, M.1 aYamada, G.1 aCirillo, M.1 aIrie, F.1 aSairenchi, T.1 aIshikawa, S.1 aYano, Y.1 aKotani, K.1 aNakamura, T.1 aJee, S., H.1 aKimm, H.1 aMok, Y.1 aChodick, G.1 aShalev, V.1 aWetzels, J., F. M.1 aBlankestijn, P., J.1 avan Zuilen, A., D.1 avan den Brand, J.1 aSarnak, M.1 aInker, L.1 aPeralta, C.1 aHiramoto, J.1 aKatz, R.1 aSarnak, M.1 aKronenberg, F.1 aKollerits, B.1 aRitz, E.1 aNitsch, D.1 aRoderick, P.1 aFletcher, A.1 aBottinger, E.1 aNadkarni, G., N.1 aEllis, S., B.1 aNadukuru, R.1 aSang, Y.1 aUeshima, H.1 aOkayama, A.1 aMiura, K.1 aTanaka, S.1 aUeshima, H.1 aOkamura, T.1 aMiura, K.1 aTanaka, S.1 aMiura, K.1 aOkayama, A.1 aKadota, A.1 aTanaka, S.1 aKenealy, T.1 aElley, C., R.1 aCollins, J., F.1 aDrury, P., L.1 aOhkubo, T.1 aAsayama, K.1 aMetoki, H.1 aKikuya, M.1 aNakayama, M.1 aNelson, R., G.1 aKnowler, W., C.1 aGansevoort, R., T.1 aBakker, S., J.1 aHak, E.1 aHeerspink, H., J. L.1 aBrunskill, N.1 aMajor, R.1 aShepherd, D.1 aMedcalf, J.1 aJassal, S., K.1 aBergstrom, J.1 aIx, J., H.1 aBarrett-Connor, E.1 aKovesdy, C.1 aKalantar-Zadeh, K.1 aSumida, K.1 aGutierrez, O., M.1 aMuntner, P.1 aWarnock, D.1 aMcClellan, W.1 aHeerspink, H., J. L.1 ade Zeeuw, D.1 aBrenner, B.1 aSedaghat, S.1 aIkram, M., A.1 aHoorn, E., J.1 aDehghan, A.1 aCarrero, J., J.1 aGasparini, A.1 aWettermark, B.1 aElinder, C., G.1 aWong, T., Y.1 aSabanayagam, C.1 aCheng, C., Y.1 aVisseren, F., L. J.1 aEvans, M.1 aSegelmark, M.1 aStendahl, M.1 aSch?n, S.1 aTangri, N.1 aSud, M.1 aNaimark, D.1 aWen, C., P.1 aTsao, C., K.1 aTsai, M., K.1 aChen, C., H.1 aKonta, T.1 aHirayama, A.1 aIchikawa, K.1 aLannfelt, L.1 aLarsson, A.1 arnl?v, J., ?1 aBilo, H., J. G.1 aLandman, G., W. D.1 avan Hateren, K., J. J.1 aKleefstra, N.1 aChair, Coresh1 aGansevoort, R., T.1 aGrams, M., E.1 aHallan, S.1 aKovesdy, C., P.1 aLevey, A., S.1 aMatsushita, K.1 aShalev, V.1 aWoodward, M.1 aBallew, S., H.1 aChen, J.1 aCoresh, J.1 aGrams, M., E.1 aKwak, L.1 aMatsushita, K.1 aSang, Y.1 aSurapaneni, A.1 aWoodward, M. uhttps://chs-nhlbi.org/node/851902440nas a2200193 4500008004100000022001400041245013300055210006900188260001600257520178400273100002302057700002302080700002802103700001602131700002002147700002002167700002302187856003602210 2019 eng d a1473-559800aThe role of functional status on the relationship between blood pressure and cognitive decline: the Cardiovascular Health Study.0 arole of functional status on the relationship between blood pres c2019 May 013 aOBJECTIVE: To examine whether self-reported functional status modified the association between blood pressure (BP) and cognitive decline among older adults.
METHODS: The study included 2097 US adults aged 75 years and older from the Cardiovascular Health Study, followed for up to 6 years. Functional status was ascertained by self-reported limitation in activities of daily living (ADL; none vs. any). Cognitive function was assessed by the Modified Mini Mental State Exam (3MSE). We used linear mixed models to examine whether the presence of at least one ADL limitation modified the association between BP and cognitive decline. Potential confounders included demographics, physiologic measures, antihypertensive medication use and apolipoprotein E ε4 allele. We conducted stratified analyses for significant interactions between BP and ADL.
RESULTS: The association between BP and change in 3MSE differed by baseline ADL limitation. Among participants without ADL limitation, elevated systolic BP (≥140 mmHg) was associated with a 0.15 decrease (95% CI -0.24 to -0.07); P value for interaction less than 0.001, whereas in those with an ADL limitation, elevated systolic BP was independently associated with a 0.30 increase in 3MSE scores per year (95% CI 0.06-0.55). Elevated diastolic BP (≥80 mmHg) was associated with an increase in cognitive function in both groups, although the increase was greater in those with ADL limitation (0.47 points per year vs. 0.18 points per year, P value for interaction = 0.01).
CONCLUSION: Elevated BP appears to be associated with a decrease in cognitive scores among functioning older adults, and modest improvements in cognitive function among poorly functioning elders.
1 aMiller, Lindsay, M1 aPeralta, Carmen, A1 aFitzpatrick, Annette, L1 aWu, Chenkai1 aPsaty, Bruce, M1 aNewman, Anne, B1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/804803253nas a2200637 4500008004100000022001400041245013600055210006900191260001600260300001400276490000800290520140100298100002001699700001901719700001701738700001701755700001501772700001701787700002401804700001601828700001401844700002401858700002101882700001701903700002001920700001701940700002201957700002201979700002202001700002802023700002002051700002002071700001902091700002102110700001802131700002002149700001802169700002302187700002102210700001602231700001702247700002002264700002702284700002002311700002102331700002402352700001702376700002102393700002202414700002102436700001902457700001802476710005402494710003102548856003602579 2019 eng d a1537-660500aSequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.0 aSequencing Analysis at 8p23 Identifies Multiple Rare Variants in c2019 Nov 07 a1057-10680 v1053 aAverage arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.
1 aLiang, Jingjing1 aCade, Brian, E1 aHe, Karen, Y1 aWang, Heming1 aLee, Jiwon1 aSofer, Tamar1 aWilliams, Stephanie1 aLi, Ruitong1 aChen, Han1 aGottlieb, Daniel, J1 aEvans, Daniel, S1 aGuo, Xiuqing1 aGharib, Sina, A1 aHale, Lauren1 aHillman, David, R1 aLutsey, Pamela, L1 aMukherjee, Sutapa1 aOchs-Balcom, Heather, M1 aPalmer, Lyle, J1 aRhodes, Jessica1 aPurcell, Shaun1 aPatel, Sanjay, R1 aSaxena, Richa1 aStone, Katie, L1 aTang, Weihong1 aTranah, Gregory, J1 aBoerwinkle, Eric1 aLin, Xihong1 aLiu, Yongmei1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aCho, Michael, H1 aManichaikul, Ani1 aSilverman, Edwin, K1 aBarr, Graham1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aRedline, Susan1 aZhu, Xiaofeng1 aNHLBI Trans-Omics for Precision Medicine (TOPMed)1 aTOPMed Sleep Working Group uhttps://chs-nhlbi.org/node/819902863nas a2200265 4500008004100000022001400041245018900055210006900244260001600313300001200329490000600341520197900347100002002326700002902346700001502375700001802390700001902408700001902427700002002446700002402466700002202490700002402512700002502536856003602561 2019 eng d a2047-998000aSerial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study.0 aSerial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesi c2019 Nov 19 ae0128810 v83 aBackground Synthesized fatty acids (FAs) from de novo lipogenesis may affect cardiometabolic health, but longitudinal associations between serially measured de novo lipogenesis-related fatty acid biomarkers and mortality or cardiovascular disease (CVD) are not well established. Methods and Results We investigated longitudinal associations between de novo lipogenesis-related fatty acids with all-cause mortality, cause-specific mortality, and incident CVD among 3869 older US adults, mean (SD) age 75 (5) years and free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), oleic acid (18:1n-9), and other risk factors were serially measured at baseline, 6 years, and 13 years. All-cause mortality, cause-specific mortality, and incident fatal and nonfatal CVD were centrally adjudicated. Risk was assessed in multivariable-adjusted Cox models with time-varying FAs and covariates. During 13 years, median follow-up (maximum 22.4 years), participants experienced 3227 deaths (1131 CVD, 2096 non-CVD) and 1753 incident CVD events. After multivariable adjustment, higher cumulative levels of 16:0, 16:1n-7, and 18:1n-9 were associated with higher all-cause mortality, with extreme-quintile hazard ratios (95% CIs) of 1.35 (1.17-1.56), 1.40 (1.21-1.62), and 1.56 (1.35-1.80), respectively, whereas higher levels of 18:0 were associated with lower mortality (hazard ratio=0.76; 95% CI=0.66-0.88). Associations were generally similar for CVD mortality versus non-CVD mortality, as well as total incident CVD. Changes in levels of 16:0 were positively, and 18:0 inversely, associated with all-cause mortality (hazard ratio=1.23, 95% CI=1.08-1.41; and hazard ratio=0.78, 95% CI=0.68-0.90). Conclusions Higher long-term levels of 16:0, 16:1n-7, and 18:1n-9 and changes in 16:0 were positively, whereas long-term levels and changes in 18:0 were inversely, associated with all-cause mortality in older adults.
1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aLee, Yujin1 aH Y Wu, Jason1 aSong, Xiaoling1 aKing, Irena, B1 aPsaty, Bruce, M1 aLemaitre, Rozenn, N1 aMcKnight, Barbara1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/827502408nas a2200361 4500008004100000022001400041245012300055210006900178260001600247520131200263100002201575700002001597700001701617700002201634700001801656700001801674700002301692700002301715700002501738700001601763700001701779700002301796700002501819700002201844700002201866700002001888700002201908700002201930700001901952700001901971710002001990856003602010 2019 eng d a1473-115000aStatin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study.0 aStatininduced LDL cholesterol response and type 2 diabetes a bid c2019 Dec 053 aIt remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, n = 40,914) and DIAGRAM (n = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (r = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.
1 aSmit, Roelof, A J1 aTrompet, Stella1 aLeong, Aaron1 aGoodarzi, Mark, O1 aPostmus, Iris1 aWarren, Helen1 aTheusch, Elizabeth1 aBarnes, Michael, R1 aArsenault, Benoit, J1 aLi, Xiaohui1 aFeng, QiPing1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aHitman, Graham, A1 aKrauss, Ronald, M1 aPsaty, Bruce, M1 aRotter, Jerome, I1 ale Cessie, Saskia1 aStein, Michael1 aJukema, Wouter1 aGIST consortium uhttps://chs-nhlbi.org/node/829202919nas a2200421 4500008004100000022001400041245010800055210006900163260001500232300000700247490000700254520170100261653003801962653001802000653001102018653001302029100002202042700002202064700002302086700002202109700002102131700002002152700002102172700002202193700001702215700002902232700001602261700001702277700001602294700001902310700002702329700002302356700001802379700002102397700002402418700001902442856003602461 2019 eng d a1474-760X00aSystematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight.0 aSystematic analysis of dark and camouflaged genes reveals diseas c2019 05 20 a970 v203 aBACKGROUND: The human genome contains "dark" gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions.
RESULTS: Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer's Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer's disease gene, found in disease cases but not in controls.
CONCLUSIONS: While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer's disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.
10aGenetic Predisposition to Disease10aGenome, Human10aHumans10aMutation1 aEbbert, Mark, T W1 aJensen, Tanner, D1 aJansen-West, Karen1 aSens, Jonathon, P1 aReddy, Joseph, S1 aRidge, Perry, G1 aKauwe, John, S K1 aBelzil, Veronique1 aPregent, Luc1 aCarrasquillo, Minerva, M1 aKeene, Dirk1 aLarson, Eric1 aCrane, Paul1 aAsmann, Yan, W1 aErtekin-Taner, Nilufer1 aYounkin, Steven, G1 aRoss, Owen, A1 aRademakers, Rosa1 aPetrucelli, Leonard1 aFryer, John, D uhttps://chs-nhlbi.org/node/810009183nas a2202869 4500008004100000022001400041245010300055210006900158260001300227300001400240490000700254520118100261100001801442700002101460700003201481700001301513700002101526700002001547700002301567700002001590700002001610700001201630700001601642700002701658700001201685700001901697700002101716700002201737700001601759700001901775700001601794700002001810700002401830700001901854700002701873700001701900700001401917700002701931700002001958700001601978700001601994700001902010700002502029700001802054700002202072700001902094700001902113700001902132700002102151700002402172700002302196700001802219700002102237700001802258700002102276700002002297700002302317700002002340700002202360700001902382700002402401700001802425700001802443700001802461700002702479700002402506700002602530700002302556700002402579700002202603700001902625700002102644700002202665700002102687700001702708700002202725700002202747700002302769700002102792700002602813700002202839700002102861700002002882700002102902700002802923700002402951700001902975700001702994700002203011700002203033700002103055700001703076700001603093700001503109700002603124700002003150700002003170700002203190700002003212700002603232700002503258700001903283700002003302700002703322700001803349700002003367700002303387700002003410700001903430700001903449700002203468700002103490700002203511700001903533700001803552700002503570700002403595700001903619700002103638700002303659700002103682700002003703700002203723700001303745700002103758700002003779700002803799700001803827700002003845700002403865700002003889700002403909700002003933700002303953700002203976700002103998700002104019700003004040700002004070700002104090700002504111700002104136700001804157700002504175700002904200700003004229700002404259700001904283700002004302700001704322700001704339700001904356700002104375700002604396700002304422700002504445700002704470700001804497700002004515700001904535700002004554700002004574700001904594700001704613700002304630700001904653700002304672700002104695700002304716700002304739700001904762700002404781700002104805700002004826700002304846700001604869700002604885700002004911700001704931700002204948700002204970700001804992700001705010700002005027700002205047700002605069700002105095700002005116700002805136700002405164700002205188700001905210700002405229700001805253700002005271700002105291700002805312700002105340700001805361700002205379700002805401700002205429700001505451700002305466700001805489700001705507700002405524700002005548700002605568700002305594700001905617700002105636700001605657700001805673700002305691700002105714700002105735700002605756700001405782700001805796700002605814700002005840700002305860700002005883700002505903700002005928700002105948700002105969700002105990700001906011700001806030700002106048700002206069700002206091700002206113700002206135700001906157710004006176710002706216710003406243856003606277 2019 eng d a1546-171800aTarget genes, variants, tissues and transcriptional pathways influencing human serum urate levels.0 aTarget genes variants tissues and transcriptional pathways influ c2019 Oct a1459-14740 v513 aElevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
1 aTin, Adrienne1 aMarten, Jonathan1 aKuhns, Victoria, L Halperin1 aLi, Yong1 aWuttke, Matthias1 aKirsten, Holger1 aSieber, Karsten, B1 aQiu, Chengxiang1 aGorski, Mathias1 aYu, Zhi1 aGiri, Ayush1 aSveinbjornsson, Gardar1 aLi, Man1 aChu, Audrey, Y1 aHoppmann, Anselm1 aO'Connor, Luke, J1 aPrins, Bram1 aNutile, Teresa1 aNoce, Damia1 aAkiyama, Masato1 aCocca, Massimiliano1 aGhasemi, Sahar1 avan der Most, Peter, J1 aHorn, Katrin1 aXu, Yizhe1 aFuchsberger, Christian1 aSedaghat, Sanaz1 aAfaq, Saima1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrumat, Marco1 aBurkhardt, Ralph1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aCiullo, Marina1 aConcas, Maria, Pina1 aCoresh, Josef1 aCorre, Tanguy1 aCusi, Daniele1 aFelicita, Sala, Cinzia1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDelgado, Graciela1 aDemirkan, Ayse1 aDevuyst, Olivier1 aDittrich, Katalin1 aEckardt, Kai-Uwe1 aEhret, Georg1 aEndlich, Karlhans1 aEvans, Michele, K1 aGansevoort, Ron, T1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHayward, Caroline1 aHicks, Andrew, A1 aHofer, Edith1 aHolm, Hilma1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aLewis, Raychel, M1 aIngelsson, Erik1 aJakobsdottir, Johanna1 aJonsdottir, Ingileif1 aJonsson, Helgi1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerr, Shona, M1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKörner, Antje1 aKovacs, Peter1 aKrämer, Bernhard, K1 aKronenberg, Florian1 aKubo, Michiaki1 aKuhnel, Brigitte1 aLa Bianca, Martina1 aLange, Leslie, A1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiu, Jun1 aLoeffler, Markus1 aLoos, Ruth, J F1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMahajan, Anubha1 aMartin, Nicholas, G1 aMärz, Winfried1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMeisinger, Christa1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aO'Donnell, Christopher, J1 aWilson, Otis, D1 aGaziano, Michael1 aMishra, Pashupati, P1 aMohlke, Karen, L1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMüller-Nurasyid, Martina1 aNadkarni, Girish, N1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey, R1 aOlafsson, Isleifur1 aPadmanabhan, Sandosh1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPeters, Annette1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPreuss, Michael, H1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRizzi, Federica1 aRobino, Antonietta1 aRudan, Igor1 aKrajcoviechova, Alena1 aCifkova, Renata1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSalvi, Erika1 aSchmidt, Helena1 aSchmidt, Reinhold1 aShaffer, Christian, M1 aSmith, Albert, V1 aSmith, Blair, H1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStumvoll, Michael1 aSulem, Patrick1 aTajuddin, Salman, M1 aTeren, Andrej1 aThiery, Joachim1 aThio, Chris, H L1 aThorsteinsdottir, Unnur1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aUitterlinden, André, G1 aVaccargiu, Simona1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aYang, Qiong1 aZhang, Weihua1 aZonderman, Alan, B1 aBochud, Murielle1 aWilson, James, G1 aPendergrass, Sarah, A1 aHo, Kevin1 aParsa, Afshin1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aBöger, Carsten, A1 aSnieder, Harold1 aButterworth, Adam, S1 aOkada, Yukinori1 aEdwards, Todd, L1 aStefansson, Kari1 aSusztak, Katalin1 aScholz, Markus1 aHeid, Iris, M1 aHung, Adriana, M1 aTeumer, Alexander1 aPattaro, Cristian1 aWoodward, Owen, M1 aVitart, Veronique1 aKöttgen, Anna1 aGerman Chronic Kidney Disease Study1 aLifeLines Cohort Study1 aV. A. Million Veteran Program uhttps://chs-nhlbi.org/node/820704711nas a2201357 4500008004100000022001400041245009500055210006900150260001300219300001000232490000700242520077200249100001601021700002501037700002101062700001701083700002001100700002101120700002401141700002201165700001601187700002001203700003001223700002701253700002201280700002301302700002301325700002101348700001801369700001501387700001301402700002501415700002401440700002001464700002101484700002001505700001901525700003301544700002301577700002101600700002001621700001801641700001901659700002101678700002701699700001501726700002701741700001901768700002001787700001801807700002301825700002101848700001901869700002101888700002301909700001901932700002401951700002101975700001601996700002102012700002302033700001602056700002202072700002002094700002102114700001902135700002402154700001702178700002102195700002402216700002502240700001702265700003002282700001602312700002302328700002002351700001902371700003202390700002302422700002102445700002402466700002202490700002002512700002702532700002302559700002502582700001602607700002102623700001502644700002402659700002002683700002202703700002302725700002202748700002102770700002002791700002402811700002402835700002902859700002302888700001802911700002102929700001802950700002302968700002002991700002803011700002103039700003003060700002103090700002103111710004303132710004803175710006603223710002803289856003603317 2019 eng d a1546-171800aTrans-ethnic association study of blood pressure determinants in over 750,000 individuals.0 aTransethnic association study of blood pressure determinants in c2019 Jan a51-620 v513 aIn this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
1 aGiri, Ayush1 aHellwege, Jacklyn, N1 aKeaton, Jacob, M1 aPark, Jihwan1 aQiu, Chengxiang1 aWarren, Helen, R1 aTorstenson, Eric, S1 aKovesdy, Csaba, P1 aSun, Yan, V1 aWilson, Otis, D1 aRobinson-Cohen, Cassianne1 aRoumie, Christianne, L1 aChung, Cecilia, P1 aBirdwell, Kelly, A1 aDamrauer, Scott, M1 aDuVall, Scott, L1 aKlarin, Derek1 aCho, Kelly1 aWang, Yu1 aEvangelou, Evangelos1 aCabrera, Claudia, P1 aWain, Louise, V1 aShrestha, Rojesh1 aMautz, Brian, S1 aAkwo, Elvis, A1 aSargurupremraj, Muralidharan1 aDebette, Stephanie1 aBoehnke, Michael1 aScott, Laura, J1 aLuan, Jian'an1 aZhao, Jing-Hua1 aWillems, Sara, M1 aThériault, Sébastien1 aShah, Nabi1 aOldmeadow, Christopher1 aAlmgren, Peter1 aLi-Gao, Ruifang1 aVerweij, Niek1 aBoutin, Thibaud, S1 aMangino, Massimo1 aNtalla, Ioanna1 aFeofanova, Elena1 aSurendran, Praveen1 aCook, James, P1 aKarthikeyan, Savita1 aLahrouchi, Najim1 aLiu, Chunyu1 aSepúlveda, Nuno1 aRichardson, Tom, G1 aKraja, Aldi1 aAmouyel, Philippe1 aFarrall, Martin1 aPoulter, Neil, R1 aLaakso, Markku1 aZeggini, Eleftheria1 aSever, Peter1 aScott, Robert, A1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aConen, David1 aPalmer, Colin, Neil Alexa1 aAttia, John1 aChasman, Daniel, I1 aRidker, Paul, M1 aMelander, Olle1 aMook-Kanamori, Dennis, Owen1 avan der Harst, Pim1 aCucca, Francesco1 aSchlessinger, David1 aHayward, Caroline1 aSpector, Tim, D1 aJarvelin, Marjo-Riitta1 aHennig, Branwen, J1 aTimpson, Nicholas, J1 aWei, Wei-Qi1 aSmith, Joshua, C1 aXu, Yaomin1 aMatheny, Michael, E1 aSiew, Edward, E1 aLindgren, Cecilia1 aHerzig, Karl-Heinz1 aDedoussis, George1 aDenny, Joshua, C1 aPsaty, Bruce, M1 aHowson, Joanna, M M1 aMunroe, Patricia, B1 aNewton-Cheh, Christopher1 aCaulfield, Mark, J1 aElliott, Paul1 aGaziano, Michael1 aConcato, John1 aWilson, Peter, W F1 aTsao, Philip, S1 aEdwards, Digna, R Velez1 aSusztak, Katalin1 aO'Donnell, Christopher, J1 aHung, Adriana, M1 aEdwards, Todd, L1 aUnderstanding Society Scientific Group1 aInternational Consortium for Blood Pressure1 aBlood Pressure-International Consortium of Exome Chip Studies1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/791402323nas a2200217 4500008004100000022001400041245013100055210006900186260001600255520161200271100002201883700001601905700001701921700001901938700002201957700002001979700003001999700002002029700002002049856003602069 2019 eng d a1941-722500aTrends in Blood Pressure and High-Sensitivity Cardiac Troponin-T with Cardiovascular Disease: The Cardiovascular Health Study.0 aTrends in Blood Pressure and HighSensitivity Cardiac TroponinT w c2019 Jun 213 aBACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) is individually associated with incident hypertension (HTN) and cardiovascular disease (CVD) events. We hypothesize that the increases in hs-cTnT with increases in blood pressure will be related to higher incidence of CVD.
METHODS: The Cardiovascular Health Study is a longitudinal cohort of older adults. Those with hs-cTnT data and CVD risk factors at baseline and follow-up (2-3 years later) were stratified based on systolic blood pressure (SBP) (optimal: <120 mmHg, intermediate: 120-139 mmHg, elevated: ≥140 mmHg) and hs-cTnT (undetectable: <5 ng/L, detectable: 5-13 ng/L, elevated: ≥14 ng/L) categories. SBP and hs-cTnT were classified as increased or decreased if they changed categories between exams, and stable if they did not. Cox regression evaluated incident CVD events over an average 9 year follow-up.
RESULTS: Among 2219 adults, 510 (23.0 %) had decreased hs-cTnT, 1,279 (57.6 %) had stable hs-cTnT, and 430 (19.4 %) had increased hs-cTnT. Those with increased hs-cTnT had a higher CVD risk with stable SBP (HR: 1.28 [1.04-1.57], p=0.02) or decreased SBP (HR: 1.57 [1.08-2.28], p=0.02) compared to those within the same SBP group but a stable hs-cTnT. In those with lower SBP at follow-up, there was an inverse relation between DBP and risk of CVD events in those with increased hs-cTnT (HR: 0.44 per 10 mmHg increase, p<0.01).
CONCLUSION: An increase in hs-cTnT over time is associated with a higher risk of CVD even when the blood pressure is stable or decreases over time.
1 aTehrani, David, M1 aFan, Wenjun1 aNambi, Vijay1 aGardin, Julius1 aHirsch, Calvin, H1 aAmsterdam, Ezra1 adeFilippi, Christopher, R1 aPolonsky, Tamar1 aWong, Nathan, D uhttps://chs-nhlbi.org/node/810802405nas a2200229 4500008004100000022001400041245010300055210006900158260001500227300001400242490000700256520169400263100002901957700002201986700001602008700002202024700002102046700002902067700002302096700002002119856003602139 2019 eng d a1464-368500aUse of a pooled cohort to impute cardiovascular disease risk factors across the adult life course.0 aUse of a pooled cohort to impute cardiovascular disease risk fac c2019 06 01 a1004-10130 v483 aBACKGROUND: In designing prevention strategies, it may be useful to understand how early and midlife cardiovascular disease risk factor (CVDRF) exposures affect outcomes that primarily occur in mid to late life. Few single US cohorts have followed participants from early adulthood to late life.
METHODS: We pooled four prospective cohorts that represent segments of the adult life course, and studied 15 001 White and Black adults aged 18 to 95 years at enrollment. We imputed early and midlife exposure to body mass index (BMI), glucose, lipids and blood pressure (BP). CVDRF trajectories were estimated using linear mixed models. Using the best linear unbiased predictions, we obtained person-specific estimates of CVDRF trajectories beginning at age 20 until each participant's end of follow-up. We then calculated for each CVDRF, summary measures of early and midlife exposure as time-weighted averages (TWAs).
RESULTS: In the pooled cohort, 33.7% were Black and 54.8% were female. CVDRF summary measures worsened in midlife compared with early life and varied by sex and race. In particular, systolic and diastolic BP were consistently higher over the adult life course among men, and BMI was higher among Blacks, particularly Black women. Simulation studies suggested acceptable imputation accuracy, especially for the younger cohorts. Correlations of true and imputed CVDRF summary measures ranged from 0.53 to 0.99, and agreement ranged from 67% to 99%.
CONCLUSIONS: These results suggest that imputed CVDRFs may be accurate enough to be useful in assessing the effects of early and midlife exposures on later life outcomes.
1 aHazzouri, Adina, Zeki Al1 aVittinghoff, Eric1 aZhang, Yiyi1 aPletcher, Mark, J1 aMoran, Andrew, E1 aBibbins-Domingo, Kirsten1 aGolden, Sherita, H1 aYaffe, Kristine uhttps://chs-nhlbi.org/node/820802509nas a2200313 4500008004100000245018300041210006900224260000700293300001000300490000600310520156400316100001401880700001401894700001301908700001801921700001901939700002001958700001201978700002001990700001702010700002102027700001502048700001902063700001802082700001902100700002102119700001902140856003602159 2019 eng d00a{Variants Associated with the Ankle Brachial Index Differ by Hispanic/Latino Ethnic Group: a genome-wide association study in the Hispanic Community Health Study/Study of Latinos0 aVariants Associated with the Ankle Brachial Index Differ by Hisp c08 a114100 v93 aLower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10-5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10-7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10-4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.1 aSofer, T.1 aEmery, L.1 aJain, D.1 aEllis, A., M.1 aLaurie, C., C.1 aAllison, M., A.1 aLee, J.1 aKurniansyah, N.1 aKerr, K., F.1 aGonz?lez, H., M.1 aTarraf, W.1 aCriqui, M., H.1 aLange, L., A.1 aPalmas, W., R.1 aFranceschini, N.1 aWassel, C., L. uhttps://chs-nhlbi.org/node/852903270nas a2200601 4500008004100000022001400041245015200055210006900207260001500276300000900291490000700300520149000307653003001797653004301827653000901870653002201879653002201901653001201923653001901935653001101954653003401965653001301999653001102012653000902023653002602032653001202058653002802070653002602098653003602124653002702160100002202187700002002209700002502229700002502254700001902279700001602298700002402314700002002338700001902358700001902377700002002396700002002416700002202436700002202458700002302480700002202503700002202525700002202547700002402569700001802593700002102611856003602632 2020 eng d a1554-657800aAlzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene.0 aAlzheimer Disease PathologyAssociated Polymorphism in a Complex c2020 01 01 a3-210 v793 aWe found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.
10aAdaptor Protein Complex 210aAdaptor Protein Complex alpha Subunits10aAged10aAged, 80 and over10aAlzheimer Disease10aAutopsy10aCohort Studies10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMinisatellite Repeats10aMucin-610aNeurofibrillary Tangles10aPolymorphism, Genetic10aPolymorphism, Single Nucleotide10aTDP-43 Proteinopathies1 aKatsumata, Yuriko1 aFardo, David, W1 aBachstetter, Adam, D1 aArtiushin, Sergey, C1 aWang, Wang-Xia1 aWei, Angela1 aBrzezinski, Lena, J1 aNelson, Bela, G1 aHuang, Qingwei1 aAbner, Erin, L1 aAnderson, Sonya1 aPatel, Indumati1 aShaw, Benjamin, C1 aPrice, Douglas, A1 aNiedowicz, Dana, M1 aWilcock, Donna, W1 aJicha, Gregory, A1 aNeltner, Janna, H1 aVan Eldik, Linda, J1 aEstus, Steven1 aNelson, Peter, T uhttps://chs-nhlbi.org/node/839602443nas a2200337 4500008004100000022001400041245008600055210006900141260001500210300001400225490000700239520146500246100002101711700002401732700002101756700002101777700002101798700002601819700002201845700002201867700002501889700002001914700002001934700002201954700001701976700002001993700001702013700002002030700001902050856003602069 2020 eng d a1526-632X00aAssociation of CD14 with incident dementia and markers of brain aging and injury.0 aAssociation of CD14 with incident dementia and markers of brain c2020 01 21 ae254-e2660 v943 aOBJECTIVE: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts.
METHODS: Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS.
RESULTS: We studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03-1.23; = 0.01) following adjustments for age, sex, ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS.
CONCLUSION: sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.
1 aPase, Matthew, P1 aHimali, Jayandra, J1 aBeiser, Alexa, S1 aDeCarli, Charles1 aMcGrath, Emer, R1 aSatizabal, Claudia, L1 aAparicio, Hugo, J1 aAdams, Hieab, H H1 aReiner, Alexander, P1 aLongstreth, W T1 aFornage, Myriam1 aTracy, Russell, P1 aLopez, Oscar1 aPsaty, Bruce, M1 aLevy, Daniel1 aSeshadri, Sudha1 aBis, Joshua, C uhttps://chs-nhlbi.org/node/828702552nas a2200229 4500008004100000022001400041245012500055210006900180260001300249300001200262490000700274520184000281100001802121700002602139700001702165700002302182700001802205700002102223700002102244700002102265856003602286 2020 eng d a1538-783600aBurden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study.0 aBurden of rare exome sequence variants in PROC gene is associate c2020 Feb a445-4530 v183 aBACKGROUND: Rare coding mutations underlying deficiencies of antithrombin and proteins C and S contribute to familial venous thromboembolism (VTE). It is uncertain whether rare variants play a role in the etiology of VTE in the general population.
OBJECTIVES: We conducted a deep whole-exome sequencing (WES) study to investigate the associations between rare coding variants and the risk of VTE in two population-based prospective cohorts.
PATIENTS/METHODS: Whole-exome sequencing was performed in the Longitudinal Investigation of Thromboembolism Etiology (LITE), which combines the Atherosclerosis Risk in Communities (ARIC) study (316 incident VTE events among 3159 African Americans [AAs] and 458 incident VTEs among 7772 European Americans [EAs]) and the Cardiovascular Healthy Study (CHS; 60 incident VTEs among 1751 EAs). We performed gene-based tests of rare variants (allele frequency < 1%, exome-wide significance P < 1.47 × 10 ) separately in each study and ancestry group, and meta-analyzed the results for the EAs in ARIC and CHS.
RESULTS: In the meta-analysis of EAs, we identified one gene, PROC, in which the burden of rare, coding variants was significantly associated with increased risk of VTE (HR = 5.42 [3.11, 9.42] for carriers versus non-carriers, P = 2.27 × 10 ). In ARIC EAs, carriers of the PROC rare variants had on average 0.75 standard deviation (SD) lower concentrations of plasma protein C and 0.28 SD higher D-dimer (P < .05) than non-carriers. Adjustment for low protein C status did not eliminate the association of PROC burden with VTE. In AAs, rare coding PROC variants were not associated with VTE.
CONCLUSIONS: Rare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample.
1 aTang, Weihong1 aStimson, Mary, Rachel1 aBasu, Saonli1 aHeckbert, Susan, R1 aCushman, Mary1 aPankow, James, S1 aFolsom, Aaron, R1 aPankratz, Nathan uhttps://chs-nhlbi.org/node/829009265nas a2203229 4500008004100000245008500041210006900126260000700195300000900202490000700211520115200218100002301370700001501393700001301408700001801421700001801439700001601457700002101473700001501494700001801509700001401527700001301541700002201554700001401576700001801590700002201608700001801630700002601648700002201674700001601696700001501712700001301727700002201740700001601762700001401778700001701792700001301809700001801822700001901840700002201859700001801881700002101899700001801920700001801938700002901956700002201985700001902007700001702026700001302043700002002056700001502076700001702091700002102108700001802129700002002147700002202167700001802189700001902207700001902226700002002245700001602265700001602281700001802297700002102315700001702336700002002353700001602373700001902389700001502408700001902423700001502442700001902457700001502476700002302491700001802514700001502532700001902547700001302566700001502579700001602594700001702610700001402627700001802641700002202659700001602681700001402697700001502711700001402726700001702740700001602757700001502773700001702788700001602805700001802821700002002839700002102859700001902880700002002899700001602919700001902935700001802954700002102972700001802993700001203011700001603023700002103039700001903060700002103079700002203100700001403122700001603136700002003152700002003172700001903192700001803211700001603229700002203245700001703267700002303284700001903307700001603326700001703342700001603359700001803375700002103393700001603414700001603430700001603446700001903462700001303481700001303494700001803507700002003525700002203545700001903567700001603586700001603602700001303618700002703631700001603658700001403674700001403688700001803702700001703720700002003737700001803757700002003775700001903795700001703814700002203831700001303853700001703866700001503883700001803898700001503916700001303931700001903944700002103963700001603984700002504000700002504025700001704050700002004067700001604087700001604103700002104119700001404140700001304154700001704167700001704184700002004201700001404221700002104235700001404256700001604270700001604286700001704302700002104319700001604340700002304356700001204379700001904391700001704410700001804427700001404445700001704459700001404476700002104490700001804511700001804529700001704547700001804564700001904582700001604601700001904617700002604636700001904662700001704681700002104698700002604719700001704745700001404762700001704776700002004793700001404813700001804827700002204845700001904867700002304886700001404909700001304923700001304936700001304949700001904962700001404981700001904995700001505014700001405029700002105043700001605064700001505080700001505095700001405110700002205124700001805146700001805164700002105182700001605203700001705219700001605236700002505252700001505277700002205292700001605314700002105330700001705351700002005368700001705388700001705405700001505422700001405437700002205451700002505473700002105498700001405519700001505533700001905548700001805567700001805585700001605603700002105619700001705640700001605657700002105673700002005694700001805714700001705732700001605749700003805765700001805803700002005821700001705841700001905858700001705877700001705894700001805911700001505929700002005944700001905964700001605983856003605999 2020 eng d00a{Cerebral small vessel disease genomics and its implications across the lifespan0 aCerebral small vessel disease genomics and its implications acro c12 a62850 v113 aWhite matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.1 aSargurupremraj, M.1 aSuzuki, H.1 aJian, X.1 aSarnowski, C.1 aEvans, T., E.1 aBis, J., C.1 aEiriksdottir, G.1 aSakaue, S.1 aTerzikhan, N.1 aHabes, M.1 aZhao, W.1 aArmstrong, N., J.1 aHofer, E.1 aYanek, L., R.1 aHagenaars, S., P.1 aKumar, R., B.1 avan den Akker, E., B.1 aMcWhirter, R., E.1 aTrompet, S.1 aMishra, A.1 aSaba, Y.1 aSatizabal, C., L.1 aBeaudet, G.1 aPetit, L.1 aTsuchida, A.1 aZago, L.1 aSchilling, S.1 aSigurdsson, S.1 aGottesman, R., F.1 aLewis, C., E.1 aAggarwal, N., T.1 aLopez, O., L.1 aSmith, J., A.1 aHern?ndez, M., C. Vald?s1 avan der Grond, J.1 aWright, M., J.1 aKnol, M., J.1 aD?rr, M.1 aThomson, R., J.1 aBordes, C.1 aLe Grand, Q.1 aDuperron, M., G.1 aSmith, A., V.1 aKnopman, D., S.1 aSchreiner, P., J.1 aEvans, D., A.1 aRotter, J., I.1 aBeiser, A., S.1 aManiega, S., M.1 aBeekman, M.1 aTrollor, J.1 aStott, D., J.1 aVernooij, M., W.1 aWittfeld, K.1 aNiessen, W., J.1 aSoumar?, A.1 aBoerwinkle, E.1 aSidney, S.1 aTurner, S., T.1 aDavies, G.1 aThalamuthu, A.1 aV?lker, U.1 avan Buchem, M., A.1 aBryan, R., N.1 aDupuis, J.1 aBastin, M., E.1 aAmes, D.1 aTeumer, A.1 aAmouyel, P.1 aKwok, J., B.1 aB?low, R.1 aDeary, I., J.1 aSchofield, P., R.1 aBrodaty, H.1 aJiang, J.1 aTabara, Y.1 aSetoh, K.1 aMiyamoto, S.1 aYoshida, K.1 aNagata, M.1 aKamatani, Y.1 aMatsuda, F.1 aPsaty, B., M.1 aBennett, D., A.1 aDe Jager, P., L.1 aMosley, T., H.1 aSachdev, P., S.1 aSchmidt, R.1 aWarren, H., R.1 aEvangelou, E.1 aTr?gou?t, D., A.1 aIkram, M., A.1 aWen, W.1 aDeCarli, C.1 aSrikanth, V., K.1 aJukema, J., W.1 aSlagboom, E., P.1 aKardia, S., L. R.1 aOkada, Y.1 aMazoyer, B.1 aWardlaw, J., M.1 aNyquist, P., A.1 aMather, K., A.1 aGrabe, H., J.1 aSchmidt, H.1 avan Duijn, C., M.1 aGudnason, V.1 aLongstreth, W., T.1 aLauner, L., J.1 aLathrop, M.1 aSeshadri, S.1 aTzourio, C.1 aAdams, H., H.1 aMatthews, P., M.1 aFornage, M.1 aDebette, S.1 aAmouyel, P.1 ade Andrade, M.1 aBasu, S.1 aBerr, C.1 aBrody, J., A.1 aChasman, D., I.1 aDartigues, J., F.1 aFolsom, A., R.1 aGermain, M.1 ade Haan, H.1 aHeit, J.1 aHouwing-Duitermaat, J.1 aKabrhel, C.1 aKraft, P.1 aLegal, G.1 aLindstr?m, S.1 aMonajemi, R.1 aMorange, P., E.1 aPsaty, B., M.1 aReitsma, P., H.1 aRidker, P., M.1 aRose, L., M.1 aRosendaal, F., R.1 aSaut, N.1 aSlagboom, E.1 aSmadja, D.1 aSmith, N., L.1 aSuchon, P.1 aTang, W.1 aTaylor, K., D.1 aTr?gou?t, D., A.1 aTzourio, C.1 ade Visser, M., C. H.1 aVlieg, van, Hylckama1 aWeng, L., C.1 aWiggins, K., L.1 aGormley, P.1 aAnttila, V.1 aWinsvold, B., S.1 aPalta, P.1 aEsko, T.1 aPers, T., H.1 aFarh, K., H.1 aCuenca-Leon, E.1 aMuona, M.1 aFurlotte, N., A.1 aKurth, T.1 aIngason, A.1 aMcMahon, G.1 aLigthart, L.1 aTerwindt, G., M.1 aKallela, M.1 aFreilinger, T., M.1 aRan, C.1 aGordon, S., G.1 aStam, A., H.1 aSteinberg, S.1 aBorck, G.1 aKoiranen, M.1 aQuaye, L.1 aAdams, H., H. H.1 aLehtim?ki, T.1 aSarin, A., P.1 aWedenoja, J.1 aHinds, D., A.1 aBuring, J., E.1 aSch?rks, M.1 aRidker, P., M.1 aHrafnsdottir, Gudlaug1 aStefansson, H.1 aRing, S., M.1 aHottenga, J., J.1 aPenninx, B., W. J. H.1 aF?rkkil?, M.1 aArtto, V.1 aKaunisto, M.1 aVeps?l?inen, S.1 aMalik, R.1 aHeath, A., C.1 aMadden, P., A. F.1 aMartin, N., G.1 aMontgomery, G., W.1 aKurki, M.1 aKals, M.1 aM?gi, R.1 aP?rn, K.1 aH?m?l?inen, E.1 aHuang, H.1 aByrnes, A., E.1 aFranke, L.1 aHuang, J.1 aStergiakouli, E.1 aLee, P., H.1 aSandor, C.1 aWebber, C.1 aCader, Z.1 aMuller-Myhsok, B.1 aSchreiber, S.1 aMeitinger, T.1 aEriksson, J., G.1 aSalomaa, V.1 aHeikkil?, K.1 aLoehrer, E.1 aUitterlinden, A., G.1 aHofman, A.1 avan Duijn, C., M.1 aCherkas, L.1 aPedersen, L., M.1 aStubhaug, A.1 aNielsen, C., S.1 aM?nnikk?, M.1 aMihailov, E.1 aMilani, L.1 aG?bel, H.1 aEsserlind, A., L.1 aChristensen, Francke1 aHansen, Folkmann1 aWerge, T.1 aKaprio, J.1 aAromaa, A., J.1 aRaitakari, O.1 aIkram, M., A.1 aSpector, T.1 aJ?rvelin, M., R.1 aMetspalu, A.1 aKubisch, C.1 aStrachan, D., P.1 aFerrari, M., D.1 aBelin, A., C.1 aDichgans, M.1 aWessman, M.1 avan den Maagdenberg, A., M. J. M.1 aZwart, J., A.1 aBoomsma, D., I.1 aSmith, Davey1 aStefansson, K.1 aEriksson, N.1 aDaly, M., J.1 aNeale, B., M.1 aOlesen, J.1 aChasman, D., I.1 aNyholt, D., R.1 aPalotie, A. uhttps://chs-nhlbi.org/node/863403329nas a2200277 4500008004100000022001400041245012700055210006900182260001600251490000600267520248500273100001902758700002302777700001102800700001902811700002002830700002102850700002002871700002302891700002302914700001502937700002302952700002002975700002002995856003603015 2020 eng d a2379-370800aCharacterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study.0 aCharacterization of cardiac mechanics and incident atrial fibril c2020 Oct 020 v53 aBACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear.
METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF.
RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain.
CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.
FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH's National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.
1 aPatel, Ravi, B1 aDelaney, Joseph, A1 aHu, Mo1 aPatel, Harnish1 aCheng, Jeanette1 aGottdiener, John1 aKizer, Jorge, R1 aMarcus, Gregory, M1 aTurakhia, Mintu, P1 aDeo, Rajat1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aShah, Sanjiv, J uhttps://chs-nhlbi.org/node/848602717nas a2200241 4500008004100000022001400041245012600055210006900181260001300250300001000263490000700273520196900280100001902249700002002268700002402288700002602312700002002338700002102358700001802379700002202397700002002419856003602439 2020 eng d a1524-462800aCholesterol Variability and Cranial Magnetic Resonance Imaging Findings in Older Adults: The Cardiovascular Health Study.0 aCholesterol Variability and Cranial Magnetic Resonance Imaging F c2020 Jan a69-740 v513 aBackground and Purpose- Serum cholesterol variability, independent of mean, has been associated with stroke, white matter hyperintensities on cranial magnetic resonance imaging (MRI), and other cardiovascular events. We sought to assess the relationship between total serum cholesterol (TC) variability and cranial MRI findings of subclinical or covert vascular brain injury in a longitudinal, population-based cohort study of older adults. Methods- In the Cardiovascular Health Study, we assessed associations between intraindividual TC mean, trend, and variability over ≈5 years with covert brain infarction (CBI) and white matter grade (WMG) on cranial MRI. Mean TC was calculated for each study participant from 4 annual TC measurements between 2 MRI scans. TC trend was calculated as the slope of the linear regression of the TC measurements, and TC variability was calculated as the SD of the residuals from the linear regression. We evaluated the association of intraindividual TC variability with incident CBI and worsening WMG between 2 MRI scans in primary analyses and with prevalent CBI number and WMG on the follow-up MRI scan in secondary analyses. Results- Among participants who were eligible for the study and free of clinical stroke before the follow-up MRI, 17.9% of 1098 had incident CBI, and 27.8% of 1351 had worsening WMG on the follow-up MRI. Mean, trend, and variability of TC were not associated with these outcomes. TC variability, independent of mean and trend, was significantly associated with the number of CBI (β=0.009 [95% CI, 0.003-0.016] =0.004; N=1604) and was associated with WMG (β, 0.009 [95% CI, -0.0002 to 0.019] =0.055; N=1602) on the follow-up MRI. Conclusions- Among older adults, TC variability was not associated with incident CBI or worsening WMG but was associated with the number of prevalent CBI on cranial MRI. More work is needed to validate and to clarify the mechanisms underlying such associations.
1 aKalani, Rizwan1 aBartz, Traci, M1 aSuchy-Dicey, Astrid1 aElkind, Mitchell, S V1 aPsaty, Bruce, M1 aLeung, Lester, Y1 aRice, Kenneth1 aTirschwell, David1 aLongstreth, W T uhttps://chs-nhlbi.org/node/828604660nas a2200793 4500008004100000022001400041245013400055210006900189260001200258300001200270490000600282520241900288653001002707653002502717653001902742653001102761653002902772653003402801653001102835653000902846653001602855653001402871653004302885653001702928653001902945100001802964700002902982700001703011700002003028700001903048700002003067700002003087700002603107700002003133700001903153700001903172700002303191700001903214700002303233700002403256700001603280700002103296700002103317700002103338700001603359700001803375700001503393700002203408700001703430700002003447700002003467700002103487700002103508700002203529700002003551700001703571700001503588700001903603700001703622700001703639700002003656700002403676700002103700700002103721700002003742710004303762710002503805856003603830 2020 eng d a2213-261900aChronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.0 aChronic obstructive pulmonary disease and related phenotypes pol c2020 07 a696-7080 v83 aBACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.
METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.
FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.
INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.
FUNDING: US National Institutes of Health, Wellcome Trust.
10aAdult10aCase-Control Studies10aCohort Studies10aFemale10aForced Expiratory Volume10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPhenotype10aPulmonary Disease, Chronic Obstructive10aRisk Factors10aVital Capacity1 aMoll, Matthew1 aSakornsakolpat, Phuwanat1 aShrine, Nick1 aHobbs, Brian, D1 aDeMeo, Dawn, L1 aJohn, Catherine1 aGuyatt, Anna, L1 aMcGeachie, Michael, J1 aGharib, Sina, A1 aObeidat, Ma'en1 aLahousse, Lies1 aWijnant, Sara, R A1 aBrusselle, Guy1 aMeyers, Deborah, A1 aBleecker, Eugene, R1 aLi, Xingnan1 aTal-Singer, Ruth1 aManichaikul, Ani1 aRich, Stephen, S1 aWon, Sungho1 aKim, Woo, Jin1 aDo, Ah, Ra1 aWashko, George, R1 aBarr, Graham1 aPsaty, Bruce, M1 aBartz, Traci, M1 aHansel, Nadia, N1 aBarnes, Kathleen1 aHokanson, John, E1 aCrapo, James, D1 aLynch, David1 aBakke, Per1 aGulsvik, Amund1 aHall, Ian, P1 aWain, Louise1 aWeiss, Scott, T1 aSilverman, Edwin, K1 aDudbridge, Frank1 aTobin, Martin, D1 aCho, Michael, H1 aInternational COPD Genetics Consortium1 aSpiroMeta Consortium uhttps://chs-nhlbi.org/node/840002913nas a2200421 4500008004100000022001400041245012900055210006900184260000900253300001300262490000700275520168700282653000901969653002201978653001402000653002802014653001602042653001102058653001102069653002002080653002502100653003102125653000902156653003702165653001802202653001702220100002402237700002002261700001802281700002802299700002302327700001802350700002402368700002402392700002002416700001902436856003602455 2020 eng d a1932-620300aCoagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study.0 aCoagulation factor VIII white matter hyperintensities and cognit c2020 ae02420620 v153 aOBJECTIVE: To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time.
METHODS: Data from the population-based Cardiovascular Health Study (n = 5,888, aged ≥65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function.
RESULTS: After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95% CI -0.97 to 0.53, N = 2,306) after confounding adjustment.
INTERPRETATION: The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.
10aAged10aBlood Coagulation10aCognition10aCross-Sectional Studies10aFactor VIII10aFemale10aHumans10aLogistic Models10aLongitudinal Studies10aMagnetic Resonance Imaging10aMale10aMental Status and Dementia Tests10aUp-Regulation10aWhite Matter1 aRohmann, Jessica, L1 aLongstreth, W T1 aCushman, Mary1 aFitzpatrick, Annette, L1 aHeckbert, Susan, R1 aRice, Kenneth1 aRosendaal, Frits, R1 aSitlani, Colleen, M1 aPsaty, Bruce, M1 aSiegerink, Bob uhttps://chs-nhlbi.org/node/863200686nas a2200193 4500008004100000022001400041245014900055210006900204260001600273100001800289700002400307700001800331700002400349700002000373700001900393700002400412700002000436856003600456 2020 eng d a1523-683800aThe Difference Between Cystatin C and Creatinine-Based Estimated GFR and Incident Frailty: An Analysis of the Cardiovascular Health Study (CHS).0 aDifference Between Cystatin C and CreatinineBased Estimated GFR c2020 Jul 091 aPotok, Alison1 aPhil, Ronit, Katz D1 aBansal, Nisha1 aSiscovick, David, S1 aOdden, Michelle1 aIx, Joachim, H1 aShlipak, Michael, G1 aRifkin, Dena, E uhttps://chs-nhlbi.org/node/840410759nas a2203805 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2020 eng d00a{Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals0 aDiscovery of rare variants associated with blood pressure regula c12 a1314–13320 v523 aGenetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.1 aSurendran, P.1 aFeofanova, E., V.1 aLahrouchi, N.1 aNtalla, I.1 aKarthikeyan, S.1 aCook, J.1 aChen, L.1 aMifsud, B.1 aYao, C.1 aKraja, A., T.1 aCartwright, J., H.1 aHellwege, J., N.1 aGiri, A.1 aTragante, V.1 aThorleifsson, G.1 aLiu, D., J.1 aPrins, B., P.1 aStewart, I., D.1 aCabrera, C., P.1 aEales, J., M.1 aAkbarov, A.1 aAuer, P., L.1 aBielak, L., F.1 aBis, J., C.1 aBraithwaite, V., S.1 aBrody, J., A.1 aDaw, E., W.1 aWarren, H., R.1 aDrenos, F.1 aNielsen, S., F.1 aFaul, J., D.1 aFauman, E., B.1 aFava, C.1 aFerreira, T.1 aFoley, C., N.1 aFranceschini, N.1 aGao, H.1 aGiannakopoulou, O.1 aGiulianini, F.1 aGudbjartsson, D., F.1 aGuo, X.1 aHarris, S., E.1 aHavulinna, A., S.1 aHelgadottir, A.1 aHuffman, J., E.1 aHwang, S., J.1 aKanoni, S.1 aKontto, J.1 aLarson, M., G.1 aLi-Gao, R.1 aLindstr?m, J.1 aLotta, L., A.1 aLu, Y.1 aLuan, J.1 aMahajan, A.1 aMalerba, G.1 aMasca, N., G. D.1 aMei, H.1 aMenni, C.1 aMook-Kanamori, D., O.1 aMosen-Ansorena, D.1 aM?ller-Nurasyid, M.1 aPar?, G.1 aPaul, D., S.1 aPerola, M.1 aPoveda, A.1 aRauramaa, R.1 aRichard, M.1 aRichardson, T., G.1 aSep?lveda, N.1 aSim, X.1 aSmith, A., V.1 aSmith, J., A.1 aStaley, J., R.1 aStan?kov?, A.1 aSulem, P.1 aTh?riault, S.1 aThorsteinsdottir, U.1 aTrompet, S.1 aVarga, T., V.1 aEdwards, D., R. Velez1 aVeronesi, G.1 aWeiss, S.1 aWillems, S., M.1 aYao, J.1 aYoung, R.1 aYu, B.1 aZhang, W.1 aZhao, J., H.1 aZhao, W.1 aZhao, W.1 aEvangelou, E.1 aAeschbacher, S.1 aAsllanaj, E.1 aBlankenberg, S.1 aBonnycastle, L., L.1 aBork-Jensen, J.1 aBrandslund, I.1 aBraund, P., S.1 aBurgess, S.1 aCho, K.1 aChristensen, C.1 aConnell, J.1 aMutsert, R.1 aDominiczak, A., F.1 aD?rr, M.1 aEiriksdottir, G.1 aFarmaki, A., E.1 aGaziano, J., M.1 aGrarup, N.1 aGrove, M., L.1 aHallmans, G.1 aHansen, T.1 aHave, C., T.1 aHeiss, G.1 aJ?rgensen, M., E.1 aJousilahti, P.1 aKajantie, E.1 aKamat, M.1 aK?r?j?m?ki, A.1 aKarpe, F.1 aKoistinen, H., A.1 aKovesdy, C., P.1 aKuulasmaa, K.1 aLaatikainen, T.1 aLannfelt, L.1 aLee, I., T.1 aLee, W., J.1 aLinneberg, A.1 aMartin, L., W.1 aMoitry, M.1 aNadkarni, G.1 aNeville, M., J.1 aPalmer, C., N. A.1 aPapanicolaou, G., J.1 aPedersen, O.1 aPeters, J.1 aPoulter, N.1 aRasheed, A.1 aRasmussen, K., L.1 aRayner, N., W.1 aM?gi, R.1 aRenstr?m, F.1 aRettig, R.1 aRossouw, J.1 aSchreiner, P., J.1 aSever, P., S.1 aSigurdsson, E., L.1 aSkaaby, T.1 aSun, Y., V.1 aSundstrom, J.1 aThorgeirsson, G.1 aEsko, T.1 aTrabetti, E.1 aTsao, P., S.1 aTuomi, T.1 aTurner, S., T.1 aTzoulaki, I.1 aVaartjes, I.1 aVergnaud, A., C.1 aWiller, C., J.1 aWilson, P., W. F.1 aWitte, D., R.1 aYonova-Doing, E.1 aZhang, H.1 aAliya, N.1 aAlmgren, P.1 aAmouyel, P.1 aAsselbergs, F., W.1 aBarnes, M., R.1 aBlakemore, A., I.1 aBoehnke, M.1 aBots, M., L.1 aBottinger, E., P.1 aBuring, J., E.1 aChambers, J., C.1 aChen, Y., I.1 aChowdhury, R.1 aConen, D.1 aCorrea, A.1 aSmith, Davey1 aBoer, R., A.1 aDeary, I., J.1 aDedoussis, G.1 aDeloukas, P.1 aDi Angelantonio, E.1 aElliott, P.1 aFelix, S., B.1 aFerri?res, J.1 aFord, I.1 aFornage, M.1 aFranks, P., W.1 aFranks, S.1 aFrossard, P.1 aGambaro, G.1 aGaunt, T., R.1 aGroop, L.1 aGudnason, V.1 aHarris, T., B.1 aHayward, C.1 aHennig, B., J.1 aHerzig, K., H.1 aIngelsson, E.1 aTuomilehto, J.1 aJ?rvelin, M., R.1 aJukema, J., W.1 aKardia, S., L. R.1 aKee, F.1 aKooner, J., S.1 aKooperberg, C.1 aLauner, L., J.1 aLind, L.1 aLoos, R., J. F.1 aMajumder, A., A. S.1 aLaakso, M.1 aMcCarthy, M., I.1 aMelander, O.1 aMohlke, K., L.1 aMurray, A., D.1 aNordestgaard, B., G.1 aOrho-Melander, M.1 aPackard, C., J.1 aPadmanabhan, S.1 aPalmas, W.1 aPolasek, O.1 aPorteous, D., J.1 aPrentice, A., M.1 aProvince, M., A.1 aRelton, C., L.1 aRice, K.1 aRidker, P., M.1 aRolandsson, O.1 aRosendaal, F., R.1 aRotter, J., I.1 aRudan, I.1 aSalomaa, V.1 aSamani, N., J.1 aSattar, N.1 aSheu, W., H.1 aSmith, B., H.1 aSoranzo, N.1 aSpector, T., D.1 aStarr, J., M.1 aSebert, S.1 aTaylor, K., D.1 aLakka, T., A.1 aTimpson, N., J.1 aTobin, M., D.1 avan der Harst, P.1 avan der Meer, P.1 aRamachandran, V., S.1 aVerweij, N.1 aVirtamo, J.1 aV?lker, U.1 aWeir, D., R.1 aZeggini, E.1 aCharchar, F., J.1 aWareham, N., J.1 aLangenberg, C.1 aTomaszewski, M.1 aButterworth, A., S.1 aCaulfield, M., J.1 aDanesh, J.1 aEdwards, T., L.1 aHolm, H.1 aHung, A., M.1 aLindgren, C., M.1 aLiu, C.1 aManning, A., K.1 aMorris, A., P.1 aMorrison, A., C.1 aO'Donnell, C., J.1 aPsaty, B., M.1 aSaleheen, D.1 aStefansson, K.1 aBoerwinkle, E.1 aChasman, D., I.1 aLevy, D.1 aNewton-Cheh, C.1 aMunroe, P., B.1 aHowson, J., M. M.1 ade Boer, R., A.1 avan der Harst, P.1 avan der Meer, P.1 aVerweij, N.1 aButterworth, A., S.1 aDanesh, J.1 aLangenberg, C.1 aDeloukas, P.1 aMcCarthy, M., I.1 aFranks, P., W.1 aRolandsson, O.1 aWareham, N., J.1 aPrins, B., P.1 aZeggini, E.1 aHellwege, J., N.1 aGiri, A.1 aEdwards, D., R. V.1 aCho, K.1 aGaziano, J., M.1 aKovesdy, C., P.1 aSun, Y., V.1 aTsao, P., S.1 aWilson, P., W. F.1 aEdwards, T., L.1 aHung, A., M.1 aO'Donnell, C., J. uhttps://chs-nhlbi.org/node/863617422nas a2206817 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2020 eng d00a{Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale0 aDynamic incorporation of multiple in silico functional annotatio cSep a969–9830 v523 aLarge-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.1 aLi, X.1 aLi, Z.1 aZhou, H.1 aGaynor, S., M.1 aLiu, Y.1 aChen, H.1 aSun, R.1 aDey, R.1 aArnett, D., K.1 aAslibekyan, S.1 aBallantyne, C., M.1 aBielak, L., F.1 aBlangero, J.1 aBoerwinkle, E.1 aBowden, D., W.1 aBroome, J., G.1 aConomos, M., P.1 aCorrea, A.1 aCupples, L., A.1 aCurran, J., E.1 aFreedman, B., I.1 aGuo, X.1 aHindy, G.1 aIrvin, M., R.1 aKardia, S., L. R.1 aKathiresan, S.1 aKhan, A., T.1 aKooperberg, C., L.1 aLaurie, C., C.1 aLiu, X., S.1 aMahaney, M., C.1 aManichaikul, A., W.1 aMartin, L., W.1 aMathias, R., A.1 aMcGarvey, S., T.1 aMitchell, B., D.1 aMontasser, M., E.1 aMoore, J., E.1 aMorrison, A., C.1 aO'Connell, J., R.1 aPalmer, N., D.1 aPampana, A.1 aPeralta, J., M.1 aPeyser, P., A.1 aPsaty, B., M.1 aRedline, S.1 aRice, K., M.1 aRich, S., S.1 aSmith, J., A.1 aTiwari, H., K.1 aTsai, M., Y.1 aVasan, R., S.1 aWang, F., F.1 aWeeks, D., E.1 aWeng, Z.1 aWilson, J., G.1 aYanek, L., R.1 aNeale, B., M.1 aSunyaev, S., R.1 aAbecasis, G., R.1 aRotter, J., I.1 aWiller, C., J.1 aPeloso, G., M.1 aNatarajan, P.1 aLin, X.1 aAbe, N.1 aAbecasis, G., R.1 aAguet, F.1 aAlbert, C.1 aAlmasy, L.1 aAlonso, A.1 aAment, S.1 aAnderson, P.1 aAnugu, P.1 aApplebaum-Bowden, D.1 aArdlie, K.1 aArking, D.1 aArnett, D., K.1 aAshley-Koch, A.1 aAslibekyan, S.1 aAssimes, T.1 aAuer, P.1 aAvramopoulos, D.1 aBarnard, J.1 aBarnes, K.1 aBarr, R., G.1 aBarron-Casella, E.1 aBarwick, L.1 aBeaty, T.1 aBeck, G.1 aBecker, D.1 aBecker, L.1 aBeer, R.1 aBeitelshees, A.1 aBenjamin, E.1 aBenos, T.1 aBezerra, M.1 aBielak, L., F.1 aBis, J.1 aBlackwell, T.1 aBlangero, J.1 aBoerwinkle, E.1 aBowden, D., W.1 aBowler, R.1 aBrody, J.1 aBroeckel, U.1 aBroome, J., G.1 aBunting, K.1 aBurchard, E.1 aBustamante, C.1 aButh, E.1 aCade, B.1 aCardwell, J.1 aCarey, V.1 aCarty, C.1 aCasaburi, R.1 aCasella, J.1 aCastaldi, P.1 aChaffin, M.1 aChang, C.1 aChang, Y., C.1 aChasman, D.1 aChavan, S.1 aChen, B., J.1 aChen, W., M.1 aChen, Y., I.1 aCho, M.1 aChoi, S., H.1 aChuang, L., M.1 aChung, M.1 aChung, R., H.1 aClish, C.1 aComhair, S.1 aConomos, M., P.1 aCornell, E.1 aCorrea, A.1 aCrandall, C.1 aCrapo, J.1 aCupples, L., A.1 aCurran, J., E.1 aCurtis, J.1 aCuster, B.1 aDamcott, C.1 aDarbar, D.1 aDas, S.1 aDavid, S.1 aDavis, C.1 aDaya, M.1 ade Andrade, M.1 aFuentes, L., L.1 aDeBaun, M.1 aDeka, R.1 aDeMeo, D.1 aDevine, S.1 aDuan, Q.1 aDuggirala, R.1 aDurda, J., P.1 aDutcher, S.1 aEaton, C.1 aEkunwe, L.1 aBoueiz, El1 aEllinor, P.1 aEmery, L.1 aErzurum, S.1 aFarber, C.1 aFingerlin, T.1 aFlickinger, M.1 aFornage, M.1 aFranceschini, N.1 aFrazar, C.1 aFu, M.1 aFullerton, S., M.1 aFulton, L.1 aGabriel, S.1 aGan, W.1 aGao, S.1 aGao, Y.1 aGass, M.1 aGelb, B.1 aGeng, X., P.1 aGeraci, M.1 aGermer, S.1 aGerszten, R.1 aGhosh, A.1 aGibbs, R.1 aGignoux, C.1 aGladwin, M.1 aGlahn, D.1 aGogarten, S.1 aGong, D., W.1 aGoring, H.1 aGraw, S.1 aGrine, D.1 aGu, C., C.1 aGuan, Y.1 aGuo, X.1 aGupta, N.1 aHaessler, J.1 aHall, M.1 aHarris, D.1 aHawley, N., L.1 aHe, J.1 aHeckbert, S.1 aHernandez, R.1 aHerrington, D.1 aHersh, C.1 aHidalgo, B.1 aHixson, J.1 aHobbs, B.1 aHokanson, J.1 aHong, E.1 aHoth, K.1 aHsiung, C., A.1 aHung, Y., J.1 aHuston, H.1 aHwu, C., M.1 aIrvin, M., R.1 aJackson, R.1 aJain, D.1 aJaquish, C.1 aJhun, M., A.1 aJohnsen, J.1 aJohnson, A.1 aJohnson, C.1 aJohnston, R.1 aJones, K.1 aKang, H., M.1 aKaplan, R.1 aKardia, S., L. R.1 aKathiresan, S.1 aKelly, S.1 aKenny, E.1 aKessler, M.1 aKhan, A., T.1 aKim, W.1 aKinney, G.1 aKonkle, B.1 aKooperberg, C., L.1 aKramer, H.1 aLange, C.1 aLange, E.1 aLange, L.1 aLaurie, C., C.1 aLaurie, C.1 aLeBoff, M.1 aLee, J.1 aLee, S., S.1 aLee, W., J.1 aLeFaive, J.1 aLevine, D.1 aLevy, D.1 aLewis, J.1 aLi, X.1 aLi, Y.1 aLin, H.1 aLin, H.1 aLin, K., H.1 aLin, X.1 aLiu, S.1 aLiu, Y.1 aLiu, Y.1 aLoos, R., J. 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R.1 aKathiresan, S.1 aKhera, A.1 aKlarin, D.1 aKooperberg, C., L.1 aKral, B.1 aLange, L.1 aLaurie, C., C.1 aLaurie, C.1 aLemaitre, R.1 aLi, Z.1 aLi, X.1 aLin, X.1 aMahaney, M., C.1 aManichaikul, A., W.1 aMartin, L., W.1 aMathias, R., A.1 aMathur, R.1 aMcGarvey, S., T.1 aMcHugh, C.1 aMcLenithan, J.1 aMikulla, J.1 aMitchell, B., D.1 aMontasser, M., E.1 aMoran, A.1 aMorrison, A., C.1 aNakao, T.1 aNatarajan, P.1 aNickerson, D.1 aNorth, K.1 aO'Connell, J., R.1 aO'Donnell, C.1 aPalmer, N., D.1 aPampana, A.1 aPatel, A.1 aPeloso, G., M.1 aPerry, J.1 aPeters, U.1 aPeyser, P., A.1 aPirruccello, J.1 aPollin, T.1 aPreuss, M.1 aPsaty, B., M.1 aRao, D., C.1 aRedline, S.1 aReed, R.1 aReiner, A.1 aRich, S., S.1 aRosenthal, S.1 aRotter, J., I.1 aSchoenberg, J.1 aSelvaraj, M., S.1 aSheu, W., H.1 aSmith, J., A.1 aSofer, T.1 aStilp, A., M.1 aSunyaev, S., R.1 aSurakka, I.1 aSztalryd, C.1 aTang, H.1 aTaylor, K., D.1 aTsai, M., Y.1 aUddin, M., M.1 aUrbut, S.1 aVerbanck, M.1 aVon Holle, A.1 aWang, H.1 aWang, F., F.1 aWiggins, K.1 aWiller, C., J.1 aWilson, J., G.1 aWolford, B.1 aXu, H.1 aYanek, L., R.1 aZaghloul, N.1 aZekavat, M.1 aZhang, J. uhttps://chs-nhlbi.org/node/845309368nas a2202785 4500008004100000022001400041245012700055210006900182260001600251520166300267100002601930700001801956700002101974700002001995700002102015700002102036700002002057700002202077700001702099700001902116700002302135700002002158700002002178700002402198700002102222700002002243700002202263700002502285700002302310700001702333700002002350700001702370700002102387700002302408700001902431700002002450700002102470700001702491700002102508700002402529700002202553700002002575700002102595700001502616700001702631700002202648700001902670700001302689700002302702700001902725700002502744700001502769700002102784700002102805700001402826700001802840700002102858700002202879700001602901700002802917700001902945700001902964700002102983700001903004700001703023700001703040700002003057700001703077700002303094700001803117700001803135700001803153700001903171700001603190700001903206700002103225700001903246700002103265700002303286700002103309700001803330700001903348700002403367700002203391700001903413700002203432700002403454700001803478700002103496700002203517700002403539700002103563700002103584700002403605700001803629700002503647700001203672700001903684700002303703700002103726700001703747700002203764700001403786700002003800700002003820700001703840700002003857700002503877700002003902700002003922700002303942700002803965700001903993700002204012700001904034700001804053700002304071700001304094700002004107700002404127700001804151700001704169700002004186700001804206700002304224700002204247700002104269700002104290700001704311700002904328700001904357700002704376700002004403700002004423700002204443700002504465700002604490700002304516700001804539700002004557700002304577700002404600700001904624700002304643700002204666700001904688700002204707700001604729700003004745700002804775700002504803700002504828700002204853700002304875700001604898700002404914700002304938700001904961700002404980700002205004700002205026700002105048700002805069700002205097700002405119700002605143700001605169700001805185700001805203700001905221700001705240700001305257700001305270700001705283700001905300700001405319700002305333700002105356700002205377700001805399700001805417700001605435700002305451700002205474700002105496700002205517700002305539700002505562700001905587700001905606700001905625700002205644700002705666700002505693700002705718700002205745700001505767700002605782700001705808700001505825700001805840700002105858700002305879700001905902700002205921700002405943700002205967700002305989700002106012700002806033700001706061700002206078700001806100700002506118700002006143700002006163700002306183700001906206700002006225700002306245700002006268700001806288700002106306700002406327700001906351700002406370700002306394700001806417700002406435700002006459700002006479700002006499710002706519856003606546 2020 eng d a1476-557800aGene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.0 aGeneeducational attainment interactions in a multiancestry genom c2020 May 053 aEducational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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Wanqing1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBowden, Donald, W1 aDeary, Ian, J1 aDörr, Marcus1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKato, Norihiro1 aLakka, Timo, A1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aMarques-Vidal, Pedro1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aBouchard, Claude1 aCooper, Richard, S1 aCorrea, Adolfo1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aPalmas, Walter, R1 aPereira, A, C1 aProvince, Michael, M1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRotimi, Charles, N1 aTai, Shyong, E1 avan Dam, Rob, M1 aDuijn, Cornelia, M1 aWong, Tien, Yin1 aRice, Kenneth1 aGauderman, James1 aMorrison, Alanna, C1 aNorth, Kari, E1 aKardia, Sharon, L R1 aCaulfield, Mark, J1 aElliott, Paul1 aMunroe, Patricia, B1 aFranks, Paul, W1 aRao, Dabeeru, C1 aFornage, Myriam1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/838113215nas a2204525 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2020 eng d a0036-807500aThe genetic architecture of the human cerebral cortex0 agenetic architecture of the human cerebral cortex cAug-03-2021 aeaay66900 v3671 aGrasby, Katrina, L.1 aJahanshad, Neda1 aPainter, Jodie, N.1 aColodro-Conde, Lucía1 aBralten, Janita1 aHibar, Derrek, P.1 aLind, Penelope, A.1 aPizzagalli, Fabrizio1 aChing, Christopher, R. K.1 aMcMahon, Mary, Agnes B.1 aShatokhina, Natalia1 aZsembik, Leo, C. P.1 aThomopoulos, Sophia, I.1 aZhu, Alyssa, H.1 aStrike, Lachlan, T.1 aAgartz, Ingrid1 aAlhusaini, Saud1 aAlmeida, Marcio, A. A.1 aAlnæs, Dag1 aAmlien, Inge, K.1 aAndersson, Micael1 aArd, Tyler1 aArmstrong, Nicola, J.1 aAshley-Koch, Allison1 aAtkins, Joshua, R.1 aBernard, Manon1 aBrouwer, Rachel, M.1 aBuimer, Elizabeth, E. L.1 aBülow, Robin1 aBürger, Christian1 aCannon, Dara, M.1 aChakravarty, Mallar1 aChen, Qiang1 aCheung, Joshua, W.1 aCouvy-Duchesne, Baptiste1 aDale, Anders, M.1 aDalvie, Shareefa1 ade Araujo, Tânia, K.1 ade Zubicaray, Greig, I.1 ade Zwarte, Sonja, M. C.1 aBraber, Anouk, den1 aDoan, Nhat, Trung1 aDohm, Katharina1 aEhrlich, Stefan1 aEngelbrecht, Hannah-Ruth1 aErk, Susanne1 aFan, Chun, Chieh1 aFedko, Iryna, O.1 aFoley, Sonya, F.1 aFord, Judith, M.1 aFukunaga, Masaki1 aGarrett, Melanie, E.1 aGe, Tian1 aGiddaluru, Sudheer1 aGoldman, Aaron, L.1 aGreen, Melissa, J.1 aGroenewold, Nynke, A.1 aGrotegerd, Dominik1 aGurholt, Tiril, P.1 aGutman, Boris, A.1 aHansell, Narelle, K.1 aHarris, Mathew, A.1 aHarrison, Marc, B.1 aHaswell, Courtney, C.1 aHauser, Michael1 aHerms, Stefan1 aHeslenfeld, Dirk, J.1 aHo, New, Fei1 aHoehn, David1 aHoffmann, Per1 aHolleran, Laurena1 aHoogman, Martine1 aHottenga, Jouke-Jan1 aIkeda, Masashi1 aJanowitz, Deborah1 aJansen, Iris, E.1 aJia, Tianye1 aJockwitz, Christiane1 aKanai, Ryota1 aKarama, Sherif1 aKasperaviciute, Dalia1 aKaufmann, Tobias1 aKelly, Sinead1 aKikuchi, Masataka1 aKlein, Marieke1 aKnapp, Michael1 aKnodt, Annchen, R.1 aKrämer, Bernd1 aLam, Max1 aLancaster, Thomas, M.1 aLee, Phil, H.1 aLett, Tristram, A.1 aLewis, Lindsay, B.1 aLopes-Cendes, Iscia1 aLuciano, Michelle1 aMacciardi, Fabio1 aMarquand, Andre, F.1 aMathias, Samuel, R.1 aMelzer, Tracy, R.1 aMilaneschi, Yuri1 aMirza-Schreiber, Nazanin1 aMoreira, Jose, C. V.1 aMühleisen, Thomas, W.1 aMüller-Myhsok, Bertram1 aNajt, Pablo1 aNakahara, Soichiro1 aNho, Kwangsik1 aLoohuis, Loes, M. Olde1 aOrfanos, Dimitri, Papadopoul1 aPearson, John, F.1 aPitcher, Toni, L.1 aPütz, Benno1 aQuidé, Yann1 aRagothaman, Anjanibhargavi1 aRashid, Faisal, M.1 aReay, William, R.1 aRedlich, Ronny1 aReinbold, Céline, S.1 aRepple, Jonathan1 aRichard, Geneviève1 aRiedel, Brandalyn, C.1 aRisacher, Shannon, L.1 aRocha, Cristiane, S.1 aMota, Nina, Roth1 aSalminen, Lauren1 aSaremi, Arvin1 aSaykin, Andrew, J.1 aSchlag, Fenja1 aSchmaal, Lianne1 aSchofield, Peter, R.1 aSecolin, Rodrigo1 aShapland, Chin, Yang1 aShen, Li1 aShin, Jean1 aShumskaya, Elena1 aSønderby, Ida, E.1 aSprooten, Emma1 aTansey, Katherine, E.1 aTeumer, Alexander1 aThalamuthu, Anbupalam1 aTordesillas-Gutierrez, Diana1 aTurner, Jessica, A.1 aUhlmann, Anne1 aVallerga, Costanza, Ludovica1 avan der Meer, Dennis1 avan Donkelaar, Marjolein, M. J.1 avan Eijk, Liza1 avan Erp, Theo, G. M.1 avan Haren, Neeltje, E. M.1 avan Rooij, Daan1 avan Tol, Marie-Jose1 aVeldink, Jan, H.1 aVerhoef, Ellen1 aWalton, Esther1 aWang, Mingyuan1 aWang, Yunpeng1 aWardlaw, Joanna, M.1 aWen, Wei1 aWestlye, Lars, T.1 aWhelan, Christopher, D.1 aWitt, Stephanie, H.1 aWittfeld, Katharina1 aWolf, Christiane1 aWolfers, Thomas1 aWu, Jing, Qin1 aYasuda, Clarissa, L.1 aZaremba, Dario1 aZhang, Zuo1 aZwiers, Marcel, P.1 aArtiges, Eric1 aAssareh, Amelia, A.1 aAyesa-Arriola, Rosa1 aBelger, Aysenil1 aBrandt, Christine, L.1 aBrown, Gregory, G.1 aCichon, Sven1 aCurran, Joanne, E.1 aDavies, Gareth, E.1 aDegenhardt, Franziska1 aDennis, Michelle, F.1 aDietsche, Bruno1 aDjurovic, Srdjan1 aDoherty, Colin, P.1 aEspiritu, Ryan1 aGarijo, Daniel1 aGil, Yolanda1 aGowland, Penny, A.1 aGreen, Robert, C.1 aHäusler, Alexander, N.1 aHeindel, Walter1 aHo, Beng-Choon1 aHoffmann, Wolfgang, U.1 aHolsboer, Florian1 aHomuth, Georg1 aHosten, Norbert1 aJack, Clifford, R.1 aJang, MiHyun1 aJansen, Andreas1 aKimbrel, Nathan, A.1 aKolskår, Knut1 aKoops, Sanne1 aKrug, Axel1 aLim, Kelvin, O.1 aLuykx, Jurjen, J.1 aMathalon, Daniel, H.1 aMather, Karen, A.1 aMattay, Venkata, S.1 aMatthews, Sarah1 aVan Son, Jaqueline, Mayoral1 aMcEwen, Sarah, C.1 aMelle, Ingrid1 aMorris, Derek, W.1 aMueller, Bryon, A.1 aNauck, Matthias1 aNordvik, Jan, E.1 aNöthen, Markus, M.1 aO’Leary, Daniel, S.1 aOpel, Nils1 aMartinot, Marie-Laure, Paillère1 aPike, Bruce1 aPreda, Adrian1 aQuinlan, Erin, B.1 aRasser, Paul, E.1 aRatnakar, Varun1 aReppermund, Simone1 aSteen, Vidar, M.1 aTooney, Paul, A.1 aTorres, Fábio, R.1 aVeltman, Dick, J.1 aVoyvodic, James, T.1 aWhelan, Robert1 aWhite, Tonya1 aYamamori, Hidenaga1 aAdams, Hieab, H. H.1 aBis, Joshua, C.1 aDebette, Stephanie1 aDeCarli, Charles1 aFornage, Myriam1 aGudnason, Vilmundur1 aHofer, Edith1 aIkram, Arfan1 aLauner, Lenore1 aLongstreth, W., T.1 aLopez, Oscar, L.1 aMazoyer, Bernard1 aMosley, Thomas, H.1 aRoshchupkin, Gennady, V.1 aSatizabal, Claudia, L.1 aSchmidt, Reinhold1 aSeshadri, Sudha1 aYang, Qiong1 aAlvim, Marina, K. M.1 aAmes, David1 aAnderson, Tim, J.1 aAndreassen, Ole, A.1 aArias-Vasquez, Alejandro1 aBastin, Mark, E.1 aBaune, Bernhard, T.1 aBeckham, Jean, C.1 aBlangero, John1 aBoomsma, Dorret, I.1 aBrodaty, Henry1 aBrunner, Han, G.1 aBuckner, Randy, L.1 aBuitelaar, Jan, K.1 aBustillo, Juan, R.1 aCahn, Wiepke1 aCairns, Murray, J.1 aCalhoun, Vince1 aCarr, Vaughan, J.1 aCaseras, Xavier1 aCaspers, Svenja1 aCavalleri, Gianpiero, L.1 aCendes, Fernando1 aCorvin, Aiden1 aCrespo-Facorro, Benedicto1 aDalrymple-Alford, John, C.1 aDannlowski, Udo1 ade Geus, Eco, J. C.1 aDeary, Ian, J.1 aDelanty, Norman1 aDepondt, Chantal1 aDesrivières, Sylvane1 aDonohoe, Gary1 aEspeseth, Thomas1 aFernández, Guillén1 aFisher, Simon, E.1 aFlor, Herta1 aForstner, Andreas, J.1 aFrancks, Clyde1 aFranke, Barbara1 aGlahn, David, C.1 aGollub, Randy, L.1 aGrabe, Hans, J.1 aGruber, Oliver1 aHåberg, Asta, K.1 aHariri, Ahmad, R.1 aHartman, Catharina, A.1 aHashimoto, Ryota1 aHeinz, Andreas1 aHenskens, Frans, A.1 aHillegers, Manon, H. J.1 aHoekstra, Pieter, J.1 aHolmes, Avram, J.1 aHong, Elliot1 aHopkins, William, D.1 aPol, Hilleke, E. Hulshof1 aJernigan, Terry, L.1 aJönsson, Erik, G.1 aKahn, René, S.1 aKennedy, Martin, A.1 aKircher, Tilo, T. J.1 aKochunov, Peter1 aKwok, John, B. J.1 aLe Hellard, Stephanie1 aLoughland, Carmel, M.1 aMartin, Nicholas, G.1 aMartinot, Jean-Luc1 aMcDonald, Colm1 aMcMahon, Katie, L.1 aMeyer-Lindenberg, Andreas1 aMichie, Patricia, T.1 aMorey, Rajendra, A.1 aMowry, Bryan1 aNyberg, Lars1 aOosterlaan, Jaap1 aOphoff, Roel, A.1 aPantelis, Christos1 aPaus, Tomáš1 aPausova, Zdenka1 aPenninx, Brenda, W. J. H.1 aPolderman, Tinca, J. C.1 aPosthuma, Danielle1 aRietschel, Marcella1 aRoffman, Joshua, L.1 aRowland, Laura, M.1 aSachdev, Perminder, S.1 aSämann, Philipp, G.1 aSchall, Ulrich1 aSchumann, Gunter1 aScott, Rodney, J.1 aSim, Kang1 aSisodiya, Sanjay, M.1 aSmoller, Jordan, W.1 aSommer, Iris, E.1 aSt Pourcain, Beate1 aStein, Dan, J.1 aToga, Arthur, W.1 aTrollor, Julian, N.1 aVan der Wee, Nic, J. A.1 aEnt, Dennis, van ’t1 aVölzke, Henry1 aWalter, Henrik1 aWeber, Bernd1 aWeinberger, Daniel, R.1 aWright, Margaret, J.1 aZhou, Juan1 aStein, Jason, L.1 aThompson, Paul, M.1 aMedland, Sarah, E.1 aAlzheimer’s Disease Neuroimaging Initiative¶1 aCHARGE Consortium¶1 aEPIGEN Consortium¶1 aIMAGEN Consortium¶1 aSYS Consortium¶1 aParkinson’s Progression Markers Initiative¶1 aEnhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group uhttps://www.sciencemag.org/lookup/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay669014016nas a2205185 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2020 eng d00a{Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults0 aGenetic correlations and genomewide associations of cortical str c09 a47960 v113 aCortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.1 aHofer, E.1 aRoshchupkin, G., V.1 aAdams, H., H. H.1 aKnol, M., J.1 aLin, H.1 aLi, S.1 aZare, H.1 aAhmad, S.1 aArmstrong, N., J.1 aSatizabal, C., L.1 aBernard, M.1 aBis, J., C.1 aGillespie, N., A.1 aLuciano, M.1 aMishra, A.1 aScholz, M.1 aTeumer, A.1 aXia, R.1 aJian, X.1 aMosley, T., H.1 aSaba, Y.1 aPirpamer, L.1 aSeiler, S.1 aBecker, J., T.1 aCarmichael, O.1 aRotter, J., I.1 aPsaty, B., M.1 aLopez, O., L.1 aAmin, N.1 avan der Lee, S., J.1 aYang, Q.1 aHimali, J., J.1 aMaillard, P.1 aBeiser, A., S.1 aDeCarli, C.1 aKarama, S.1 aLewis, L.1 aHarris, M.1 aBastin, M., E.1 aDeary, I., J.1 aWitte, Veronica1 aBeyer, F.1 aLoeffler, M.1 aMather, K., A.1 aSchofield, P., R.1 aThalamuthu, A.1 aKwok, J., B.1 aWright, M., J.1 aAmes, D.1 aTrollor, J.1 aJiang, J.1 aBrodaty, H.1 aWen, W.1 aVernooij, M., W.1 aHofman, A.1 aUitterlinden, A., G.1 aNiessen, W., J.1 aWittfeld, K.1 aB?low, R.1 aV?lker, U.1 aPausova, Z.1 aPike, Bruce1 aMaingault, S.1 aCrivello, F.1 aTzourio, C.1 aAmouyel, P.1 aMazoyer, B.1 aNeale, M., C.1 aFranz, C., E.1 aLyons, M., J.1 aPanizzon, M., S.1 aAndreassen, O., A.1 aDale, A., M.1 aLogue, M.1 aGrasby, K., L.1 aJahanshad, N.1 aPainter, J., N.1 aColodro-Conde, L.1 aBralten, J.1 aHibar, D., P.1 aLind, P., A.1 aPizzagalli, F.1 aStein, J., L.1 aThompson, P., M.1 aMedland, S., E.1 aSachdev, P., S.1 aKremen, W., S.1 aWardlaw, J., M.1 aVillringer, A.1 avan Duijn, C., M.1 aGrabe, H., J.1 aLongstreth, W., T.1 aFornage, M.1 aPaus, T.1 aDebette, S.1 aIkram, Arfan1 aSchmidt, H.1 aSchmidt, R.1 aSeshadri, S.1 aGrasby, K., L.1 aJahanshad, N.1 aPainter, J., N.1 aColodro-Conde, L.1 aBralten, J.1 aHibar, D., P.1 aLind, P., A.1 aPizzagalli, F.1 aChing, C., R. K.1 aMcMahon, M., A. B.1 aShatokhina, N.1 aZsembik, L., C. P.1 aAgartz, I.1 aAlhusaini, S.1 aAlmeida, M., A. A.1 aAln?s, D.1 aAmlien, I., K.1 aAndersson, M.1 aArd, T.1 aArmstrong, N., J.1 aAshley-Koch, A.1 aBernard, M.1 aBrouwer, R., M.1 aBuimer, E., E. L.1 aB?low, R.1 aB?rger, C.1 aCannon, D., M.1 aChakravarty, M.1 aChen, Q.1 aCheung, J., W.1 aCouvy-Duchesne, B.1 aDale, A., M.1 aDalvie, S.1 ade Araujo, T., K.1 ade Zubicaray, G., I.1 ade Zwarte, S., M. C.1 aBraber, den1 aDoan, N., T.1 aDohm, K.1 aEhrlich, S.1 aEngelbrecht, H., R.1 aErk, S.1 aFan, C., C.1 aFedko, I., O.1 aFoley, S., F.1 aFord, J., M.1 aFukunaga, M.1 aGarrett, M., E.1 aGe, T.1 aGiddaluru, S.1 aGoldman, A., L.1 aGroenewold, N., A.1 aGrotegerd, D.1 aGurholt, T., P.1 aGutman, B., A.1 aHansell, N., K.1 aHarris, M., A.1 aHarrison, M., B.1 aHaswell, C., C.1 aHauser, M.1 aHerms, S.1 aHeslenfeld, D., J.1 aHo, N., F.1 aHoehn, D.1 aHoffmann, P.1 aHolleran, L.1 aHoogman, M.1 aHottenga, J., J.1 aIkeda, M.1 aJanowitz, D.1 aJansen, I., E.1 aJia, T.1 aJockwitz, C.1 aKanai, R.1 aKarama, S.1 aKasperaviciute, D.1 aKaufmann, T.1 aKelly, S.1 aKikuchi, M.1 aKlein, M.1 aKnapp, M.1 aKnodt, A., R.1 aKr?mer, B.1 aLam, M.1 aLancaster, T., M.1 aLee, P., H.1 aLett, T., A.1 aLewis, L., B.1 aLopes-Cendes, I.1 aLuciano, M.1 aMacciardi, F.1 aMarquand, A., F.1 aMathias, S., R.1 aMelzer, T., R.1 aMilaneschi, Y.1 aMirza-Schreiber, N.1 aMoreira, J., C. V.1 aM?hleisen, T., W.1 aM?ller-Myhsok, B.1 aNajt, P.1 aNakahara, S.1 aNho, K.1 aLoohuis, L., M. Olde1 aOrfanos, D., P.1 aPearson, J., F.1 aPitcher, T., L.1 aP?tz, B.1 aRagothaman, A.1 aRashid, F., M.1 aRedlich, R.1 aReinbold, C., S.1 aRepple, J.1 aRichard, G.1 aRiedel, B., C.1 aRisacher, S., L.1 aRocha, C., S.1 aMota, N., R.1 aSalminen, L.1 aSaremi, A.1 aSaykin, A., J.1 aSchlag, F.1 aSchmaal, L.1 aSchofield, P., R.1 aSecolin, R.1 aShapland, C., Y.1 aShen, L.1 aShin, J.1 aShumskaya, E.1 aS?nderby, I., E.1 aSprooten, E.1 aStrike, L., T.1 aTansey, K., E.1 aTeumer, A.1 aThalamuthu, A.1 aThomopoulos, S., I.1 aTordesillas-Guti?rrez, D.1 aTurner, J., A.1 aUhlmann, A.1 aVallerga, C., L.1 avan der Meer, D.1 avan Donkelaar, M., M. J.1 avan Eijk, L.1 avan Erp, T., G. M.1 avan Haren, N., E. M.1 avan Rooij, D.1 avan Tol, M., J.1 aVeldink, J., H.1 aVerhoef, E.1 aWalton, E.1 aWang, M.1 aWang, Y.1 aWardlaw, J., M.1 aWen, W.1 aWestlye, L., T.1 aWhelan, C., D.1 aWitt, S., H.1 aWittfeld, K.1 aWolf, C.1 aWolfers, T.1 aYasuda, C., L.1 aZaremba, D.1 aZhang, Z.1 aZhu, A., H.1 aZwiers, M., P.1 aArtiges, E.1 aAssareh, A., A.1 aAyesa-Arriola, R.1 aBelger, A.1 aBrandt, C., L.1 aBrown, G., G.1 aCichon, S.1 aCurran, J., E.1 aDavies, G., E.1 aDegenhardt, F.1 aDietsche, B.1 aDjurovic, S.1 aDoherty, C., P.1 aEspiritu, R.1 aGarijo, D.1 aGil, Y.1 aGowland, P., A.1 aGreen, R., C.1 aH?usler, A., N.1 aHeindel, W.1 aHo, B., C.1 aHoffmann, W., U.1 aHolsboer, F.1 aHomuth, G.1 aHosten, N.1 aJack, C., R.1 aJang, M.1 aJansen, A.1 aKolsk?r, K.1 aKoops, S.1 aKrug, A.1 aLim, K., O.1 aLuykx, J., J.1 aMathalon, D., H.1 aMather, K., A.1 aMattay, V., S.1 aMatthews, S.1 aSon, J., M. V.1 aMcEwen, S., C.1 aMelle, I.1 aMorris, D., W.1 aMueller, B., A.1 aNauck, M.1 aNordvik, J., E.1 aN?then, M., M.1 aO'Leary, D., S.1 aOpel, N.1 aMartinot, M., -P.1 aPike, G., B.1 aPreda, A.1 aQuinlan, E., B.1 aRatnakar, V.1 aReppermund, S.1 aSteen, V., M.1 aTorres, F., R.1 aVeltman, D., J.1 aVoyvodic, J., T.1 aWhelan, R.1 aWhite, T.1 aYamamori, H.1 aAlvim, M., K. M.1 aAmes, D.1 aAnderson, T., J.1 aAndreassen, O., A.1 aArias-Vasquez, A.1 aBastin, M., E.1 aBaune, B., T.1 aBlangero, J.1 aBoomsma, D., I.1 aBrodaty, H.1 aBrunner, H., G.1 aBuckner, R., L.1 aBuitelaar, J., K.1 aBustillo, J., R.1 aCahn, W.1 aCalhoun, V.1 aCaseras, X.1 aCaspers, S.1 aCavalleri, G., L.1 aCendes, F.1 aCorvin, A.1 aCrespo-Facorro, B.1 aDalrymple-Alford, J., C.1 aDannlowski, U.1 ade Geus, E., J. C.1 aDeary, I., J.1 aDelanty, N.1 aDepondt, C.1 aDesrivi?res, S.1 aDonohoe, G.1 aEspeseth, T.1 aFern?ndez, G.1 aFisher, S., E.1 aFlor, H.1 aForstner, A., J.1 aFrancks, C.1 aFranke, B.1 aGlahn, D., C.1 aGollub, R., L.1 aGrabe, H., J.1 aGruber, O.1 aH?berg, A., K.1 aHariri, A., R.1 aHartman, C., A.1 aHashimoto, R.1 aHeinz, A.1 aHillegers, M., H. J.1 aHoekstra, P., J.1 aHolmes, A., J.1 aHong, L., E.1 aHopkins, W., D.1 aPol, H., E. Hulshof1 aJernigan, T., L.1 aJ?nsson, E., G.1 aKahn, R., S.1 aKennedy, M., A.1 aKircher, T., T. J.1 aKochunov, P.1 aKwok, J., B. J.1 aHellard, S., L.1 aMartin, N., G.1 aMartinot, J., -1 aMcDonald, C.1 aMcMahon, K., L.1 aMeyer-Lindenberg, A.1 aMorey, R., A.1 aNyberg, L.1 aOosterlaan, J.1 aOphoff, R., A.1 aPaus, T.1 aPausova, Z.1 aPenninx, B., W. J. H.1 aPolderman, T., J. C.1 aPosthuma, D.1 aRietschel, M.1 aRoffman, J., L.1 aRowland, L., M.1 aSachdev, P., S.1 aS?mann, P., G.1 aSchumann, G.1 aSim, K.1 aSisodiya, S., M.1 aSmoller, J., W.1 aSommer, I., E.1 aPourcain, B., S.1 aStein, D., J.1 aToga, A., W.1 aTrollor, J., N.1 aVan der Wee, N., J. A.1 aEnt, van, 't1 aV?lzke, H.1 aWalter, H.1 aWeber, B.1 aWeinberger, D., R.1 aWright, M., J.1 aZhou, J.1 aStein, J., L.1 aThompson, P., M.1 aMedland, S., E. uhttps://chs-nhlbi.org/node/848403568nas a2200817 4500008004100000245010200041210006900143260000800212520141500220100001701635700001701652700001701669700002001686700001701706700002201723700001501745700001201760700001501772700001501787700001201802700001201814700001801826700002401844700001601868700001601884700002501900700001901925700001501944700001601959700001901975700002001994700001702014700002002031700002102051700001902072700002102091700001802112700001902130700001502149700002002164700001102184700001502195700001802210700001702228700001702245700001802262700002102280700001602301700001502317700001902332700002202351700002302373700002102396700002202417700001302439700001502452700002002467700001902487700002602506700001302532700001802545700001802563700001502581700001902596700001902615700002102634700002002655700002002675700001902695856003602714 2020 eng d00a{Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation0 aGenetic Determinants of Electrocardiographic Pwave Duration and cAug3 aBackground - The P-wave duration (PWD) is an electrocardiographic (ECG) measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome chip data to examine the associations between common and rare variants with PWD. Methods - Fifteen studies comprising 64,440 individuals (56,943 European, 5,681 African, 1,186 Hispanic, 630 Asian), and 230,000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and SKAT tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF GWAS. Results - We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (e.g., PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions - Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.1 aWeng, L., C.1 aHall, A., W.1 aChoi, S., H.1 aJurgens, S., J.1 aHaessler, J.1 aBihlmeyer, N., A.1 aGrarup, N.1 aLin, H.1 aTeumer, A.1 aLi-Gao, R.1 aYao, J.1 aGuo, X.1 aBrody, J., A.1 aM?ller-Nurasyid, M.1 aSchramm, K.1 aVerweij, N.1 avan den Berg, M., E.1 avan Setten, J.1 aIsaacs, A.1 aRam?rez, J.1 aWarren, H., R.1 aPadmanabhan, S.1 aKors, J., A.1 ade Boer, R., A.1 avan der Meer, P.1 aSinner, M., F.1 aWaldenberger, M.1 aPsaty, B., M.1 aTaylor, K., D.1 aV?lker, U.1 aKanters, J., K.1 aLi, M.1 aAlonso, A.1 aPerez, M., V.1 aVaartjes, I.1 aBots, M., L.1 aHuang, P., L.1 aHeckbert, S., R.1 aLin, H., J.1 aKornej, J.1 aMunroe, P., B.1 avan Duijn, C., M.1 aAsselbergs, F., W.1 aStricker, B., H.1 avan der Harst, P.1 aK??b, S.1 aPeters, A.1 aSotoodehnia, N.1 aRotter, J., I.1 aMook-Kanamori, D., O.1 aD?rr, M.1 aFelix, S., B.1 aLinneberg, A.1 aHansen, T.1 aArking, D., E.1 aKooperberg, C.1 aBenjamin, E., J.1 aLunetta, K., L.1 aEllinor, P., T.1 aLubitz, S., A. uhttps://chs-nhlbi.org/node/845204618nas a2200805 4500008004100000022001400041245019400055210006900249260000900318300001300327490000700340520222500347653001002572653002802582653002802610653001102638653004002649653001702689653003402706653001102740653002602751653003602777653002402813100001602837700001602853700002202869700001902891700002202910700002102932700001902953700001802972700002302990700002603013700001703039700002003056700002103076700002103097700002103118700002303139700002203162700002103184700001703205700002203222700001903244700002003263700001903283700002203302700002603324700002103350700002103371700002003392700002603412700002203438700002203460700002003482700002803502700001703530700001903547700001303566700002303579700001803602700002403620700002303644700001603667700002003683700001903703700003003722700002403752856003603776 2020 eng d a1932-620300aGenetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.0 aGenetic loci associated with prevalent and incident myocardial i c2020 ae02300350 v153 aBACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.
METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.
CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
10aAging10aCoronary Artery Disease10aCross-Sectional Studies10aEurope10aEuropean Continental Ancestry Group10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies1 aHahn, Julie1 aFu, Yi-Ping1 aBrown, Michael, R1 aBis, Joshua, C1 ade Vries, Paul, S1 aFeitosa, Mary, F1 aYanek, Lisa, R1 aWeiss, Stefan1 aGiulianini, Franco1 aSmith, Albert, Vernon1 aGuo, Xiuqing1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aChen, Yii-Der Ida1 aFranco, Oscar, H1 aGrove, Megan1 aHarris, Tamara, B1 aHofman, Albert1 aHwang, Shih-Jen1 aKral, Brian, G1 aLauner, Lenore, J1 aMarkus, Marcello, R P1 aRice, Kenneth, M1 aRich, Stephen, S1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aUitterlinden, André, G1 aVölker, Uwe1 aVölzke, Henry1 aYao, Jie1 aChasman, Daniel, I1 aDörr, Marcus1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aPost, Wendy1 aPsaty, Bruce, M1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aMorrison, Alanna, C uhttps://chs-nhlbi.org/node/862505314nas a2201501 4500008004100000022001400041245010000055210006900155260001600224520106300240100002301303700001801326700002801344700002001372700002101392700002401413700002301437700002101460700002301481700002101504700002501525700001801550700001701568700002101585700002001606700001801626700001601644700001901660700003401679700001901713700002101732700002101753700001701774700002801791700002101819700002401840700002401864700002001888700002001908700001901928700002301947700001601970700001701986700002002003700002202023700002102045700001802066700002202084700002102106700002302127700002902150700002802179700001902207700002202226700002302248700002202271700001702293700002202310700001902332700002302351700002102374700002402395700002202419700002102441700002002462700002002482700002202502700002202524700001202546700001502558700001802573700001802591700002102609700002102630700002702651700002802678700002902706700002202735700002302757700002002780700002302800700002202823700002202845700002002867700002302887700002102910700001602931700002402947700002002971700002202991700002803013700001303041700001303054700001703067700001903084700001803103700002003121700002303141700002003164700001703184700001803201700002003219700002003239700002203259700002503281700002203306700002003328700002203348700002503370700002103395700002203416700002003438700002103458700002003479700002003499700001903519700002603538700002503564700002203589700002403611700002503635700002503660700002103685700002303706700001903729700002803748856003603776 2020 eng d a1939-327X00aGenetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.0 aGenetic Studies of Leptin Concentrations Implicate Leptin in the c2020 Sep 113 aLeptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.
1 aYaghootkar, Hanieh1 aZhang, Yiying1 aSpracklen, Cassandra, N1 aKaraderi, Tugce1 aHuang, Lam, Opal1 aBradfield, Jonathan1 aSchurmann, Claudia1 aFine, Rebecca, S1 aPreuss, Michael, H1 aKutalik, Zoltán1 aWittemans, Laura, Bl1 aLu, Yingchang1 aMetz, Sophia1 aWillems, Sara, M1 aLi-Gao, Ruifang1 aGrarup, Niels1 aWang, Shuai1 aMolnos, Sophie1 aSandoval-Zárate, América, A1 aNalls, Mike, A1 aLange, Leslie, A1 aHaesser, Jeffrey1 aGuo, Xiuqing1 aLyytikäinen, Leo-Pekka1 aFeitosa, Mary, F1 aSitlani, Colleen, M1 aVenturini, Cristina1 aMahajan, Anubha1 aKacprowski, Tim1 aWang, Carol, A1 aChasman, Daniel, I1 aAmin, Najaf1 aBroer, Linda1 aRobertson, Neil1 aYoung, Kristin, L1 aAllison, Matthew1 aAuer, Paul, L1 aBlüher, Matthias1 aBorja, Judith, B1 aBork-Jensen, Jette1 aCarrasquilla, Germán, D1 aChristofidou, Paraskevi1 aDemirkan, Ayse1 aDoege, Claudia, A1 aGarcia, Melissa, E1 aGraff, Mariaelisa1 aGuo, Kaiying1 aHakonarson, Hakon1 aHong, Jaeyoung1 aChen, Yii-Der, Ida1 aJackson, Rebecca1 aJakupović, Hermina1 aJousilahti, Pekka1 aJustice, Anne, E1 aKähönen, Mika1 aKizer, Jorge, R1 aKriebel, Jennifer1 aLeDuc, Charles, A1 aLi, Jin1 aLind, Lars1 aLuan, Jian'an1 aMackey, David1 aMangino, Massimo1 aMännistö, Satu1 aCarli, Jayne, F Martin1 aMedina-Gómez, Carolina1 aMook-Kanamori, Dennis, O1 aMorris, Andrew, P1 ade Mutsert, Renée1 aNauck, Matthias1 aNedeljkovic, Ivana1 aPennell, Craig, E1 aPradhan, Arund, D1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aScott, Robert, A1 aSkaaby, Tea1 aStrauch, Konstantin1 aTaylor, Kent, D1 aTeumer, Alexander1 aUitterlinden, André, G1 aWu, Ying1 aYao, Jie1 aWalker, Mark1 aNorth, Kari, E1 aKovacs, Peter1 aIkram, Arfan, M1 aDuijn, Cornelia, M1 aRidker, Paul, M1 aLye, Stephen1 aHomuth, Georg1 aIngelsson, Erik1 aSpector, Tim, D1 aMcKnight, Barbara1 aProvince, Michael, A1 aLehtimäki, Terho1 aAdair, Linda, S1 aRotter, Jerome, I1 aReiner, Alexander, P1 aWilson, James, G1 aHarris, Tamara, B1 aRipatti, Samuli1 aGrallert, Harald1 aMeigs, James, B1 aSalomaa, Veikko1 aHansen, Torben1 avan Dijk, Ko, Willems1 aWareham, Nicholas, J1 aGrant, Struan, Fa1 aLangenberg, Claudia1 aFrayling, Timothy, M1 aLindgren, Cecilia, M1 aMohlke, Karen, L1 aLeibel, Rudolph, L1 aLoos, Ruth, Jf1 aKilpeläinen, Tuomas, O uhttps://chs-nhlbi.org/node/849107527nas a2202557 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2020 eng d00a{Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure0 aGenomewide association and Mendelian randomisation analysis prov c01 a1630 v113 aHeart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.1 aShah, S.1 aHenry, A.1 aRoselli, C.1 aLin, H.1 aSveinbj?rnsson, G.1 aFatemifar, G.1 aHedman, ?., K.1 aWilk, J., B.1 aMorley, M., P.1 aChaffin, M., D.1 aHelgadottir, A.1 aVerweij, N.1 aDehghan, A.1 aAlmgren, P.1 aAndersson, C.1 aAragam, K., G.1 arnl?v, J., ?1 aBackman, J., D.1 aBiggs, M., L.1 aBloom, H., L.1 aBrandimarto, J.1 aBrown, M., R.1 aBuckbinder, L.1 aCarey, D., J.1 aChasman, D., I.1 aChen, X.1 aChen, X.1 aChung, J.1 aChutkow, W.1 aCook, J., P.1 aDelgado, G., E.1 aDenaxas, S.1 aDoney, A., S.1 aD?rr, M.1 aDudley, S., C.1 aDunn, M., E.1 aEngstr?m, G.1 aEsko, T.1 aFelix, S., B.1 aFinan, C.1 aFord, I.1 aGhanbari, M.1 aGhasemi, S.1 aGiedraitis, V.1 aGiulianini, F.1 aGottdiener, J., S.1 aGross, S.1 aGu?bjartsson, D., F.1 aGutmann, R.1 aHaggerty, C., M.1 avan der Harst, P.1 aHyde, C., L.1 aIngelsson, E.1 aJukema, J., W.1 aKavousi, M.1 aKhaw, K., T.1 aKleber, M., E.1 aK?ber, L.1 aKoekemoer, A.1 aLangenberg, C.1 aLind, L.1 aLindgren, C., M.1 aLondon, B.1 aLotta, L., A.1 aLovering, R., C.1 aLuan, J.1 aMagnusson, P.1 aMahajan, A.1 aMargulies, K., B.1 aM?rz, W.1 aMelander, O.1 aMordi, I., R.1 aMorgan, T.1 aMorris, A., D.1 aMorris, A., P.1 aMorrison, A., C.1 aNagle, M., W.1 aNelson, C., P.1 aNiessner, A.1 aNiiranen, T.1 aO'Donoghue, M., L.1 aOwens, A., T.1 aPalmer, C., N. A.1 aParry, H., M.1 aPerola, M.1 aPortilla-Fernandez, E.1 aPsaty, B., M.1 aRice, K., M.1 aRidker, P., M.1 aRomaine, S., P. R.1 aRotter, J., I.1 aSalo, P.1 aSalomaa, V.1 avan Setten, J.1 aShalaby, A., A.1 aSmelser, D., T.1 aSmith, N., L.1 aStender, S.1 aStott, D., J.1 aSvensson, P.1 aTammesoo, M., L.1 aTaylor, K., D.1 aTeder-Laving, M.1 aTeumer, A.1 aThorgeirsson, G.1 aThorsteinsdottir, U.1 aTorp-Pedersen, C.1 aTrompet, S.1 aTyl, B.1 aUitterlinden, A., G.1 aVeluchamy, A.1 aV?lker, U.1 aVoors, A., A.1 aWang, X.1 aWareham, N., J.1 aWaterworth, D.1 aWeeke, P., E.1 aWeiss, R.1 aWiggins, K., L.1 aXing, H.1 aYerges-Armstrong, L., M.1 aYu, B.1 aZannad, F.1 aZhao, J., H.1 aHemingway, H.1 aSamani, N., J.1 aMcMurray, J., J. V.1 aYang, J.1 aVisscher, P., M.1 aNewton-Cheh, C.1 aMalarstig, A.1 aHolm, H.1 aLubitz, S., A.1 aSattar, N.1 aHolmes, M., V.1 aCappola, T., P.1 aAsselbergs, F., W.1 aHingorani, A., D.1 aKuchenbaecker, K.1 aEllinor, P., T.1 aLang, C., C.1 aStefansson, K.1 aSmith, J., G.1 aVasan, R., S.1 aSwerdlow, D., I.1 aLumbers, R., T.1 aAbecasis, G.1 aBackman, J.1 aBai, X.1 aBalasubramanian, S.1 aBanerjee, N.1 aBaras, A.1 aBarnard, L.1 aBeechert, C.1 aBlumenfeld, A.1 aCantor, M.1 aChai, Y.1 aChung, J.1 aCoppola, G.1 aDamask, A.1 aDewey, F.1 aEconomides, A.1 aEom, G.1 aForsythe, C.1 aFuller, E., D.1 aGu, Z.1 aGurski, L.1 aGuzzardo, P., M.1 aHabegger, L.1 aHahn, Y.1 aHawes, A.1 avan Hout, C.1 aJones, M., B.1 aKhalid, S.1 aLattari, M.1 aLi, A.1 aLin, N.1 aLiu, D.1 aLopez, A.1 aManoochehri, K.1 aMarchini, J.1 aMarcketta, A.1 aMaxwell, E., K.1 aMcCarthy, S.1 aMitnaul, L., J.1 aO'Dushlaine, C.1 aOverton, J., D.1 aPadilla, M., S.1 aPaulding, C.1 aPenn, J.1 aPradhan, M.1 aReid, J., G.1 aSchleicher, T., D.1 aSchurmann, C.1 aShuldiner, A.1 aStaples, J., C.1 aSun, D.1 aToledo, K.1 aUlloa, R., H.1 aWidom, L.1 aWolf, S., E.1 aYadav, A.1 aYe, B. uhttps://chs-nhlbi.org/node/828903512nas a2200685 4500008004100000245014200041210006900183260000800252300001600260490000700276520167300283100001801956700002101974700001601995700002002011700002102031700001802052700001302070700001402083700001802097700002002115700001702135700001702152700001702169700001802186700002202204700001802226700001902244700001502263700001902278700001602297700001802313700001802331700001502349700001702364700002202381700001802403700001902421700001202440700001402452700001202466700002302478700001802501700001902519700001802538700001402556700001502570700001602585700001702601700001802618700001902636700002202655700001902677700002702696700001702723700001402740700002002754700001602774856003602790 2020 eng d00a{Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke0 aGenomeWide Association Study MetaAnalysis of Stroke in 22 000 In cAug a2454–24630 v513 aStroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans.\ The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts.\ In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci.\ These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.1 aKeene, K., L.1 aHyacinth, H., I.1 aBis, J., C.1 aKittner, S., J.1 aMitchell, B., D.1 aCheng, Y., C.1 aPare, G.1 aChong, M.1 aO'Donnell, M.1 aMeschia, J., F.1 aChen, W., M.1 aSale, M., M.1 aRich, S., S.1 aNalls, M., A.1 aZonderman, A., B.1 aEvans, M., K.1 aWilson, J., G.1 aCorrea, A.1 aMarkus, H., S.1 aTraylor, M.1 aLewis, C., M.1 aCarty, C., L.1 aReiner, A.1 aHaessler, J.1 aLangefeld, C., D.1 aGottesman, R.1 aMosley, T., H.1 aWoo, D.1 aYaffe, K.1 aLiu, Y.1 aLongstreth, W., T.1 aPsaty, B., M.1 aKooperberg, C.1 aLange, L., A.1 aSacco, R.1 aRundek, T.1 aLee, J., M.1 aCruchaga, C.1 aFurie, K., L.1 aArnett, D., K.1 aBenavente, O., R.1 aGrewal, R., P.1 aPeddareddygari, L., R.1 aDichgans, M.1 aMalik, R.1 aWorrall, B., B.1 aFornage, M. uhttps://chs-nhlbi.org/node/845402407nas a2200253 4500008004100000022001400041245016800055210006900223260001500292300000700307490000700314520158100321100002401902700001901926700002201945700002101967700001901988700002302007700002002030700002202050700002002072700002502092856003602117 2020 eng d a1471-228800aIncorporating sampling weights into robust estimation of Cox proportional hazards regression model, with illustration in the Multi-Ethnic Study of Atherosclerosis.0 aIncorporating sampling weights into robust estimation of Cox pro c2020 03 14 a620 v203 aBACKGROUND: Cox proportional hazards regression models are used to evaluate associations between exposures of interest and time-to-event outcomes in observational data. When exposures are measured on only a sample of participants, as they are in a case-cohort design, the sampling weights must be incorporated into the regression model to obtain unbiased estimating equations.
METHODS: Robust Cox methods have been developed to better estimate associations when there are influential outliers in the exposure of interest, but these robust methods do not incorporate sampling weights. In this paper, we extend these robust methods, which already incorporate influence weights, so that they also accommodate sampling weights.
RESULTS: Simulations illustrate that in the presence of influential outliers, the association estimate from the weighted robust method is closer to the true value than the estimate from traditional weighted Cox regression. As expected, in the absence of outliers, the use of robust methods yields a small loss of efficiency. Using data from a case-cohort study that is nested within the Multi-Ethnic Study of Atherosclerosis (MESA) longitudinal cohort study, we illustrate differences between traditional and robust weighted Cox association estimates for the relationships between immune cell traits and risk of stroke.
CONCLUSIONS: Robust weighted Cox regression methods are a new tool to analyze time-to-event data with sampling, e.g. case-cohort data, when exposures of interest contain outliers.
1 aSitlani, Colleen, M1 aLumley, Thomas1 aMcKnight, Barbara1 aRice, Kenneth, M1 aOlson, Nels, C1 aDoyle, Margaret, F1 aHuber, Sally, A1 aTracy, Russell, P1 aPsaty, Bruce, M1 aDelaney, Joseph, A C uhttps://chs-nhlbi.org/node/840502887nas a2200445 4500008004100000245015800041210006900199260000700268300001000275490000700285520163400292100001701926700002001943700001801963700001801981700002201999700001902021700002002040700002002060700002202080700001702102700002002119700001702139700002402156700001702180700001402197700001902211700001402230700001602244700001502260700001902275700001802294700001602312700001602328700001402344700001602358700001502374700001602389856003602405 2020 eng d00a{An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms0 aindividual participant data analysis of prospective cohort studi c11 a191110 v103 a{In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck's Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval = - 0.17 to 0.761 aWildisen, L.1 aDel Giovane, C.1 aMoutzouri, E.1 aBeglinger, S.1 aSyrogiannouli, L.1 aCollet, T., H.1 aCappola, A., R.1 asvold, B., O. ?1 aBakker, S., J. L.1 aYeap, B., B.1 aAlmeida, O., P.1 aCeresini, G.1 aDullaart, R., P. F.1 aFerrucci, L.1 aGrabe, H.1 aJukema, J., W.1 aNauck, M.1 aTrompet, S.1 aV?lzke, H.1 aWestendorp, R.1 aGussekloo, J.1 aKl?ppel, S.1 aAujesky, D.1 aBauer, D.1 aPeeters, R.1 aFeller, M.1 aRodondi, N. uhttps://chs-nhlbi.org/node/863806570nas a2201753 4500008004100000022001400041245007100055210006900126260001200195300001200207490000800219520164100227100002301868700002501891700002601916700002201942700001701964700002401981700002002005700001902025700002602044700001902070700001602089700002002105700002902125700002702154700001602181700002202197700002002219700002002239700002502259700002402284700001902308700002002327700001902347700002002366700002402386700002002410700002602430700002702456700002502483700002402508700001402532700002202546700002302568700002102591700002302612700001902635700002302654700001702677700002302694700001802717700002102735700001902756700002302775700002502798700002202823700002402845700002402869700001902893700002702912700001902939700001702958700002202975700001902997700002103016700001903037700002203056700001903078700001903097700002003116700002203136700002203158700002503180700001903205700002103224700002303245700002103268700002303289700002303312700002203335700001903357700001803376700002203394700002103416700002203437700002103459700002103480700002003501700001903521700002003540700002203560700001803582700002203600700002003622700001703642700001703659700001603676700001503692700002703707700002303734700001703757700002403774700002103798700002003819700002103839700002403860700002503884700002403909700002303933700002503956700002303981700002104004700001904025700002004044700001904064700002804083700001804111700002104129700002104150700002304171700001804194700002004212700002304232700001804255700002404273700002104297700002504318700002104343700001704364700001704381700001804398700002104416700002204437700002104459700001704480700002204497700002004519700002304539700002304562700002504585700002404610700002204634700002304656700002204679700002304701710005604724856003604780 2020 eng d a1476-468700aInherited causes of clonal haematopoiesis in 97,691 whole genomes.0 aInherited causes of clonal haematopoiesis in 97691 whole genomes c2020 10 a763-7680 v5863 aAge is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
1 aBick, Alexander, G1 aWeinstock, Joshua, S1 aNandakumar, Satish, K1 aFulco, Charles, P1 aBao, Erik, L1 aZekavat, Seyedeh, M1 aSzeto, Mindy, D1 aLiao, Xiaotian1 aLeventhal, Matthew, J1 aNasser, Joseph1 aChang, Kyle1 aLaurie, Cecelia1 aBurugula, Bala, Bharathi1 aGibson, Christopher, J1 aLin, Amy, E1 aTaub, Margaret, A1 aAguet, Francois1 aArdlie, Kristin1 aMitchell, Braxton, D1 aBarnes, Kathleen, C1 aMoscati, Arden1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aSilverman, Edwin, K1 aWeiss, Scott, T1 aPalmer, Nicholette, D1 aVasan, Ramachandran, S1 aBurchard, Esteban, G1 aKardia, Sharon, L R1 aHe, Jiang1 aKaplan, Robert, C1 aSmith, Nicholas, L1 aArnett, Donna, K1 aSchwartz, David, A1 aCorrea, Adolfo1 ade Andrade, Mariza1 aGuo, Xiuqing1 aKonkle, Barbara, A1 aCuster, Brian1 aPeralta, Juan, M1 aGui, Hongsheng1 aMeyers, Deborah, A1 aMcGarvey, Stephen, T1 aChen, Ida Yii-Der1 aShoemaker, Benjamin1 aPeyser, Patricia, A1 aBroome, Jai, G1 aGogarten, Stephanie, M1 aWang, Fei, Fei1 aWong, Quenna1 aMontasser, May, E1 aDaya, Michelle1 aKenny, Eimear, E1 aNorth, Kari, E1 aLauner, Lenore, J1 aCade, Brian, E1 aBis, Joshua, C1 aCho, Michael, H1 aLasky-Su, Jessica1 aBowden, Donald, W1 aCupples, Adrienne, L1 aC Y Mak, Angel1 aBecker, Lewis, C1 aSmith, Jennifer, A1 aKelly, Tanika, N1 aAslibekyan, Stella1 aHeckbert, Susan, R1 aTiwari, Hemant, K1 aYang, Ivana, V1 aHeit, John, A1 aLubitz, Steven, A1 aJohnsen, Jill, M1 aCurran, Joanne, E1 aWenzel, Sally, E1 aWeeks, Daniel, E1 aRao, Dabeeru, C1 aDarbar, Dawood1 aMoon, Jee-Young1 aTracy, Russell, P1 aButh, Erin, J1 aRafaels, Nicholas1 aLoos, Ruth, J F1 aDurda, Peter1 aLiu, Yongmei1 aHou, Lifang1 aLee, Jiwon1 aKachroo, Priyadarshini1 aFreedman, Barry, I1 aLevy, Daniel1 aBielak, Lawrence, F1 aHixson, James, E1 aFloyd, James, S1 aWhitsel, Eric, A1 aEllinor, Patrick, T1 aIrvin, Marguerite, R1 aFingerlin, Tasha, E1 aRaffield, Laura, M1 aArmasu, Sebastian, M1 aWheeler, Marsha, M1 aSabino, Ester, C1 aBlangero, John1 aWilliams, Keoki1 aLevy, Bruce, D1 aSheu, Wayne, Huey-Herng1 aRoden, Dan, M1 aBoerwinkle, Eric1 aManson, JoAnn, E1 aMathias, Rasika, A1 aDesai, Pinkal1 aTaylor, Kent, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aKooperberg, Charles1 aLaurie, Cathy, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aZhao, Hongyu1 aLange, Ethan1 aLange, Leslie1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aScheet, Paul1 aKitzman, Jacob, O1 aLander, Eric, S1 aEngreitz, Jesse, M1 aEbert, Benjamin, L1 aReiner, Alexander, P1 aJaiswal, Siddhartha1 aAbecasis, Goncalo1 aSankaran, Vijay, G1 aKathiresan, Sekar1 aNatarajan, Pradeep1 aNHLBI Trans-Omics for Precision Medicine Consortium uhttps://chs-nhlbi.org/node/862102512nas a2200229 4500008004100000022001400041245012000055210006900175260001200244300001000256490000800266520180100274100001902075700002402094700002302118700002002141700002002161700002202181700002002203700002302223856003602246 2020 eng d a1879-148400aInnate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts.0 aInnate and adaptive immune cell subsets as risk factors for coro c2020 05 a47-530 v3003 aBACKGROUND AND AIMS: Cell-mediated immunity is implicated in atherosclerosis. We evaluated whether innate and adaptive immune cell subsets in peripheral blood are risk factors for coronary heart disease.
METHODS: A nested case-cohort study (n = 2155) was performed within the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Cases of incident myocardial infarction (MI) and incident angina (n = 880 total cases) were compared with a cohort random sample (n = 1275). Immune cell phenotypes (n = 34, including CD14 monocytes, natural killer cells, γδ T cells, CD4, CD8 and CD19 lymphocyte subsets) were measured from cryopreserved cells by flow cytometry. Cox proportional hazards models with adjustment for cardiovascular disease risk factors were used to evaluate associations of cell phenotypes with incident MI and a composite phenotype of incident MI or incident angina (MI-angina) over a median 9.3 years of follow-up. Th1, Th2, Th17, T regulatory (CD4CD25CD127), naive (CD4CD45RA), memory (CD4CD45RO), and CD4CD28 cells were specified as primary hypotheses. In secondary analyses, 27 additional cell phenotypes were investigated.
RESULTS: After correction for multiple testing, there were no statistically significant associations of CD4 naive, memory, CD28, or T helper cell subsets with MI or MI-angina in MESA, CHS, or combined-cohort meta analyses. Null associations were also observed for monocyte subsets, natural killer cells, γδ T cells, CD19 B cell and differentiated CD4 and CD8 cell subsets.
CONCLUSIONS: The proportions of peripheral blood monocyte and lymphocyte subsets are not strongly related to the future occurrence of MI or angina in adults free of autoimmune disease.
1 aOlson, Nels, C1 aSitlani, Colleen, M1 aDoyle, Margaret, F1 aHuber, Sally, A1 aLanday, Alan, L1 aTracy, Russell, P1 aPsaty, Bruce, M1 aDelaney, Joseph, A uhttps://chs-nhlbi.org/node/840302307nas a2200241 4500008004100000022001400041245011000055210006900165260001600234520155400250100002401804700001901828700001801847700002001865700002001885700002401905700002101929700001601950700002201966700001801988700002302006856003602029 2020 eng d a1758-535X00aLevel and change in N-terminal pro B-type Natriuretic Peptide and kidney function and survival to age 90.0 aLevel and change in Nterminal pro Btype Natriuretic Peptide and c2020 May 173 aBACKGROUND: Many traditional cardiovascular risk factors do not predict survival to very old age. Studies have shown associations of estimated glomerular filtration rate (eGFR) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with cardiovascular disease and mortality in older populations. This study aimed to evaluate the associations of the level and change in eGFR and NT-pro-BNP with longevity to age 90 years.
METHODS: The population included participants (n=3,645) in the Cardiovascular Health Study, aged between 67-75 at baseline. The main exposures were eGFR, calculated with the Berlin Initiative Study equation (BIS2), and NT-pro-BNP, and the main outcome was survival to age 90. Mixed models were used to estimate level and change of the main exposures.
RESULTS: There was an association between baseline level and change of both eGFR and NT-pro-BNP and survival to 90, and this association persisted after adjustment for covariates. Each 10 ml/min per 1.73 m2 higher eGFR level was associated with an adjusted odds ratio (OR) of 1.23 (95% CI: 1.13, 1.34) of survival to 90, and a 0.5 ml/min/ 1.73 m2 slower decline in eGFR was associated with an OR of 1.51 (95% CI: 1.31, 1.74). A 2-fold higher level of NT-pro-BNP level had an adjusted OR of 0.67 (95% CI: 0.61, 0.73), and a 1.05-fold increase per year in NT-pro-BNP had an OR of 0.53 (95% CI: 0.43, 0.65) for survival to age 90.
CONCLUSION: eGFR and NT-pro-BNP appear to be important risk factors for longevity to age 90.
1 aHäberle, Astrid, D1 aBiggs, Mary, L1 aCushman, Mary1 aPsaty, Bruce, M1 aNewman, Anne, B1 aShlipak, Michael, G1 aGottdiener, John1 aWu, Chenkai1 aGardin, Julius, M1 aBansal, Nisha1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/839506209nas a2201549 4500008004100000022001400041245014600055210006900201260001300270300001200283490000700295520185100302100001502153700001502168700001702183700001802200700001802218700001502236700002402251700001902275700001702294700002002311700001802331700001902349700002202368700001902390700002802409700002002437700001802457700001902475700002802494700002402522700001902546700002302565700001602588700002202604700002002626700002602646700001902672700002202691700002102713700002602734700002002760700002402780700001902804700002002823700002102843700002502864700003202889700002002921700002102941700001902962700002002981700001403001700002803015700001903043700002203062700002203084700001903106700002403125700002103149700002503170700001303195700002103208700002203229700001903251700002203270700002403292700002203316700001803338700002603356700002003382700001903402700001603421700001803437700002303455700002203478700001903500700001703519700001403536700001703550700002103567700002203588700002103610700002003631700002003651700002103671700002203692700002003714700002403734700002303758700001703781700002503798700002903823700002203852700001703874700001803891700002603909700002003935700002303955700002003978700001903998700002804017700002304045700002004068700002204088700001704110700002104127700001904148700002404167700002204191700002204213700002504235700001904260700002204279700002104301700002004322700002104342700002304363700002504386700002404411700001904435700002104454700002104475700002904496700002504525700002004550700001904570700002304589700001104612856003604623 2020 eng d a1573-728400aMendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.0 aMendelian randomization analysis does not support causal associa c2020 Jul a685-6970 v353 aEpidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.
1 aZheng, Yan1 aHuang, Tao1 aWang, Tiange1 aMei, Zhendong1 aSun, Zhonghan1 aZhang, Tao1 aEllervik, Christina1 aChai, Jin-Fang1 aSim, Xueling1 avan Dam, Rob, M1 aTai, E-Shyong1 aKoh, Woon-Puay1 aDorajoo, Rajkumar1 aSaw, Seang-Mei1 aSabanayagam, Charumathi1 aWong, Tien, Yin1 aGupta, Preeti1 aRossing, Peter1 aAhluwalia, Tarunveer, S1 aVinding, Rebecca, K1 aBisgaard, Hans1 aBønnelykke, Klaus1 aWang, Yujie1 aGraff, Mariaelisa1 aVoortman, Trudy1 avan Rooij, Frank, J A1 aHofman, Albert1 avan Heemst, Diana1 aNoordam, Raymond1 aEstampador, Angela, C1 aVarga, Tibor, V1 aEnzenbach, Cornelia1 aScholz, Markus1 aThiery, Joachim1 aBurkhardt, Ralph1 aOrho-Melander, Marju1 aSchulz, Christina-Alexandra1 aEricson, Ulrika1 aSonestedt, Emily1 aKubo, Michiaki1 aAkiyama, Masato1 aZhou, Ang1 aKilpeläinen, Tuomas, O1 aHansen, Torben1 aKleber, Marcus, E1 aDelgado, Graciela1 aMcCarthy, Mark1 aLemaitre, Rozenn, N1 aFelix, Janine, F1 aJaddoe, Vincent, W V1 aWu, Ying1 aMohlke, Karen, L1 aLehtimäki, Terho1 aWang, Carol, A1 aPennell, Craig, E1 aSchunkert, Heribert1 aKessler, Thorsten1 aZeng, Lingyao1 aWillenborg, Christina1 aPeters, Annette1 aLieb, Wolfgang1 aGrote, Veit1 aRzehak, Peter1 aKoletzko, Berthold1 aErdmann, Jeanette1 aMunz, Matthias1 aWu, Tangchun1 aHe, Meian1 aYu, Caizheng1 aLecoeur, Cécile1 aFroguel, Philippe1 aCorella, Dolores1 aMoreno, Luis, A1 aLai, Chao-Qiang1 aPitkänen, Niina1 aBoreham, Colin, A1 aRidker, Paul, M1 aRosendaal, Frits, R1 ade Mutsert, Renée1 aPower, Chris1 aPaternoster, Lavinia1 aSørensen, Thorkild, I A1 aTjønneland, Anne1 aOvervad, Kim1 aDjoussé, Luc1 aRivadeneira, Fernando1 aLee, Nanette, R1 aRaitakari, Olli, T1 aKähönen, Mika1 aViikari, Jorma1 aLanghendries, Jean-Paul1 aEscribano, Joaquin1 aVerduci, Elvira1 aDedoussis, George1 aKönig, Inke1 aBalkau, Beverley1 aColtell, Oscar1 aDallongeville, Jean1 aMeirhaeghe, Aline1 aAmouyel, Philippe1 aGottrand, Frédéric1 aPahkala, Katja1 aNiinikoski, Harri1 aHyppönen, Elina1 aMärz, Winfried1 aMackey, David, A1 aGruszfeld, Dariusz1 aTucker, Katherine, L1 aFumeron, Frédéric1 aEstruch, Ramon1 aOrdovas, Jose, M1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aMozaffarian, Dariush1 aPsaty, Bruce, M1 aNorth, Kari, E1 aChasman, Daniel, I1 aQi, Lu uhttps://chs-nhlbi.org/node/841006654nas a2201705 4500008004100000022001400041245009500055210006900150260001600219520183100235100002002066700001802086700001302104700002902117700002102146700002002167700002102187700002202208700002302230700002102253700001902274700001902293700002402312700002102336700001902357700002102376700001702397700001202414700001902426700001902445700002302464700002202487700001802509700001502527700002202542700002802564700001902592700002502611700002002636700001802656700001902674700002102693700002402714700002102738700002302759700001902782700001802801700002002819700002002839700001802859700002402877700002302901700002102924700002202945700001802967700002502985700002103010700002303031700002103054700002203075700001703097700001403114700001703128700002103145700002803166700002603194700002003220700002003240700002703260700002003287700002203307700002103329700001803350700002503368700002103393700002103414700002203435700001903457700002003476700002103496700002803517700002303545700002203568700001903590700002103609700002503630700001803655700002603673700002403699700002003723700001703743700001703760700001903777700002803796700002503824700002603849700002703875700002303902700002003925700002303945700002303968700001903991700002404010700002104034700002904055700001904084700002204103700002804125700002004153700002204173700002004195700003204215700002004247700002604267700002404293700002004317700002004337700002204357700001804379700001504397700002704412700001804439700001704457700002604474700002004500700002404520700002104544700002104565700001904586700001904605700001604624700002104640700003104661700001504692700002004707700002204727700002304749700001904772700002404791700002204815700001804837710002704855710003004882856003604912 2020 eng d a1523-175500aMeta-analysis uncovers genome-wide significant variants for rapid kidney function decline.0 aMetaanalysis uncovers genomewide significant variants for rapid c2020 Oct 303 aRapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
1 aGorski, Mathias1 aJung, Bettina1 aLi, Yong1 aMatias-Garcia, Pamela, R1 aWuttke, Matthias1 aCoassin, Stefan1 aThio, Chris, H L1 aKleber, Marcus, E1 aWinkler, Thomas, W1 aWanner, Veronika1 aChai, Jin-Fang1 aChu, Audrey, Y1 aCocca, Massimiliano1 aFeitosa, Mary, F1 aGhasemi, Sahar1 aHoppmann, Anselm1 aHorn, Katrin1 aLi, Man1 aNutile, Teresa1 aScholz, Markus1 aSieber, Karsten, B1 aTeumer, Alexander1 aTin, Adrienne1 aWang, Judy1 aTayo, Bamidele, O1 aAhluwalia, Tarunveer, S1 aAlmgren, Peter1 aBakker, Stephan, J L1 aBanas, Bernhard1 aBansal, Nisha1 aBiggs, Mary, L1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBrenner, Hermann1 aCarroll, Robert, J1 aChalmers, John1 aChee, Miao-Li1 aChee, Miao-Ling1 aCheng, Ching-Yu1 aCoresh, Josef1 ade Borst, Martin, H1 aDegenhardt, Frauke1 aEckardt, Kai-Uwe1 aEndlich, Karlhans1 aFranke, Andre1 aFreitag-Wolf, Sandra1 aGampawar, Piyush1 aGansevoort, Ron, T1 aGhanbari, Mohsen1 aGieger, Christian1 aHamet, Pavel1 aHo, Kevin1 aHofer, Edith1 aHolleczek, Bernd1 aFoo, Valencia, Hui Xian1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aJosyula, Navya, Shilpa1 aKähönen, Mika1 aKhor, Chiea-Chuen1 aKoenig, Wolfgang1 aKramer, Holly1 aKrämer, Bernhard, K1 aKuhnel, Brigitte1 aLange, Leslie, A1 aLehtimäki, Terho1 aLieb, Wolfgang1 aLoos, Ruth, J F1 aLukas, Mary, Ann1 aLyytikäinen, Leo-Pekka1 aMeisinger, Christa1 aMeitinger, Thomas1 aMelander, Olle1 aMilaneschi, Yuri1 aMishra, Pashupati, P1 aMononen, Nina1 aMychaleckyj, Josyf, C1 aNadkarni, Girish, N1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aO'Donoghue, Michelle, L1 aOrho-Melander, Marju1 aPendergrass, Sarah, A1 aPenninx, Brenda, W J H1 aPreuss, Michael, H1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRosenkranz, Alexander, R1 aRossing, Peter1 aRotter, Jerome, I1 aSabanayagam, Charumathi1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSchöttker, Ben1 aSchulz, Christina-Alexandra1 aSedaghat, Sanaz1 aShaffer, Christian, M1 aStrauch, Konstantin1 aSzymczak, Silke1 aTaylor, Kent, D1 aTremblay, Johanne1 aChaker, Layal1 aHarst, Pim1 avan der Most, Peter, J1 aVerweij, Niek1 aVölker, Uwe1 aWaldenberger, Melanie1 aWallentin, Lars1 aWaterworth, Dawn, M1 aWhite, Harvey, D1 aWilson, James, G1 aWong, Tien-Yin1 aWoodward, Mark1 aYang, Qiong1 aYasuda, Masayuki1 aYerges-Armstrong, Laura, M1 aZhang, Yan1 aSnieder, Harold1 aWanner, Christoph1 aBöger, Carsten, A1 aKöttgen, Anna1 aKronenberg, Florian1 aPattaro, Cristian1 aHeid, Iris, M1 aLifeLines Cohort Study1 aRegeneron Genetics Center uhttps://chs-nhlbi.org/node/862402792nas a2200325 4500008004100000245006800041210006700109260000800176300000800184490000700192520192600199100001302125700001802138700002002156700001702176700002102193700001502214700002302229700002302252700001702275700001902292700001602311700001702327700001702344700001702361700001702378700001602395700001902411856003602430 2020 eng d00a{Mitochondrial DNA copy number and incident atrial fibrillation0 aMitochondrial DNA copy number and incident atrial fibrillation cSep a2460 v183 aMechanistic studies suggest that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown.\ We conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study (CHS). mtDNA-CN from the peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA and from multiplexed real-time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates.\ The median follow-up time was 21.4 years in ARIC, 12.9 years in MESA, and 11.0 years in CHS, during which 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups.\ Mitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management of atrial fibrillation risk.1 aZhao, D.1 aBartz, T., M.1 aSotoodehnia, N.1 aPost, W., S.1 aHeckbert, S., R.1 aAlonso, A.1 aLongchamps, R., J.1 aCastellani, C., A.1 aHong, Y., S.1 aRotter, J., I.1 aLin, H., J.1 aO'Rourke, B.1 aPankratz, N.1 aLane, J., A.1 aYang, S., Y.1 aGuallar, E.1 aArking, D., E. uhttps://chs-nhlbi.org/node/849403309nas a2200421 4500008004100000022001400041245012200055210006900177260001600246300000700262490000700269520208500276100002902361700002402390700002202414700002402436700001802460700002002478700001802498700002302516700002002539700002002559700002002579700001902599700001802618700001802636700002102654700002002675700002002695700002002715700002102735700001602756700001702772700002202789700002102811700001902832856003602851 2020 eng d a1756-994X00aMitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.0 aMitochondrial DNA copy number can influence mortality and cardio c2020 Sep 28 a840 v123 aBACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.
METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.
RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10), as well as the TFAM knockout methylation (P = 4.41 × 10) and expression (P = 4.30 × 10) studies.
CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.
1 aCastellani, Christina, A1 aLongchamps, Ryan, J1 aSumpter, Jason, A1 aNewcomb, Charles, E1 aLane, John, A1 aGrove, Megan, L1 aBressler, Jan1 aBrody, Jennifer, A1 aFloyd, James, S1 aBartz, Traci, M1 aTaylor, Kent, D1 aWang, Penglong1 aTin, Adrienne1 aCoresh, Josef1 aPankow, James, S1 aFornage, Myriam1 aGuallar, Eliseo1 aO'Rourke, Brian1 aPankratz, Nathan1 aLiu, Chunyu1 aLevy, Daniel1 aSotoodehnia, Nona1 aBoerwinkle, Eric1 aArking, Dan, E uhttps://chs-nhlbi.org/node/848007958nas a2202377 4500008004100000022001400041245011500055210006900170260001600239300000900255490000700264520122900271100001901500700001801519700002501537700002401562700002701586700002201613700002201635700002101657700002201678700002301700700002001723700002101743700002201764700002101786700002201807700002401829700002101853700002001874700001801894700001901912700001601931700002401947700003201971700002902003700002002032700002902052700002602081700002002107700002002127700002202147700002602169700001602195700002002211700002102231700001902252700001502271700002502286700002202311700002702333700002202360700002202382700002402404700001802428700002002446700002502466700001802491700001702509700002302526700002102549700002502570700002202595700002302617700001902640700002302659700002602682700001702708700001802725700002702743700002602770700002202796700002802818700002302846700002602869700002002895700002002915700002102935700001802956700001702974700002302991700001903014700002403033700002203057700002203079700002103101700002403122700002003146700002403166700002303190700001903213700001303232700001803245700002203263700003003285700002003315700002603335700002103361700002403382700002203406700002703428700001503455700001803470700001903488700002303507700002203530700002403552700002303576700001803599700001803617700001903635700001803654700002403672700001803696700001903714700001903733700002303752700002003775700001803795700002203813700002603835700002703861700002203888700002603910700001403936700001903950700002503969700002003994700001804014700002204032700001704054700001804071700002204089700001604111700002504127700002004152700001704172700002304189700001804212700002204230700002004252700001304272700002304285700001804308700002904326700002104355700002104376700001404397700002304411700001504434700002304449700001704472700001904489700003204508700002404540700002204564700002304586700002004609700002304629700002404652700002804676700002204704700002404726700002404750700001904774700002504793700002104818700001904839700001904858700002104877700002004898700002404918700002204942700002704964700002204991700002105013700002305034700002005057700001705077700001905094700002405113700002205137700001905159700001905178700002905197700002005226700002805246700001605274700001905290700002505309700002805334700002805362700002405390700001905414700002105433700002405454700002005478700002205498700002405520856003605544 2020 eng d a2041-172300aMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.0 aMultiancestry GWAS of the electrocardiographic PR interval ident c2020 May 21 a25420 v113 aThe electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
1 aNtalla, Ioanna1 aWeng, Lu-Chen1 aCartwright, James, H1 aHall, Amelia, Weber1 aSveinbjornsson, Gardar1 aTucker, Nathan, R1 aChoi, Seung, Hoan1 aChaffin, Mark, D1 aRoselli, Carolina1 aBarnes, Michael, R1 aMifsud, Borbala1 aWarren, Helen, R1 aHayward, Caroline1 aMarten, Jonathan1 aCranley, James, J1 aConcas, Maria, Pina1 aGasparini, Paolo1 aBoutin, Thibaud1 aKolcic, Ivana1 aPolasek, Ozren1 aRudan, Igor1 aAraujo, Nathalia, M1 aLima-Costa, Maria, Fernanda1 aRibeiro, Antonio, Luiz P1 aSouza, Renan, P1 aTarazona-Santos, Eduardo1 aGiedraitis, Vilmantas1 aIngelsson, Erik1 aMahajan, Anubha1 aMorris, Andrew, P1 aM, Fabiola, del Greco1 aFoco, Luisa1 aGögele, Martin1 aHicks, Andrew, A1 aCook, James, P1 aLind, Lars1 aLindgren, Cecilia, M1 aSundström, Johan1 aNelson, Christopher, P1 aRiaz, Muhammad, B1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aUlivi, Sheila1 aKähönen, Mika1 aMishra, Pashupati, P1 aMononen, Nina1 aNikus, Kjell1 aCaulfield, Mark, J1 aDominiczak, Anna1 aPadmanabhan, Sandosh1 aMontasser, May, E1 aO'Connell, Jeff, R1 aRyan, Kathleen1 aShuldiner, Alan, R1 aAeschbacher, Stefanie1 aConen, David1 aRisch, Lorenz1 aThériault, Sébastien1 aHutri-Kähönen, Nina1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aRaitakari, Olli, T1 aBarnes, Catriona, L K1 aCampbell, Harry1 aJoshi, Peter, K1 aWilson, James, F1 aIsaacs, Aaron1 aKors, Jan, A1 aDuijn, Cornelia, M1 aHuang, Paul, L1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSmith, Albert, V1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aNadkarni, Girish, N1 aPreuss, Michael, H1 aCorrea, Adolfo1 aMei, Hao1 aWilson, James1 aMeitinger, Thomas1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aWaldenberger, Melanie1 aMangino, Massimo1 aSpector, Timothy, D1 aRienstra, Michiel1 avan de Vegte, Yordi, J1 aHarst, Pim1 aVerweij, Niek1 aKääb, Stefan1 aSchramm, Katharina1 aSinner, Moritz, F1 aStrauch, Konstantin1 aCutler, Michael, J1 aFatkin, Diane1 aLondon, Barry1 aOlesen, Morten1 aRoden, Dan, M1 aShoemaker, Benjamin1 aSmith, Gustav1 aBiggs, Mary, L1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aRice, Kenneth1 aSotoodehnia, Nona1 aDe Grandi, Alessandro1 aFuchsberger, Christian1 aPattaro, Cristian1 aPramstaller, Peter, P1 aFord, Ian1 aJukema, Wouter1 aMacfarlane, Peter, W1 aTrompet, Stella1 aDörr, Marcus1 aFelix, Stephan, B1 aVölker, Uwe1 aWeiss, Stefan1 aHavulinna, Aki, S1 aJula, Antti1 aSääksjärvi, Katri1 aSalomaa, Veikko1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aLin, Henry, J1 aRotter, Jerome, I1 aTaylor, Kent, D1 aYao, Jie1 ade Mutsert, Renée1 aMaan, Arie, C1 aMook-Kanamori, Dennis, O1 aNoordam, Raymond1 aCucca, Francesco1 aDing, Jun1 aLakatta, Edward, G1 aQian, Yong1 aTarasov, Kirill, V1 aLevy, Daniel1 aLin, Honghuang1 aNewton-Cheh, Christopher, H1 aLunetta, Kathryn, L1 aMurray, Alison, D1 aPorteous, David, J1 aSmith, Blair, H1 aStricker, Bruno, H1 aUitterlinden, Andre1 avan den Berg, Marten, E1 aHaessler, Jeffrey1 aJackson, Rebecca, D1 aKooperberg, Charles1 aPeters, Ulrike1 aReiner, Alexander, P1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBoerwinkle, Eric1 aEhret, Georg, B1 aSoliman, Elsayed, Z1 aAvery, Christy, L1 aGogarten, Stephanie, M1 aKerr, Kathleen, F1 aLaurie, Cathy, C1 aSeyerle, Amanda, A1 aStilp, Adrienne1 aAssa, Solmaz1 aSaid, Abdullah1 avan der Ende, Yldau1 aLambiase, Pier, D1 aOrini, Michele1 aRamirez, Julia1 aVan Duijvenboden, Stefan1 aArnar, David, O1 aGudbjartsson, Daniel, F1 aHolm, Hilma1 aSulem, Patrick1 aThorleifsson, Gudmar1 aThorolfsdottir, Rosa, B1 aThorsteinsdottir, Unnur1 aBenjamin, Emelia, J1 aTinker, Andrew1 aStefansson, Kari1 aEllinor, Patrick, T1 aJamshidi, Yalda1 aLubitz, Steven, A1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/836802279nas a2200193 4500008004100000022001400041245009300055210006900148260001600217520167000233100002301903700002501926700002101951700001801972700001901990700002002009700002002029856003602049 2020 eng d a1758-535X00aPatterns of Cardiovascular Risk Factors in Old Age and Survival and Health Status at 90.0 aPatterns of Cardiovascular Risk Factors in Old Age and Survival c2020 Apr 083 aBACKGROUND: The population age 90 years and older is the fastest growing segment of the U.S. population. Only recently is it possible to study the factors that portend survival to this age.
METHODS: Among participants of the Cardiovascular Health Study, we studied the association of repeated measures of cardiovascular risk factors measured over 15-23 years of follow-up and not only survival to 90 years of age, but also healthy aging outcomes among the population who reached age 90. We included participants aged 67-75 years at baseline (n = 3,613/5,888) to control for birth cohort effects, and followed participants until death or age 90 (median follow-up = 14.7 years).
RESULTS: Higher systolic blood pressure was associated with a lower likelihood of survival to age 90, although this association was attenuated at older ages (p-value for interaction <.001) and crossed the null for measurements taken in participants' 80's. Higher levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and body mass index (BMI) were associated with greater longevity. Among the survivors to age 90, those with worse cardiovascular profile (high blood pressure, LDL cholesterol, glucose, and BMI; low HDL cholesterol) had lower likelihood of remaining free of cardiovascular disease, cognitive impairment, and disability.
CONCLUSION: In summary, we observed paradoxical associations between some cardiovascular risk factors and survival to old age; whereas, among those who survive to very old age, these risk factors were associated with higher risk of adverse health outcomes.
1 aOdden, Michelle, C1 aRawlings, Andreea, M1 aArnold, Alice, M1 aCushman, Mary1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/840105208nas a2200541 4500008004100000022001400041245012300055210006900178260001500247300001300262490000600275520365800281653001003939653000903949653002003958653002803978653001904006653002404025653001104049653001104060653002504071653000904096653001604105653003204121653002404153653002004177653001704197100001704214700002104231700002004252700002704272700002204299700002304321700001704344700002404361700002304385700002304408700001804431700002304449700002704472700002104499700001904520700002704539700002104566700002304587700002004610856003604630 2020 eng d a2574-380500aPerformance of the Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Body Mass Index.0 aPerformance of the Pooled Cohort Equations to Estimate Atheroscl c2020 10 01 ae20232420 v33 aImportance: Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.
Objective: To assess performance of the PCE across clinical BMI categories.
Design, Setting, and Participants: This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020.
Exposures: Participant BMI category: underweight (<18.5), normal weight (18.5 to <25), overweight (25 to <30), mild obesity (30 to <35), and moderate to severe obesity (≥35).
Main Outcomes and Measures: Discrimination (Harrell C statistic) and calibration (Nam-D'Agostino χ2 goodness-of-fit test) of the PCE across BMI categories. Improvement in discrimination and net reclassification with addition of BMI, waist circumference, and high-sensitivity C-reactive protein (hsCRP) to the PCE.
Results: Among 37 311 participants (mean [SD] age, 58.6 [11.8] years; 21 897 [58.7%] women), 380 604 person-years of follow-up were conducted. Mean (SD) baseline BMI was 29.0 (6.2), and 360 individuals (1.0%) were in the underweight category, 9937 individuals (26.6%) were in the normal weight category, 13 601 individuals (36.4%) were in the overweight category, 7783 individuals (20.9%) were in the mild obesity category, and 5630 individuals (15.1%) were in the moderate to severe obesity category. Median (interquartile range [IQR]) 10-year estimated ASCVD risk was 7.1% (2.5%-15.4%), and 3709 individuals (9.9%) developed ASCVD over a median (IQR) 10.8 [8.5-12.6] years. The PCE overestimated ASCVD risk in the overall cohort (estimated/observed [E/O] risk ratio, 1.22; 95% CI, 1.18-1.26) and across all BMI categories except the underweight category. Calibration was better near the clinical decision threshold in all BMI groups but worse among individuals with moderate or severe obesity (E/O risk ratio, 1.36; 95% CI, 1.25-1.47) and among those with the highest estimated ASCVD risk ≥20%. The PCE C statistic overall was 0.760 (95% CI, 0.753-0.767), with lower discrimination in the moderate or severe obesity group (C statistic, 0.742; 95% CI, 0.721-0.763) compared with the normal-range BMI group (C statistic, 0.785; 95% CI, 0.772-0.798). Waist circumference (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.03-1.11) and hsCRP (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.05-1.09), but not BMI, were associated with increased ASCVD risk when added to the PCE. However, these factors did not improve model performance (C statistic, 0.760; 95% CI, 0.753-0.767) with or without added metrics.
Conclusions and Relevance: These findings suggest that the PCE had acceptable model discrimination and were well calibrated at clinical decision thresholds but overestimated risk of ASCVD for individuals in overweight and obese categories, particularly individuals with high estimated risk. Incorporation of the usual clinical measures of obesity did not improve risk estimation of the PCE. Future research is needed to determine whether incorporation of alternative high-risk obesity markers (eg, weight trajectory or measures of visceral or ectopic fat) into the PCE may improve risk prediction.
10aAdult10aAged10aBody Mass Index10aCardiovascular Diseases10aCohort Studies10aCorrelation of Data10aFemale10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors1 aKhera, Rohan1 aPandey, Ambarish1 aAyers, Colby, R1 aCarnethon, Mercedes, R1 aGreenland, Philip1 aNdumele, Chiadi, E1 aNambi, Vijay1 aSeliger, Stephen, L1 aChaves, Paulo, H M1 aSafford, Monika, M1 aCushman, Mary1 aXanthakis, Vanessa1 aVasan, Ramachandran, S1 aMentz, Robert, J1 aCorrea, Adolfo1 aLloyd-Jones, Donald, M1 aBerry, Jarett, D1 ade Lemos, James, A1 aNeeland, Ian, J uhttps://chs-nhlbi.org/node/862602717nas a2200277 4500008004100000022001400041245011400055210006900169260001600238300001200254490000600266520186100272100002002133700002202153700002502175700002402200700002202224700001902246700002402265700002002289700002302309700002502332700002202357700002402379856003602403 2020 eng d a2047-998000aPlasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study.0 aPlasma Ceramides and Sphingomyelins in Relation to Atrial Fibril c2020 Feb 18 ae0128530 v93 aBackground Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76 years; 40% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7 years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.
1 aJensen, Paul, N1 aFretts, Amanda, M1 aHoofnagle, Andrew, N1 aSitlani, Colleen, M1 aMcKnight, Barbara1 aKing, Irena, B1 aSiscovick, David, S1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMozaffarian, Dariush1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/828405243nas a2201489 4500008004100000022001400041245006800055210006300123260001600186300001800202490000800220520113000228100002201358700001701380700001801397700002101415700001801436700001501454700002001469700002301489700002301512700002501535700002201560700001601582700002201598700002801620700002301648700002201671700001801693700001901711700002201730700001701752700001701769700002001786700002001806700002101826700002001847700002301867700002401890700002301914700002601937700002901963700002301992700002002015700001702035700003002052700001602082700002002098700001802118700001602136700002202152700002202174700002002196700001702216700001802233700002002251700001202271700002402283700001902307700001902326700002402345700001502369700002002384700002002404700002002424700002302444700002002467700002402487700002302511700002102534700002202555700002102577700001702598700002802615700002102643700002002664700002102684700001802705700002402723700002402747700001702771700002102788700001902809700002002828700002002848700002302868700002102891700002902912700002302941700002202964700002002986700002803006700002303034700001403057700002403071700002103095700001703116700001903133700002503152700001803177700001203195700001803207700002103225700002003246700002303266700001503289700001203304700002003316700002203336700002003358700001903378700002503397700002003422700002203442700002003464700002303484700001803507700002203525700002503547700002503572700002403597700002203621700002303643700002003666710003103686856003603717 2020 eng d a1097-417200aThe Polygenic and Monogenic Basis of Blood Traits and Diseases.0 aPolygenic and Monogenic Basis of Blood Traits and Diseases c2020 Sep 03 a1214-1231.e110 v1823 aBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
1 aVuckovic, Dragana1 aBao, Erik, L1 aAkbari, Parsa1 aLareau, Caleb, A1 aMousas, Abdou1 aJiang, Tao1 aChen, Ming-Huei1 aRaffield, Laura, M1 aTardaguila, Manuel1 aHuffman, Jennifer, E1 aRitchie, Scott, C1 aMegy, Karyn1 aPonstingl, Hannes1 aPenkett, Christopher, J1 aAlbers, Patrick, K1 aWigdor, Emilie, M1 aSakaue, Saori1 aMoscati, Arden1 aManansala, Regina1 aLo, Ken, Sin1 aQian, Huijun1 aAkiyama, Masato1 aBartz, Traci, M1 aBen-Shlomo, Yoav1 aBeswick, Andrew1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrody, Jennifer, A1 avan Rooij, Frank, J A1 aChitrala, Kumaraswamy, N1 aWilson, Peter, W F1 aChoquet, Helene1 aDanesh, John1 aDi Angelantonio, Emanuele1 aDimou, Niki1 aDing, Jingzhong1 aElliott, Paul1 aEsko, Tõnu1 aEvans, Michele, K1 aFelix, Stephan, B1 aFloyd, James, S1 aBroer, Linda1 aGrarup, Niels1 aGuo, Michael, H1 aGuo, Qi1 aGreinacher, Andreas1 aHaessler, Jeff1 aHansen, Torben1 aHowson, Joanna, M M1 aHuang, Wei1 aJorgenson, Eric1 aKacprowski, Tim1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKarthikeyan, Savita1 aKoskeridis, Fotios1 aLange, Leslie, A1 aLehtimäki, Terho1 aLinneberg, Allan1 aLiu, Yongmei1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMatsuda, Koichi1 aMohlke, Karen, L1 aMononen, Nina1 aMurakami, Yoshinori1 aNadkarni, Girish, N1 aNikus, Kjell1 aPankratz, Nathan1 aPedersen, Oluf1 aPreuss, Michael1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRich, Stephen, S1 aRodriguez, Benjamin, A T1 aRosen, Jonathan, D1 aRotter, Jerome, I1 aSchubert, Petra1 aSpracklen, Cassandra, N1 aSurendran, Praveen1 aTang, Hua1 aTardif, Jean-Claude1 aGhanbari, Mohsen1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Nicholas, A1 aWeiss, Stefan1 aCai, Na1 aKundu, Kousik1 aWatt, Stephen, B1 aWalter, Klaudia1 aZonderman, Alan, B1 aCho, Kelly1 aLi, Yun1 aLoos, Ruth, J F1 aKnight, Julian, C1 aGeorges, Michel1 aStegle, Oliver1 aEvangelou, Evangelos1 aOkada, Yukinori1 aRoberts, David, J1 aInouye, Michael1 aJohnson, Andrew, D1 aAuer, Paul, L1 aAstle, William, J1 aReiner, Alexander, P1 aButterworth, Adam, S1 aOuwehand, Willem, H1 aLettre, Guillaume1 aSankaran, Vijay, G1 aSoranzo, Nicole1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/849002534nas a2200181 4500008004100000022001400041245015900055210006900214260001600283300001200299490000600311520191100317100002302228700002302251700002302274700001902297856003602316 2020 eng d a2047-998000aPredicting Risk of Atherosclerotic Cardiovascular Disease Using Pooled Cohort Equations in Older Adults With Frailty, Multimorbidity, and Competing Risks.0 aPredicting Risk of Atherosclerotic Cardiovascular Disease Using c2020 Sep 15 ae0160030 v93 aBackground Assessment of atherosclerotic cardiovascular disease (ASCVD) risk is crucial for prevention and management, but the performance of the pooled cohort equations in older adults with frailty and multimorbidity is unknown. We evaluated the pooled cohort equations in these subgroups and the impact of competing risks. Methods and Results In 4249 community-dwelling adults, aged ≥65 years, from the CHS (Cardiovascular Health Study), we calculated 10-year risk of hard ASCVD. Frailty was determined using the Fried phenotype. Latent class analysis was used to identify individuals with multimorbidity patterns using chronic conditions. We assessed discrimination using the C-statistic and calibration by comparing predicted ASCVD risks with estimated risk using cause-specific and cumulative incidence models, by multimorbidity patterns and frailty status. A total of 917 (21.6%) participants had an ASCVD event, and 706 (16.6%) had a competing event of death. C-statistic was 0.68 in men and 0.69 in women; calibration was good when compared with cause-specific and cumulative incidence estimated risks (males, -0.1% and 3.3%; females, 0.6% and 1.4%). Latent class analysis identified 4 patterns: minimal disease, cardiometabolic, low cognition, musculoskeletal-lung depression. In the cardiometabolic pattern, ASCVD risk was overpredicted compared with cumulative incidence risk in men (7.4%) and women (6.8%). Risk was underpredicted in men (-10.7%) and women (-8.2%) with frailty compared with cause-specific risk. Miscalibration occurred mostly at high predicted risk ranges. Conclusions ASCVD prediction was good in this cohort of adults aged ≥65 years. Although calibration varied by multimorbidity patterns, frailty, and competing risks, miscalibration was mostly present at high predicted risk ranges and thus less likely to alter decision making for primary prevention therapy.
1 aNguyen, Quoc, Dinh1 aOdden, Michelle, C1 aPeralta, Carmen, A1 aKim, Dae, Hyun uhttps://chs-nhlbi.org/node/848503264nas a2200409 4500008004100000022001400041245010500055210006900160260001300229300001400242490000700256520207500263100002202338700001702360700002102377700001702398700002102415700002102436700002402457700002402481700001702505700002302522700001902545700002702564700002202591700002302613700001902636700001802655700002102673700001902694700002002713700001902733700001502752700002902767700002202796856003602818 2020 eng d a1532-541500aPutative Cut-Points in Sarcopenia Components and Incident Adverse Health Outcomes: An SDOC Analysis.0 aPutative CutPoints in Sarcopenia Components and Incident Adverse c2020 Jul a1429-14370 v683 aOBJECTIVES: Analyses performed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) identified cut-points in several metrics of grip strength for consideration in a definition of sarcopenia. We describe the associations between the SDOC-identified metrics of low grip strength (absolute or standardized to body size/composition); low dual-energy x-ray absorptiometry (DXA) lean mass as previously defined in the literature (appendicular lean mass [ALM]/ht ); and slowness (walking speed <.8 m/s) with subsequent adverse outcomes (falls, hip fractures, mobility limitation, and mortality).
DESIGN: Individual-level, sex-stratified pooled analysis. We calculated odds ratios (ORs) or hazard ratios (HRs) for incident falls, mobility limitation, hip fractures, and mortality. Follow-up time ranged from 1 year for falls to 8.8 ± 2.3 years for mortality.
SETTING: Eight prospective observational cohort studies.
PARTICIPANTS: A total of 13,421 community-dwelling men and 4,828 community-dwelling women. MEASUREMENTS Grip strength by hand dynamometry, gait speed, and lean mass by DXA.
RESULTS: Low grip strength (absolute or standardized to body size/composition) was associated with incident outcomes, usually independently of slowness, in both men and women. ORs and HRs generally ranged from 1.2 to 3.0 for those below vs above the cut-point. DXA lean mass was not consistently associated with these outcomes. When considered together, those who had both muscle weakness by absolute grip strength (<35.5 kg in men and <20 kg in women) and slowness were consistently more likely to have a fall, hip fracture, mobility limitation, or die than those without either slowness or muscle weakness.
CONCLUSION: Older men and women with both muscle weakness and slowness have a higher likelihood of adverse health outcomes. These results support the inclusion of grip strength and walking speed as components in a summary definition of sarcopenia. J Am Geriatr Soc 68:1429-1437, 2020.
1 aCawthon, Peggy, M1 aManini, Todd1 aPatel, Sheena, M1 aNewman, Anne1 aTravison, Thomas1 aKiel, Douglas, P1 aSantanasto, Adam, J1 aEnsrud, Kristine, E1 aXue, Qian-Li1 aShardell, Michelle1 aDuchowny, Kate1 aErlandson, Kristine, M1 aPencina, Karol, M1 aFielding, Roger, A1 aMagaziner, Jay1 aKwok, Timothy1 aKarlsson, Magnus1 aOhlsson, Claes1 aMellström, Dan1 aHirani, Vasant1 aRibom, Eva1 aCorrea-de-Araujo, Rosaly1 aBhasin, Shalender uhttps://chs-nhlbi.org/node/837702591nas a2200205 4500008004100000022001400041245012300055210006900178260001600247520190400263100002402167700002102191700002702212700002402239700002602263700002002289700002002309700002002329856003602349 2020 eng d a1879-191300aRelation of Biomarkers of Cardiac Injury, Stress, and Fibrosis With Cardiac Mechanics in Patients ≥ 65 Years of Age.0 aRelation of Biomarkers of Cardiac Injury Stress and Fibrosis Wit c2020 Sep 163 aHigh sensitivity cardiac troponin T (hscTnT), soluble ST2 (sST2), N-terminal B-type natriuretic peptide (NT-proBNP), and galectin-3 are biomarkers of cardiac injury, stress, myocardial stretch, and fibrosis. Elevated levels are associated with poor outcomes. However, their association with cardiac mechanics in older persons is unknown. Associations between these biomarkers and cardiac mechanics derived from speckle tracking echocardiography, including left ventricular longitudinal strain (LVLS), early diastolic strain, and left atrial reservoir strain (LARS) were evaluated using standardized beta coefficients () in a cross sectional analysis with cardiac biomarkers in older patients without cardiovascular disease, low ejection fraction, or wall motion abnormalities. Biomarker associations with strain were attenuated by demographics and risk factors. In adjusted models, LVLS was associated with continuous measures of hscTnT (β-0.06, p = 0.020), sST2 (β -0.05, p = 0.024) and NT-proBNP (β -0.06, p = 0.007). "High" levels (i.e., greater than prognostic cutpoint) of hscTnT (>13 ng/ml), sST2 (>35 ng/ml), and NT-proBNP (>190 pg/ml) were also associated with worse LVLS. In risk factor adjusted models, LARS was associated with hscTnT (β -0.08, p = 0.003) and NT-proBNP (β-0.18, p <0.0001). High hscTnT (>13 ng/ml) and high NT-proBNP (>190 pg/ml) were also both associated with worse LARS. Gal-3 was not associated with any strain measure. In conclusion, in persons ≥ 65 years of age, without cardiovascular disease, low ejection fraction, or wall motion abnormalities, hscTnT, sST2, and NT-proBNP are associated with worse LVLS. HscTnT and NT-proBNP are associated with worse LARS. In conclusion, these subclinical increases in blood biomarkers, and their associations with subtle diastolic and systolic dysfunction, may represent pre-clinical heart failure.
1 aGottdiener, John, S1 aSeliger, Stephen1 aDeFilippi, Christopher1 aChristenson, Robert1 aBaldridge, Abigail, S1 aKizer, Jorge, R1 aPsaty, Bruce, M1 aShah, Sanjiv, J uhttps://chs-nhlbi.org/node/848203741nas a2200625 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520194400253100001402197700001402211700002002225700002402245700002302269700002102292700002302313700001702336700001502353700002102368700002402389700001702413700001602430700002502446700002202471700002202493700001502515700002402530700002002554700002002574700002102594700002502615700002002640700002402660700002302684700002602707700001302733700001402746700002002760700002402780700002402804700001802828700002902846700002502875700002002900700001902920700002002939700002202959700002102981700002403002710005303026856003603079 2020 eng d a2574-830000aRole of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.0 aRole of Rare and LowFrequency Variants in GeneAlcohol Interactio c2020 Aug ae0027720 v133 aBACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.
METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.
RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .
CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
1 aWang, Zhe1 aChen, Han1 aBartz, Traci, M1 aBielak, Lawrence, F1 aChasman, Daniel, I1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aLim, Elise1 aNoordam, Raymond1 aRichard, Melissa, A1 aWang, Heming1 aCade, Brian1 aCupples, Adrienne, L1 ade Vries, Paul, S1 aGiulanini, Franco1 aLee, Jiwon1 aLemaitre, Rozenn, N1 aMartin, Lisa, W1 aReiner, Alex, P1 aRich, Stephen, S1 aSchreiner, Pamela, J1 aSidney, Stephen1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 avan Dijk, Ko, Willems1 aYao, Jie1 aZhao, Wei1 aFornage, Myriam1 aKardia, Sharon, L R1 aKooperberg, Charles1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRidker, Paul, M1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aMorrison, Alanna, C1 aCHARGE Gene-Lifestyle Interactions Working Group uhttps://chs-nhlbi.org/node/840703481nas a2200493 4500008004100000022001400041245010600055210006900161260001600230300001400246490000700260520202600267100002002293700001802313700002202331700002602353700002202379700002002401700002402421700002402445700002002469700002202489700001702511700002202528700002502550700002102575700001802596700002002614700002002634700003002654700002502684700001902709700002702728700002202755700002002777700002202797700002202819700002302841700002002864700002402884700002002908700002302928856003602951 2020 eng d a1558-359700aSex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure.0 aSexSpecific Associations of Cardiovascular Risk Factors and Biom c2020 Sep 22 a1455-14650 v763 aBACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.
OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF.
METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.
RESULTS: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001).
CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.
1 aSuthahar, Navin1 aLau, Emily, S1 aBlaha, Michael, J1 aPaniagua, Samantha, M1 aLarson, Martin, G1 aPsaty, Bruce, M1 aBenjamin, Emelia, J1 aAllison, Matthew, A1 aBartz, Traci, M1 aJanuzzi, James, L1 aLevy, Daniel1 aMeems, Laura, M G1 aBakker, Stephan, J L1 aLima, João, A C1 aCushman, Mary1 aLee, Douglas, S1 aWang, Thomas, J1 adeFilippi, Christopher, R1 aHerrington, David, M1 aNayor, Matthew1 aVasan, Ramachandran, S1 aGardin, Julius, M1 aKizer, Jorge, R1 aBertoni, Alain, G1 aAllen, Norrina, B1 aGansevoort, Ron, T1 aShah, Sanjiv, J1 aGottdiener, John, S1 aHo, Jennifer, E1 ade Boer, Rudolf, A uhttps://chs-nhlbi.org/node/848802530nas a2200229 4500008004100000022001400041245007700055210006900132260001300201300001200214490000700226520185800233100002402091700002102115700002302136700002002159700002102179700002402200700002002224700002002244856003602264 2020 eng d a1532-841400aSoluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults.0 aSoluble CD14 and Risk of Heart Failure and Its Subtypes in Older c2020 May a410-4190 v263 aBACKGROUND: CD14 is a membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation. Soluble CD14 (sCD14) levels carry a poor prognosis in chronic heart failure (HF), but whether elevations in sCD14 precede HF is unknown. We tested the hypothesis that sCD14 is associated with HF incidence and its subtypes independent of major inflammatory biomarkers among older adults.
METHODS AND RESULTS: We included participants in the Cardiovascular Health Study without preexisting HF and available baseline sCD14. We evaluated the associations of sCD14, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and white blood cell count (WBC) with incident HF and subtypes using Cox regression. Among 5217 participants, 1878 had incident HF over 13.6 years (609 classifiable as HF with preserved ejection fraction [HFpEF] and 419 as HF with reduced ejection fraction [HFrEF]). After adjusting for clinical and laboratory covariates, sCD14 was significantly associated with incident HF (hazard ratio [HR]: 1.56 per doubling, 95% confidence interval [CI]: 1.29-1.89), an association that was numerically stronger than for hsCRP (HR per doubling: 1.10, 95% CI: 1.06-1.15), IL-6 (HR: 1.18, 95% CI: 1.10-1.25), and WBC (HR: 1.24, 95% CI: 1.09-1.42), and that remained significant after adjustment for the other markers of inflammation. This association for sCD14 was observed with HFpEF (HR: 1.50, 95% CI: 1.07-2.10) but not HFrEF (HR: 0.99, 95% CI: 0.67-1.49).
CONCLUSIONS: Plasma sCD14 was associated with incident HF independently and numerically more strongly than other major inflammatory markers. This association was only observed with HFpEF in the subset with classifiable HF subtypes. Pending replication, these findings have potentially important therapeutic implications.
1 aAl-Kindi, Sadeer, G1 aBůzková, Petra1 aShitole, Sanyog, G1 aReiner, Alex, P1 aGarg, Parveen, K1 aGottdiener, John, S1 aPsaty, Bruce, M1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/837603249nas a2200385 4500008004100000022001400041245014700055210006900202260001600271520204100287100001902328700001902347700003002366700002602396700003102422700001902453700002102472700002102493700002502514700001702539700002102556700002502577700001602602700002302618700002102641700002002662700001902682700001902701700002202720700001802742700001802760700002802778700002102806856003602827 2020 eng d a1523-175500aA systematic review and participant-level meta-analysis found little association of retinal microvascular caliber and reduced kidney function.0 asystematic review and participantlevel metaanalysis found little c2020 Aug 153 aPreviously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 μm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2 % of 33,222 and 11.3 % of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95- 1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.
1 aLye, Weng, Kit1 aPaterson, Euan1 aPatterson, Christopher, C1 aMaxwell, Alexander, P1 aAbdul, Riswana, Banu Binte1 aTai, Shyong, E1 aCheng, Ching, Yu1 aKayama, Takamasa1 aYamashita, Hidetoshi1 aSarnak, Mark1 aShlipak, Michael1 aMatsushita, Kunihiro1 aMutlu, Unal1 aIkram, Mohammad, A1 aKlaver, Caroline1 aKifley, Annette1 aMitchell, Paul1 aMyers, Chelsea1 aKlein, Barbara, E1 aKlein, Ronald1 aWong, Tien, Y1 aSabanayagam, Charumathi1 aMcKay, Gareth, J uhttps://chs-nhlbi.org/node/862805226nas a2201465 4500008004100000022001400041245010900055210006900164260001600233300001800249490000800267520110800275100002001383700002301403700001801426700001801444700002501462700001901487700001901506700001501525700001801540700002201558700001701580700001501597700002201612700002501634700001701659700001701676700001701693700002101710700002301731700001901754700002001773700002001793700002101813700002001834700002301854700002401877700002301901700002601924700003101950700001501981700002001996700001902016700001702035700003002052700001602082700002002098700001802118700001602136700002202152700002002174700001702194700001802211700002002229700002402249700001902273700001902292700002402311700002002335700001502355700002002370700002002390700002002410700002302430700002002453700002402473700002202497700002102519700002202540700002102562700002102583700001702604700002802621700002102649700002202670700002002692700002102712700001802733700002402751700002402775700002002799700001702819700002402836700002102860700001902881700002002900700002002920700002302940700002202963700002102985700002903006700002303035700002203058700002003080700002803100700002303128700001403151700002403165700002503189700002103214700001703235700001903252700002503271700002303296700002303319700001203342700002503354700002803379700002803407700001703435700002003452700002203472700002503494700002303519700002303542700002003565700002003585700002303605700002503628700001803653700002203671710003103693856003603724 2020 eng d a1097-417200aTrans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.0 aTransethnic and AncestrySpecific BloodCell Genetics in 746667 In c2020 Sep 03 a1198-1213.e140 v1823 aMost loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
1 aChen, Ming-Huei1 aRaffield, Laura, M1 aMousas, Abdou1 aSakaue, Saori1 aHuffman, Jennifer, E1 aMoscati, Arden1 aTrivedi, Bhavi1 aJiang, Tao1 aAkbari, Parsa1 aVuckovic, Dragana1 aBao, Erik, L1 aZhong, Xue1 aManansala, Regina1 aLaplante, Véronique1 aChen, Minhui1 aLo, Ken, Sin1 aQian, Huijun1 aLareau, Caleb, A1 aBeaudoin, Mélissa1 aHunt, Karen, A1 aAkiyama, Masato1 aBartz, Traci, M1 aBen-Shlomo, Yoav1 aBeswick, Andrew1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrody, Jennifer, A1 avan Rooij, Frank, J A1 aChitrala, Kumaraswamynaidu1 aCho, Kelly1 aChoquet, Helene1 aCorrea, Adolfo1 aDanesh, John1 aDi Angelantonio, Emanuele1 aDimou, Niki1 aDing, Jingzhong1 aElliott, Paul1 aEsko, Tõnu1 aEvans, Michele, K1 aFloyd, James, S1 aBroer, Linda1 aGrarup, Niels1 aGuo, Michael, H1 aGreinacher, Andreas1 aHaessler, Jeff1 aHansen, Torben1 aHowson, Joanna, M M1 aHuang, Qin, Qin1 aHuang, Wei1 aJorgenson, Eric1 aKacprowski, Tim1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKarthikeyan, Savita1 aKoskeridis, Fotis1 aLange, Leslie, A1 aLehtimäki, Terho1 aLerch, Markus, M1 aLinneberg, Allan1 aLiu, Yongmei1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMartin, Hilary, C1 aMatsuda, Koichi1 aMohlke, Karen, L1 aMononen, Nina1 aMurakami, Yoshinori1 aNadkarni, Girish, N1 aNauck, Matthias1 aNikus, Kjell1 aOuwehand, Willem, H1 aPankratz, Nathan1 aPedersen, Oluf1 aPreuss, Michael1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRoberts, David, J1 aRich, Stephen, S1 aRodriguez, Benjamin, A T1 aRosen, Jonathan, D1 aRotter, Jerome, I1 aSchubert, Petra1 aSpracklen, Cassandra, N1 aSurendran, Praveen1 aTang, Hua1 aTardif, Jean-Claude1 aTrembath, Richard, C1 aGhanbari, Mohsen1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Nicholas, A1 aZonderman, Alan, B1 aWilson, Peter, W F1 aLi, Yun1 aButterworth, Adam, S1 aGauchat, Jean-François1 aChiang, Charleston, W K1 aLi, Bingshan1 aLoos, Ruth, J F1 aAstle, William, J1 aEvangelou, Evangelos1 avan Heel, David, A1 aSankaran, Vijay, G1 aOkada, Yukinori1 aSoranzo, Nicole1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aAuer, Paul, L1 aLettre, Guillaume1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/848104340nas a2200733 4500008004100000022001400041245013200055210006900187260001300256300001200269490000700281520227500288100001602563700002202579700002002601700002502621700002302646700001302669700002702682700001902709700001602728700002602744700001902770700001702789700002202806700002002828700001702848700002802865700002102893700002402914700001702938700002402955700001802979700002602997700002003023700002003043700002103063700002403084700002003108700002203128700002303150700002403173700002003197700001603217700001803233700001803251700001503269700002003284700002103304700002103325700001503346700001803361700001603379700002303395700001703418700001603435700001803451700002703469700001703496700002003513700002003533700001703553856003603570 2020 eng d a2574-830000aWhole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality.0 aWhole Blood DNA Methylation Signatures of Diet Are Associated Wi c2020 Aug ae0027660 v133 aBACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied.
METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.
RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10).
CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.
1 aMa, Jiantao1 aRebholz, Casey, M1 aBraun, Kim, V E1 aReynolds, Lindsay, M1 aAslibekyan, Stella1 aXia, Rui1 aBiligowda, Niranjan, G1 aHuan, Tianxiao1 aLiu, Chunyu1 aMendelson, Michael, M1 aJoehanes, Roby1 aHu, Emily, A1 aVitolins, Mara, Z1 aWood, Alexis, C1 aLohman, Kurt1 aOchoa-Rosales, Carolina1 avan Meurs, Joyce1 aUitterlinden, Andre1 aLiu, Yongmei1 aElhadad, Mohamed, A1 aHeier, Margit1 aWaldenberger, Melanie1 aPeters, Annette1 aColicino, Elena1 aWhitsel, Eric, A1 aBaldassari, Antoine1 aGharib, Sina, A1 aSotoodehnia, Nona1 aBrody, Jennifer, A1 aSitlani, Colleen, M1 aTanaka, Toshiko1 aHill, David1 aCorley, Janie1 aDeary, Ian, J1 aZhang, Yan1 aSchöttker, Ben1 aBrenner, Hermann1 aWalker, Maura, E1 aYe, Shumao1 aNguyen, Steve1 aPankow, Jim1 aDemerath, Ellen, W1 aZheng, Yinan1 aHou, Lifang1 aLiang, Liming1 aLichtenstein, Alice, H1 aHu, Frank, B1 aFornage, Myriam1 aVoortman, Trudy1 aLevy, Daniel uhttps://chs-nhlbi.org/node/844604776nas a2201261 4500008004100000022001400041245010300055210006900158260001500227300000900242490000700251520104900258653001001307653002201317653000901339653002201348653005001370653002901420653002401449653001101473653002201484653001701506653003801523653003401561653001101595653005001606653000901656653000901665653001601674653003601690653004101726653004301767653004001810653004601850653002801896100001701924700001601941700001801957700001801975700001501993700001502008700001702023700001902040700001702059700003002076700002902106700002202135700002302157700001302180700002102193700001902214700001902233700001502252700002002267700001902287700002302306700002002329700002502349700002002374700002002394700002402414700002002438700002702458700002102485700002002506700001702526700001902543700002002562700001702582700001702599700002202616700002302638700002002661700002502681700002802706700002202734700002402756700001702780700002602797700002002823700002302843700003102866700002502897700001902922700002002941700002102961700002402982700001903006700002003025700002103045700002403066700002503090700002403115700002203139700002003161700002103181700002503202700002303227700002603250700002503276700002403301700001703325700002003342700002103362710006503383710003003448856003603478 2020 eng d a2041-172300aWhole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.0 aWhole genome sequence analysis of pulmonary function and COPD in c2020 10 14 a51820 v113 aChronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aCalcium-Binding Proteins10aFeasibility Studies10aFemale10aFollow-Up Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aIntracellular Signaling Peptides and Proteins10aLung10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Inhibitors of Activated STAT10aPulmonary Disease, Chronic Obstructive10aRespiratory Physiological Phenomena10aSmall Ubiquitin-Related Modifier Proteins10aWhole Genome Sequencing1 aZhao, Xutong1 aQiao, Dandi1 aYang, Chaojie1 aKasela, Silva1 aKim, Wonji1 aMa, Yanlin1 aShrine, Nick1 aBatini, Chiara1 aSofer, Tamar1 aTaliun, Sarah, A Gagliano1 aSakornsakolpat, Phuwanat1 aBalte, Pallavi, P1 aProkopenko, Dmitry1 aYu, Bing1 aLange, Leslie, A1 aDupuis, Josée1 aCade, Brian, E1 aLee, Jiwon1 aGharib, Sina, A1 aDaya, Michelle1 aLaurie, Cecelia, A1 aRuczinski, Ingo1 aCupples, Adrienne, L1 aLoehr, Laura, R1 aBartz, Traci, M1 aMorrison, Alanna, C1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aWilson, James, G1 aTaylor, Kent, D1 aDurda, Peter1 aJohnson, Craig1 aCornell, Elaine1 aGuo, Xiuqing1 aLiu, Yongmei1 aTracy, Russell, P1 aArdlie, Kristin, G1 aAguet, Francois1 aVanDenBerg, David, J1 aPapanicolaou, George, J1 aRotter, Jerome, I1 aBarnes, Kathleen, C1 aJain, Deepti1 aNickerson, Deborah, A1 aMuzny, Donna, M1 aMetcalf, Ginger, A1 aDoddapaneni, Harshavardhan1 aDugan-Perez, Shannon1 aGupta, Namrata1 aGabriel, Stacey1 aRich, Stephen, S1 aO'Connor, George, T1 aRedline, Susan1 aReed, Robert, M1 aLaurie, Cathy, C1 aDaviglus, Martha, L1 aPreudhomme, Liana, K1 aBurkart, Kristin, M1 aKaplan, Robert, C1 aWain, Louise, V1 aTobin, Martin, D1 aLondon, Stephanie, J1 aLappalainen, Tuuli1 aOelsner, Elizabeth, C1 aAbecasis, Goncalo, R1 aSilverman, Edwin, K1 aBarr, Graham1 aCho, Michael, H1 aManichaikul, Ani1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Lung Working Group uhttps://chs-nhlbi.org/node/863902650nas a2200241 4500008004100000022001400041245010200055210006900157260001600226520189900242100002102141700001102162700002302173700002002196700001902216700002302235700003002258700002002288700002402308700002002332700002002352856003602372 2021 eng d a1468-201X00aAdverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study.0 aAdverse cardiac mechanics and incident coronary heart disease in c2021 Jul 133 aOBJECTIVES: Speckle-tracking echocardiography enables detection of abnormalities in cardiac mechanics with higher sensitivity than conventional measures of left ventricular (LV) dysfunction and may provide insight into the pathogenesis of coronary heart disease (CHD). We investigated the relationship of LV longitudinal strain, LV early diastolic strain rate (SR) and left atrial (LA) reservoir strain with long-term CHD incidence in community-dwelling older adults.
METHODS: The association of all three strain measures with incidence of non-fatal and fatal CHD (primary outcome of revascularisation, non-fatal and fatal myocardial infarction) was examined in the population-based Cardiovascular Health Study using multivariable Cox proportional hazards models. Follow-up was truncated at 10 years.
RESULTS: We included 3313 participants (mean (SD) age 72.6 (5.5) years). During a median follow-up of 10.0 (25th-75th percentile 7.7-10.0) years, 439 CHD events occurred. LV longitudinal strain (HR=1.25 per SD decrement, 95% CI 1.09 to 1.43) and LV early diastolic SR (HR=1.31 per SD decrement, 95% CI 1.14 to 1.50) were associated with a significantly greater risk of incident CHD after adjustment for potential confounders. By contrast, LA reservoir strain was not associated with incident CHD (HR=1.06 per SD decrement, 95% CI 0.94 to 1.19). Additional adjustment for biochemical and echocardiographic measures of myocardial stress, dysfunction and remodelling did not meaningfully alter these associations.
CONCLUSION: We found an association between echocardiographic measures of subclinically altered LV mechanics and incident CHD. These findings inform the underlying biology of subclinical LV dysfunction and CHD. Early detection of asymptomatic myocardial dysfunction may offer an opportunity for prevention and early intervention.
1 aMassera, Daniele1 aHu, Mo1 aDelaney, Joseph, A1 aBartz, Traci, M1 aBach, Megan, E1 aDvorak, Stephen, J1 adeFilippi, Christopher, R1 aPsaty, Bruce, M1 aGottdiener, John, S1 aKizer, Jorge, R1 aShah, Sanjiv, J uhttps://chs-nhlbi.org/node/883302635nas a2200241 4500008004100000022001400041245006200055210006100117260001300178300001200191490000700203520196100210100002002171700002002191700002202211700002002233700001602253700002202269700002302291700002002314700002302334856003602357 2021 eng d a1942-008000aAssociation Between Myocardial Strain and Frailty in CHS.0 aAssociation Between Myocardial Strain and Frailty in CHS c2021 May ae0121160 v143 aBACKGROUND: Myocardial strain, measured by speckle-tracking echocardiography, is a novel measure of subclinical cardiovascular disease and may reflect myocardial aging. We evaluated the association between myocardial strain and frailty-a clinical syndrome of lack of physiological reserve.
METHODS: Frailty was defined in participants of the CHS (Cardiovascular Health Study) as having ≥3 of the following clinical criteria: weakness, slowness, weight loss, exhaustion, and inactivity. Using speckle-tracking echocardiography data, we examined the cross-sectional (n=3206) and longitudinal (n=1431) associations with frailty among participants who had at least 1 measure of myocardial strain, left ventricular longitudinal strain (LVLS), left ventricular early diastolic strain rate and left atrial reservoir strain, and no history of cardiovascular disease or heart failure at the time of echocardiography.
RESULTS: In cross-sectional analyses, lower (worse) LVLS was associated with prevalent frailty; this association was robust to adjustment for left ventricular ejection fraction (adjusted odds ratio, 1.32 [95% CI, 1.07-1.61] per 1-SD lower strain; =0.007) and left ventricular stroke volume (adjusted OR, 1.32 [95% CI, 1.08-1.61] per 1-SD lower strain; =0.007). In longitudinal analyses, adjusted associations of LVLS and left ventricular early diastolic strain with incident frailty were 1.35 ([95% CI, 0.96-1.89] =0.086) and 1.58 ([95% CI, 1.11-2.27] =0.013, respectively). Participants who were frail and had the worst LVLS had a 2.2-fold increased risk of death (hazard ratio, 2.20 [95% CI, 1.81-2.66]; <0.0001).
CONCLUSIONS: In community-dwelling older adults without prevalent cardiovascular disease, worse LVLS by speckle-tracking echocardiography, reflective of subclinical myocardial dysfunction, was associated with frailty. Frailty and LVLS have an additive effect on mortality risk.
1 aTan, Annabel, X1 aShah, Sanjiv, J1 aSanders, Jason, L1 aPsaty, Bruce, M1 aWu, Chenkai1 aGardin, Julius, M1 aPeralta, Carmen, A1 aNewman, Anne, B1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/879004156nas a2200889 4500008004100000022001400041245009300055210006900148260001500217300000800232490000700240520170200247653001001949653001001959653001401969653003401983653001602017653001102033653003602044653003002080100001802110700001702128700002102145700001802166700001902184700001702203700002202220700001602242700002302258700002002281700001602301700002202317700001802339700002102357700002102378700001802399700002402417700002502441700002602466700002002492700001702512700001702529700002402546700001902570700001802589700002002607700002502627700001802652700001902670700001902689700002302708700001602731700002602747700002002773700002202793700002002815700002202835700002002857700002302877700002502900700001802925700002302943700002002966700001602986700001403002700002403016700002203040700002803062700002003090700002003110700001703130700002303147700002003170700002203190700001803212856003603230 2021 eng d a2158-318800aAssociation of low-frequency and rare coding variants with information processing speed.0 aAssociation of lowfrequency and rare coding variants with inform c2021 12 04 a6130 v113 aMeasures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
10aAdult10aAging10aCognition10aGenome-Wide Association Study10aGeroscience10aHumans10aPolymorphism, Single Nucleotide10aUbiquitin-Protein Ligases1 aBressler, Jan1 aDavies, Gail1 aSmith, Albert, V1 aSaba, Yasaman1 aBis, Joshua, C1 aJian, Xueqiu1 aHayward, Caroline1 aYanek, Lisa1 aSmith, Jennifer, A1 aMirza, Saira, S1 aWang, Ruiqi1 aAdams, Hieab, H H1 aBecker, Diane1 aBoerwinkle, Eric1 aCampbell, Archie1 aCox, Simon, R1 aEiriksdottir, Gudny1 aFawns-Ritchie, Chloe1 aGottesman, Rebecca, F1 aGrove, Megan, L1 aGuo, Xiuqing1 aHofer, Edith1 aKardia, Sharon, L R1 aKnol, Maria, J1 aKoini, Marisa1 aLopez, Oscar, L1 aMarioni, Riccardo, E1 aNyquist, Paul1 aPattie, Alison1 aPolasek, Ozren1 aPorteous, David, J1 aRudan, Igor1 aSatizabal, Claudia, L1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSidney, Stephen1 aSimino, Jeannette1 aSmith, Blair, H1 aTurner, Stephen, T1 avan der Lee, Sven, J1 aWare, Erin, B1 aWhitmer, Rachel, A1 aYaffe, Kristine1 aYang, Qiong1 aZhao, Wei1 aGudnason, Vilmundur1 aLauner, Lenore, J1 aFitzpatrick, Annette, L1 aPsaty, Bruce, M1 aFornage, Myriam1 aIkram, Arfan1 aDuijn, Cornelia, M1 aSeshadri, Sudha1 aMosley, Thomas, H1 aDeary, Ian, J uhttps://chs-nhlbi.org/node/898802667nas a2200301 4500008004100000022001400041245011000055210006900165260001300234300001200247490000700259520176900266100002002035700002202055700002202077700002202099700002002121700002102141700002302162700002302185700002002208700001602228700002202244700002602266700002102292700001602313856003602329 2021 eng d a1532-841400aAssociation of Midlife Cardiovascular Risk Factors With the Risk of Heart Failure Subtypes Later in Life.0 aAssociation of Midlife Cardiovascular Risk Factors With the Risk c2021 Apr a435-4440 v273 aBACKGROUND: Independent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied.
METHODS: We pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF.
RESULTS: A total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF.
CONCLUSIONS: Midlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.
1 aCohen, Laura, P1 aVittinghoff, Eric1 aPletcher, Mark, J1 aAllen, Norrina, B1 aShah, Sanjiv, J1 aWilkins, John, T1 aChang, Patricia, P1 aNdumele, Chiadi, E1 aNewman, Anne, B1 aIves, Diane1 aMaurer, Mathew, S1 aOelsner, Elizabeth, C1 aMoran, Andrew, E1 aZhang, Yiyi uhttps://chs-nhlbi.org/node/870302650nas a2200589 4500008004100000022001400041245008000055210006900135260001600204490000600220520090300226100001301129700002401142700002201166700002301188700002401211700001401235700002701249700002501276700001301301700001701314700002501331700002401356700002101380700002101401700002001422700002401442700002301466700002001489700002501509700002101534700002001555700002401575700002301599700002701622700001701649700002801666700002001694700001401714700001901728700002201747700002001769700002101789700001701810700002201827700001901849700002601868700001901894700001601913710009501929856003602024 2021 eng d a2666-979X00aAssociation of mitochondrial DNA copy number with cardiometabolic diseases.0 aAssociation of mitochondrial DNA copy number with cardiometaboli c2021 Oct 130 v13 aMitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 × 10) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 × 10), hypertension ( = 2.8 × 10), diabetes ( = 3.6 × 10), and hyperlipidemia ( = 6.3 × 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.
1 aLiu, Xue1 aLongchamps, Ryan, J1 aWiggins, Kerri, L1 aRaffield, Laura, M1 aBielak, Lawrence, F1 aZhao, Wei1 aPitsillides, Achilleas1 aBlackwell, Thomas, W1 aYao, Jie1 aGuo, Xiuqing1 aKurniansyah, Nuzulul1 aThyagarajan, Bharat1 aPankratz, Nathan1 aRich, Stephen, S1 aTaylor, Kent, D1 aPeyser, Patricia, A1 aHeckbert, Susan, R1 aSeshadri, Sudha1 aCupples, Adrienne, L1 aBoerwinkle, Eric1 aGrove, Megan, L1 aLarson, Nicholas, B1 aSmith, Jennifer, A1 aVasan, Ramachandran, S1 aSofer, Tamar1 aFitzpatrick, Annette, L1 aFornage, Myriam1 aDing, Jun1 aCorrea, Adolfo1 aAbecasis, Goncalo1 aPsaty, Bruce, M1 aWilson, James, G1 aLevy, Daniel1 aRotter, Jerome, I1 aBis, Joshua, C1 aSatizabal, Claudia, L1 aArking, Dan, E1 aLiu, Chunyu1 aTOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/899702102nas a2200265 4500008004100000022001400041245012100055210006900176260001600245520123800261100002001499700002101519700001501540700001601555700001801571700001801589700002001607700002401627700003101651700002801682700002401710700002301734710004301757856003601800 2021 eng d a1552-527900aAssociation of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease.0 aAssociation of mitochondrial variants and haplogroups identified c2021 Jun 203 aINTRODUCTION: Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent.
METHODS: We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O.
RESULTS: Analysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L missense variant (rs28709356; minor allele frequency = 0.002; P = 7.3 × 10 ) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10 ). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10 ). The expression of TAMM41 was lower in AD cases than controls (P = .00046) or mild cognitive impairment cases (P = .03).
DISCUSSION: Significant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD.
1 aZhang, Xiaoling1 aFarrell, John, J1 aTong, Tong1 aHu, Junming1 aZhu, Congcong1 aSan Wang, Li-1 aMayeux, Richard1 aHaines, Jonathan, L1 aPericak-Vance, Margaret, A1 aSchellenberg, Gerard, D1 aLunetta, Kathryn, L1 aFarrer, Lindsay, A1 aAlzheimer's Disease Sequencing Project uhttps://chs-nhlbi.org/node/879404157nas a2200289 4500008004100000022001400041245013900055210006900194260001600263300001300279490000600292520325200298100002403550700002003574700001703594700002203611700002203633700001503655700001903670700002203689700002903711700002003740700002403760700002203784700002503806856003603831 2021 eng d a2574-380500aAssociation of Trimethylamine N-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes: The Cardiovascular Health Study.0 aAssociation of Trimethylamine NOxide and Related Metabolites in c2021 Aug 02 ae21228440 v43 aImportance: Although rodent studies suggest that trimethylamine N-oxide (TMAO) influences glucose homeostasis and risk of type 2 diabetes, evidence in humans is limited.
Objective: To examine the associations of serial measures of plasma TMAO and related metabolite concentrations with incident type 2 diabetes, fasting plasma insulin and glucose levels, and the Gutt insulin sensitivity index (ISI).
Design, Setting, and Participants: This prospective cohort design assessed the association of plasma TMAO and related metabolite concentrations with diabetes outcome, whereas a cross-sectional design assessed the association with insulin and glucose levels and Gutt ISI. The participants were a cohort of older US adults from the Cardiovascular Health Study (CHS). Data from June 1989 to May 1990, from November 1992 to June 1993, and from June 1995 to June 1997 were included, with follow-up through June 2010. Levels of TMAO and related metabolites were measured in CHS plasma samples. Data were analyzed from July 2019 to September 2020.
Exposures: Plasma concentrations of TMAO, carnitine, betaine, choline, crotonobetaine, and γ-butyrobetaine, measured by high-performance liquid chromatography and mass spectrometry.
Main Outcomes and Measures: Linear regression for associations of TMAO and related metabolites with insulin and glucose levels and Gutt ISI, and proportional hazards regression for associations with diabetes.
Results: The study included 4442 participants without diabetes at baseline (mean [SD] age, 73 [6] years at entry; 2710 [61%] women). In multivariable analyses, plasma TMAO, carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level (insulin mean geometric ratio comparing fifth with first quintiles of metabolite concentration: 1.07 [95% CI, 1.04-1.10] for TMAO; 1.07 [95% CI, 1.03-1.10] for carnitine; 1.05 [95% CI, 1.02-1.08] for crotonobetaine; and 1.06 [95% CI, 1.02-1.09] for γ-butyrobetaine). In contrast, betaine and choline concentrations were associated with greater insulin sensitivity (mean difference in Gutt ISI comparing fifth with first quintiles: 6.46 [95% CI, 4.32-8.60] and 2.27 [95% CI, 0.16-4.38], respectively). Incident diabetes was identified in 661 participants during a median 12.1 (interquartile range, 6.9-17.1) years of follow-up. In multivariable analyses, TMAO and metabolites were not significantly associated with type 2 diabetes risk (hazard ratios of diabetes comparing fifth with first quintile: 1.20 [95% CI, 0.94-1.55] for TMAO; 0.96 [95% CI, 0.74-1.24] for choline; 0.88 [95% CI, 0.67-1.15] for betaine; 1.07 [95% CI, 0.83-1.37] for carnitine; 0.79 [95% CI, 0.60-1.04] for γ-butyrobetaine; and 1.06 [95% CI, 0.83-1.35] for crotonobetaine).
Conclusions and Relevance: Plasma TMAO and related metabolites were not significantly associated with type 2 diabetes among older adults. The metabolites TMAO, carnitine, γ-butyrobetaine, and crotonobetaine may be associated with insulin resistance, and betaine and choline may be associated with greater insulin sensitivity, but temporality of the associations was not established.
1 aLemaitre, Rozenn, N1 aJensen, Paul, N1 aWang, Zeneng1 aFretts, Amanda, M1 aMcKnight, Barbara1 aNemet, Ina1 aBiggs, Mary, L1 aSotoodehnia, Nona1 aOtto, Marcia, C de Olive1 aPsaty, Bruce, M1 aSiscovick, David, S1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/892203411nas a2200505 4500008004100000022001400041245011400055210006900169260001500238300001600253490000800269520201200277653001502289653001002304653001502314653002002329653002202349653001102371653002202382653001102404653000902415653001202424653001502436653001402451653002402465653001702489653001802506653002402524653001602548100001802564700002202582700002202604700002602626700002202652700002302674700001902697700002402716700002402740700002402764700001902788700002502807700002102832700001602853856003602869 2021 eng d a1945-719700aAssociations of Body Mass Index and Waist Circumference in Young Adulthood with Later Life Incident Diabetes.0 aAssociations of Body Mass Index and Waist Circumference in Young c2021 11 19 ae5011-e50200 v1063 aCONTEXT: The independent contribution of young adult exposure to overweight and obesity to later-life incident diabetes is not well studied.
OBJECTIVE: To assess the associations of exposures to elevated body mass index (BMI) and waist circumference (WC) in young adulthood (ages 18-39 years) with incident diabetes later in life (≥40 years).
DESIGN: Pooled data from 6 US prospective cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Risk Development in Young Adults Study, Cardiovascular Health Study, (4) Framingham Heart Study Offspring Cohort, (5) Health, Aging and Body Composition Study, and (6) Multi-Ethnic Study of Atherosclerosis.
SETTING: Population-based cohort studies.
PARTICIPANTS: 30 780 participants (56.1% female, 69.8% non-Hispanic white) without a diagnosis of diabetes by age 40.
INTERVENTIONS: We imputed BMI and WC trajectories from age 18 for every participant and estimated time-weighted average exposures to BMI or WC during young adulthood and later life.
MAIN OUTCOME MEASURE(S): Incident diabetes defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or use of diabetes medications.
RESULTS: During a 9-year median follow-up, 4323 participants developed incident diabetes. Young adult BMI and WC were associated with later-life incident diabetes after controlling for later-life exposures [hazard ratios (HR) 1.99 for BMI ≥ 30 kg/m2 and 2.13 for WC > 88cm (women)/>102cm (men) compared to normal ranges]. Young adult homeostatic model of insulin resistance mediated 49% and 44% of the association between BMI and WC with later-life incident diabetes. High-density lipoproteins and triglycerides mediated a smaller proportion of these associations.
CONCLUSIONS: Elevated BMI and WC during young adulthood were independently associated with later-life incident diabetes. Insulin resistance may be a key mediator.
10aAdolescent10aAdult10aBiomarkers10aBody Mass Index10aDiabetes Mellitus10aFemale10aFollow-Up Studies10aHumans10aMale10aObesity10aOverweight10aPrognosis10aProspective Studies10aRisk Factors10aUnited States10aWaist Circumference10aYoung Adult1 aNair, Nandini1 aVittinghoff, Eric1 aPletcher, Mark, J1 aOelsner, Elizabeth, C1 aAllen, Norrina, B1 aNdumele, Chiadi, E1 aWest, Nancy, A1 aStrotmeyer, Elsa, S1 aMukamal, Kenneth, J1 aSiscovick, David, S1 aBiggs, Mary, L1 aLaferrère, Blandine1 aMoran, Andrew, E1 aZhang, Yiyi uhttps://chs-nhlbi.org/node/900003306nas a2200565 4500008004100000022001400041245014400055210006900199260001600268490000600284520159100290100001701881700001501898700002501913700001701938700002301955700002701978700002402005700001702029700001202046700002402058700002202082700002702104700002502131700002402156700002002180700002002200700001402220700002602234700001502260700002402275700002002299700002002319700002202339700002002361700002102381700001702402700002102419700002402440700002102464700002302485700002102508700002002529700001902549700002302568700002102591700002702612710006502639856003602704 2021 eng d a2666-247700aBinomiRare: A robust test for association of a rare genetic variant with a binary outcome for mixed models and any case-control proportion.0 aBinomiRare A robust test for association of a rare genetic varia c2021 Jul 080 v23 aWhole-genome sequencing (WGS) and whole-exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g., family or household) when testing genetic associations. However, no existing tests of the association of a rare variant with a binary outcome in the presence of correlated data control the type 1 error where there are (1) few individuals harboring the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing a framework for testing rare variant association with a binary trait in individuals harboring at least one risk allele. In this framework, we estimate outcome probabilities under the null hypothesis and then use them, within the individuals with at least one risk allele, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small-vessel disease (SVD) stroke, short sleep, and venous thromboembolism (VTE), in whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program.
1 aSofer, Tamar1 aLee, Jiwon1 aKurniansyah, Nuzulul1 aJain, Deepti1 aLaurie, Cecelia, A1 aGogarten, Stephanie, M1 aConomos, Matthew, P1 aHeavner, Ben1 aHu, Yao1 aKooperberg, Charles1 aHaessler, Jeffrey1 aVasan, Ramachandran, S1 aCupples, Adrienne, L1 aCoombes, Brandon, J1 aSeyerle, Amanda1 aGharib, Sina, A1 aChen, Han1 aO'Connell, Jeffrey, R1 aZhang, Man1 aGottlieb, Daniel, J1 aPsaty, Bruce, M1 aLongstreth, W T1 aRotter, Jerome, I1 aTaylor, Kent, D1 aRich, Stephen, S1 aGuo, Xiuqing1 aBoerwinkle, Eric1 aMorrison, Alanna, C1 aPankow, James, S1 aJohnson, Andrew, D1 aPankratz, Nathan1 aReiner, Alex, P1 aRedline, Susan1 aSmith, Nicholas, L1 aRice, Kenneth, M1 aSchifano, Elizabeth, D1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/883803731nas a2200973 4500008004100000022001400041245010000055210006900155260001500224300000900239490000700248520100600255653000901261653002201270653001901292653002501311653001101336653002201347653001101369653000901380653001601389653002501405653002401430653002301454653001701477100002301494700002201517700002101539700001601560700003001576700002001606700001801626700002201644700003001666700001701696700002301713700002301736700002201759700002001781700002201801700002101823700002301844700001601867700002301883700002501906700002101931700002401952700002101976700002601997700002102023700002402044700002202068700001902090700002102109700001802130700001902148700001502167700002102182700001902203700001802222700001802240700001702258700002402275700001602299700002002315700001702335700002602352700002402378700002202402700002102424700001602445700002002461700002102481700002502502700002002527700001802547700001402565700001202579700002402591700002402615700002502639710005702664856003602721 2021 eng d a2041-172300aBlood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.0 aBlood n3 fatty acid levels and total and causespecific mortality c2021 04 22 a23290 v123 aThe health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
10aAged10aAged, 80 and over10aCause of Death10aFatty Acids, Omega-310aFemale10aFollow-Up Studies10aHumans10aMale10aMiddle Aged10aMortality, Premature10aProspective Studies10aProtective Factors10aRisk Factors1 aHarris, William, S1 aTintle, Nathan, L1 aImamura, Fumiaki1 aQian, Frank1 aKorat, Andres, V Ardisson1 aMarklund, Matti1 aDjoussé, Luc1 aBassett, Julie, K1 aCarmichael, Pierre-Hugues1 aChen, Yun-Yu1 aHirakawa, Yoichiro1 aKüpers, Leanne, K1 aLaguzzi, Federica1 aLankinen, Maria1 aMurphy, Rachel, A1 aSamieri, Cecilia1 aSenn, Mackenzie, K1 aShi, Peilin1 aVirtanen, Jyrki, K1 aBrouwer, Ingeborg, A1 aChien, Kuo-Liong1 aEiriksdottir, Gudny1 aForouhi, Nita, G1 aGeleijnse, Johanna, M1 aGiles, Graham, G1 aGudnason, Vilmundur1 aHelmer, Catherine1 aHodge, Allison1 aJackson, Rebecca1 aKhaw, Kay-Tee1 aLaakso, Markku1 aLai, Heidi1 aLaurin, Danielle1 aLeander, Karin1 aLindsay, Joan1 aMicha, Renata1 aMursu, Jaako1 aNinomiya, Toshiharu1 aPost, Wendy1 aPsaty, Bruce, M1 aRiserus, Ulf1 aRobinson, Jennifer, G1 aShadyab, Aladdin, H1 aSnetselaar, Linda1 aSala-Vila, Aleix1 aSun, Yangbo1 aSteffen, Lyn, M1 aTsai, Michael, Y1 aWareham, Nicholas, J1 aWood, Alexis, C1 aH Y Wu, Jason1 aHu, Frank1 aSun, Qi1 aSiscovick, David, S1 aLemaitre, Rozenn, N1 aMozaffarian, Dariush1 aFatty Acids and Outcomes Research Consortium (FORCE) uhttps://chs-nhlbi.org/node/877705153nas a2201369 4500008004100000022001400041245011700055210006900172260001500241300000900256490000700265520124400272100002301516700001901539700002101558700002701579700002001606700002201626700001901648700002601667700002601693700002001719700002001739700002301759700003001782700001901812700002301831700002901854700002801883700002401911700001901935700001901954700001201973700002401985700002102009700001702030700002502047700001902072700001802091700001502109700002402124700002002148700002002168700002202188700002002210700001702230700002602247700002602273700002102299700002402320700002302344700001802367700001902385700002102404700001902425700002102444700002202465700002102487700002102508700001902529700002102548700002202569700002002591700002102611700002002632700001902652700002202671700001802693700002202711700002402733700002002757700002302777700002002800700001802820700002202838700001402860700002002874700002002894700002202914700002402936700001802960700001702978700002402995700002103019700001803040700002403058700002003082700002203102700002303124700003003147700002503177700002503202700002603227700001903253700001903272700002103291700002003312700001403332700001903346700002503365700001703390700001903407700002103426700002203447700002703469700002203496700002503518700002203543700002403565700002103589700002003610700002003630700002003650710006503670710001203735856003603747 2021 eng d a2041-172300aChromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.0 aChromosome Xq23 is associated with lower atherogenic lipid conce c2021 04 12 a21820 v123 aAutosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
1 aNatarajan, Pradeep1 aPampana, Akhil1 aGraham, Sarah, E1 aRuotsalainen, Sanni, E1 aPerry, James, A1 ade Vries, Paul, S1 aBroome, Jai, G1 aPirruccello, James, P1 aHonigberg, Michael, C1 aAragam, Krishna1 aWolford, Brooke1 aBrody, Jennifer, A1 aAntonacci-Fulton, Lucinda1 aArden, Moscati1 aAslibekyan, Stella1 aAssimes, Themistocles, L1 aBallantyne, Christie, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aCade, Brian, E1 aDo, Ron1 aDoddapaneni, Harsha1 aEmery, Leslie, S1 aHung, Yi-Jen1 aIrvin, Marguerite, R1 aKhan, Alyna, T1 aLange, Leslie1 aLee, Jiwon1 aLemaitre, Rozenn, N1 aMartin, Lisa, W1 aMetcalf, Ginger1 aMontasser, May, E1 aMoon, Jee-Young1 aMuzny, Donna1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aStilp, Adrienne, M1 aTsai, Michael1 aWang, Fei, Fei1 aWeeks, Daniel, E1 aYanek, Lisa, R1 aWilson, James, G1 aAbecasis, Goncalo1 aArnett, Donna, K1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aChoi, Won, Jung1 aCorrea, Adolfo1 aCurran, Joanne, E1 aDaly, Mark, J1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aFornage, Myriam1 aFreedman, Barry, I1 aGabriel, Stacey1 aGermer, Soren1 aGibbs, Richard, A1 aHe, Jiang1 aHveem, Kristian1 aJarvik, Gail, P1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKenny, Eimear1 aKim, Ryan, W1 aKooperberg, Charles1 aLaurie, Cathy, C1 aLee, Seonwook1 aLloyd-Jones, Don, M1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aMathias, Rasika, A1 aMartinez, Karine, A Viaud1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aNickerson, Deborah, A1 aNorth, Kari, E1 aPalotie, Aarno1 aPark, Cheol, Joo1 aPsaty, Bruce, M1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSmith, Albert, V1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aKathiresan, Sekar1 aCupples, Adrienne, L1 aRotter, Jerome, I1 aMorrison, Alanna, C1 aRich, Stephen, S1 aRipatti, Samuli1 aWiller, Cristen1 aPeloso, Gina, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aFinnGen uhttps://chs-nhlbi.org/node/871102485nas a2200253 4500008004100000022001400041245010100055210006900156260001600225300001400241490000700255520171100262100002201973700002001995700002502015700002202040700002402062700002402086700001902110700002002129700002202149700002402171856003602195 2021 eng d a1530-856100aCirculating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study.0 aCirculating Ceramides and Sphingomyelins and Risk of Mortality T c2021 Nov 26 a1650-16590 v673 aBACKGROUND: Recent studies suggest that associations of ceramides (Cer) and sphingomyelins (SM) with health outcomes differ according to the fatty acid acylated to the sphingoid backbone. The purpose of this study was to assess associations of Cer and SM species with mortality.
METHODS: The study population included participants from the Cardiovascular Health Study (CHS), a community-based cohort of adults aged ≥65 years who were followed from 1992-2015 (n = 4612). Associations of plasma Cer and SM species carrying long-chain (i.e., 16:0) and very-long-chain (i.e., 20:0, 22:0, 24:0) saturated fatty acids with mortality were assessed using Cox proportional hazards models.
RESULTS: During a median follow-up of 10.2 years, 4099 deaths occurred. High concentrations of Cer and SM carrying fatty acid 16:0 were each associated with an increased risk of mortality. Conversely, high concentrations of several ceramide and sphingomyelin species carrying longer fatty acids were each associated with a decreased risk of mortality. The hazard ratios for total mortality per 2-fold difference in each Cer and SM species were: 1.89 (95% CI), 1.65-2.17 for Cer-16, 0.79 (95% CI, 0.70-0.88) for Cer-22, 0.74 (95% CI, 0.65-0.84) for Cer-24, 2.51 (95% CI, 2.01-3.14) for SM-16, 0.68 (95% CI, 0.58-0.79) for SM-20, 0.57 (95% CI, 0.49-0.67) for SM-22, and 0.66 (0.57-0.75) for SM-24. We found no association of Cer-20 with risk of death.
CONCLUSIONS: Associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid. Future studies are needed to explore mechanisms underlying these relationships.
1 aFretts, Amanda, M1 aJensen, Paul, N1 aHoofnagle, Andrew, N1 aMcKnight, Barbara1 aSitlani, Colleen, M1 aSiscovick, David, S1 aKing, Irena, B1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/891002603nas a2200229 4500008004100000022001400041245010000055210006900155260001600224520188800240100002002128700002002148700002102168700002102189700001902210700002202229700002002251700002202271700002402293700002002317856003602337 2021 eng d a1468-201X00aCumulative burden of clinically significant aortic stenosis in community-dwelling older adults.0 aCumulative burden of clinically significant aortic stenosis in c c2021 Jun 023 aOBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.
METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.
RESULTS: The cohort comprised 5795 participants (age 73±6, 42.2% male, 14.3% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69% (probable/definite) to 4.67% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88% to 3.71%. Of incident cases, about 85% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95% CI 0.23 to 0.81]).
CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.
1 aOwens, David, S1 aBartz, Traci, M1 aBůzková, Petra1 aMassera, Daniele1 aBiggs, Mary, L1 aCarlson, Selma, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/878706377nas a2201849 4500008004100000022001400041245011300055210006900168260001500237300000900252490000700261520114200268653001001410653003701420653001501457653003001472653001801502653001001520653003801530653001301568653001101581653003101592653001501623653002001638100002301658700002401681700001601705700002001721700001701741700002001758700002001778700001801798700001601816700001901832700001901851700002001870700002101890700001901911700002401930700001501954700003101969700001602000700002902016700001802045700001902063700002102082700002502103700002102128700002202149700002702171700002202198700002002220700001702240700001802257700002002275700001902295700002902314700002102343700001902364700002302383700002802406700001902434700003102453700002802484700002202512700002102534700003602555700002402591700001802615700001602633700001702649700002402666700001502690700002002705700001902725700002602744700002402770700003202794700002102826700002602847700002502873700002002898700001702918700002002935700002502955700002602980700002203006700001903028700001903047700001803066700002003084700001703104700002103121700002103142700001703163700002003180700002303200700002003223700003603243700002003279700002203299700002603321700002103347700002203368700002403390700001903414700002203433700003003455700001903485700002303504700002103527700001903548700001903567700002003586700002003606700002503626700003103651700002103682700002203703700002103725700002303746700001703769700001603786700002103802700001803823700002403841700002403865700001803889700001903907700002203926700001903948700002003967700002103987700002204008700002204030700002304052700002404075700002004099700002704119700002104146700002104167700001904188700001904207700001804226700002204244700002104266700002004287700002004307700002304327700002604350700002104376700002004397700002504417700002104442710002804463856003604491 2021 eng d a2041-172300aDeterminants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.0 aDeterminants of penetrance and variable expressivity in monogeni c2021 06 09 a35050 v123 aHundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
10aAdult10aBiological Variation, Population10aBiomarkers10aDiabetes Mellitus, Type 210aDyslipidemias10aExome10aGenetic Predisposition to Disease10aGenotype10aHumans10aMultifactorial Inheritance10aPenetrance10aRisk Assessment1 aGoodrich, Julia, K1 aSinger-Berk, Moriel1 aSon, Rachel1 aSveden, Abigail1 aWood, Jordan1 aEngland, Eleina1 aCole, Joanne, B1 aWeisburd, Ben1 aWatts, Nick1 aCaulkins, Lizz1 aDornbos, Peter1 aKoesterer, Ryan1 aZappala, Zachary1 aZhang, Haichen1 aMaloney, Kristin, A1 aDahl, Andy1 aAguilar-Salinas, Carlos, A1 aAtzmon, Gil1 aBarajas-Olmos, Francisco1 aBarzilai, Nir1 aBlangero, John1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBottinger, Erwin1 aBowden, Donald, W1 aCenteno-Cruz, Federico1 aChambers, John, C1 aChami, Nathalie1 aChan, Edmund1 aChan, Juliana1 aCheng, Ching-Yu1 aCho, Yoon Shin1 aContreras-Cubas, Cecilia1 aCórdova, Emilio1 aCorrea, Adolfo1 aDeFronzo, Ralph, A1 aDuggirala, Ravindranath1 aDupuis, Josée1 aGaray-Sevilla, Ma, Eugenia1 aGarcía-Ortiz, Humberto1 aGieger, Christian1 aGlaser, Benjamin1 aGonzález-Villalpando, Clicerio1 aGonzalez, Ma, Elena1 aGrarup, Niels1 aGroop, Leif1 aGross, Myron1 aHaiman, Christopher1 aHan, Sohee1 aHanis, Craig, L1 aHansen, Torben1 aHeard-Costa, Nancy, L1 aHenderson, Brian, E1 aHernandez, Juan, Manuel Mal1 aHwang, Mi, Yeong1 aIslas-Andrade, Sergio1 aJørgensen, Marit, E1 aKang, Hyun, Min1 aKim, Bong-Jo1 aKim, Young, Jin1 aKoistinen, Heikki, A1 aKooner, Jaspal, Singh1 aKuusisto, Johanna1 aKwak, Soo-Heon1 aLaakso, Markku1 aLange, Leslie1 aLee, Jong-Young1 aLee, Juyoung1 aLehman, Donna, M1 aLinneberg, Allan1 aLiu, Jianjun1 aLoos, Ruth, J F1 aLyssenko, Valeriya1 aMa, Ronald, C W1 aMartínez-Hernández, Angélica1 aMeigs, James, B1 aMeitinger, Thomas1 aMendoza-Caamal, Elvia1 aMohlke, Karen, L1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aC Y Ng, Maggie1 aNilsson, Peter, M1 aO'Donnell, Christopher, J1 aOrozco, Lorena1 aPalmer, Colin, N A1 aPark, Kyong, Soo1 aPost, Wendy, S1 aPedersen, Oluf1 aPreuss, Michael1 aPsaty, Bruce, M1 aReiner, Alexander, P1 aRevilla-Monsalve, Cristina1 aRich, Stephen, S1 aRotter, Jerome, I1 aSaleheen, Danish1 aSchurmann, Claudia1 aSim, Xueling1 aSladek, Rob1 aSmall, Kerrin, S1 aSo, Wing, Yee1 aSpector, Timothy, D1 aStrauch, Konstantin1 aStrom, Tim, M1 aTai, Shyong, E1 aTam, Claudia, H T1 aTeo, Yik, Ying1 aThameem, Farook1 aTomlinson, Brian1 aTracy, Russell, P1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 avan Dam, Rob, M1 aVasan, Ramachandran, S1 aWilson, James, G1 aWitte, Daniel, R1 aWong, Tien-Yin1 aBurtt, Noel, P1 aZaitlen, Noah1 aMcCarthy, Mark, I1 aBoehnke, Michael1 aPollin, Toni, I1 aFlannick, Jason1 aMercader, Josep, M1 aO'Donnell-Luria, Anne1 aBaxter, Samantha1 aFlorez, Jose, C1 aMacArthur, Daniel, G1 aUdler, Miriam, S1 aAMP-T2D-GENES Consortia uhttps://chs-nhlbi.org/node/877409591nas a2202833 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2021 eng d a1537-660500aDiscovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.0 aDiscovery and finemapping of height loci via highdensity imputat c2021 Apr 01 a564-5820 v1083 aAlthough many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
1 aGraff, Mariaelisa1 aJustice, Anne, E1 aYoung, Kristin, L1 aMarouli, Eirini1 aZhang, Xinruo1 aFine, Rebecca, S1 aLim, Elise1 aBuchanan, Victoria1 aRand, Kristin1 aFeitosa, Mary, F1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aShao, Yaming1 aRohde, Rebecca1 aAdeyemo, Adebowale, A1 aAldrich, Melinda, C1 aAllison, Matthew, A1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aAmos, Christopher1 aArnett, Donna, K1 aAtwood, Larry1 aBandera, Elisa, V1 aBartz, Traci1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBielak, Lawrence, F1 aBlot, William, J1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBradfield, Jonathan, P1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aBurke, Gregory1 aCade, Brian, E1 aCai, Qiuyin1 aCaporaso, Neil1 aCarlson, Chris1 aCarpten, John1 aCasey, Graham1 aChanock, Stephen, J1 aChen, Guanjie1 aChen, Minhui1 aChen, Yii-der, I1 aChen, Wei-Min1 aChesi, Alessandra1 aChiang, Charleston, W K1 aChu, Lisa1 aCoetzee, Gerry, A1 aConti, David, V1 aCooper, Richard, S1 aCushman, Mary1 aDemerath, Ellen1 aDeming, Sandra, L1 aDimitrov, Latchezar1 aDing, Jingzhong1 aDiver, Ryan1 aDuan, Qing1 aEvans, Michele, K1 aFalusi, Adeyinka, G1 aFaul, Jessica, D1 aFornage, Myriam1 aFox, Caroline1 aFreedman, Barry, I1 aGarcia, Melissa1 aGillanders, Elizabeth, M1 aGoodman, Phyllis1 aGottesman, Omri1 aGrant, Struan, F A1 aGuo, Xiuqing1 aHakonarson, Hakon1 aHaritunians, Talin1 aHarris, Tamara, B1 aHarris, Curtis, C1 aHenderson, Brian, E1 aHennis, Anselm1 aHernandez, Dena, G1 aHirschhorn, Joel, N1 aMcNeill, Lorna, Haughton1 aHoward, Timothy, D1 aHoward, Barbara1 aHsing, Ann, W1 aHsu, Yu-Han, H1 aHu, Jennifer, J1 aHuff, Chad, D1 aHuo, Dezheng1 aIngles, Sue, A1 aIrvin, Marguerite, R1 aJohn, Esther, M1 aJohnson, Karen, C1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKang, Sun, J1 aKardia, Sharon, L1 aKeating, Brendan, J1 aKittles, Rick, A1 aKlein, Eric, A1 aKolb, Suzanne1 aKolonel, Laurence, N1 aKooperberg, Charles1 aKuller, Lewis1 aKutlar, Abdullah1 aLange, Leslie1 aLangefeld, Carl, D1 aLe Marchand, Loïc1 aLeonard, Hampton1 aLettre, Guillaume1 aLevin, Albert, M1 aLi, Yun1 aLi, Jin1 aLiu, Yongmei1 aLiu, Youfang1 aLiu, Simin1 aLohman, Kurt1 aLotay, Vaneet1 aLu, Yingchang1 aMaixner, William1 aManson, JoAnn, E1 aMcKnight, Barbara1 aMeng, Yan1 aMonda, Keri, L1 aMonroe, Kris1 aMoore, Jason, H1 aMosley, Thomas, H1 aMudgal, Poorva1 aMurphy, Adam, B1 aNadukuru, Raj1 aNalls, Mike, A1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aNeslund-Dudas, Christine1 aNeuhouser, Marian, L1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgundiran, Temidayo, O1 aOgunniyi, Adesola1 aOjengbede, Oladosu1 aOkut, Hayrettin1 aOlopade, Olufunmilayo, I1 aOlshan, Andrew1 aPadhukasahasram, Badri1 aPalmer, Julie1 aPalmer, Cameron, D1 aPalmer, Nicholette, D1 aPapanicolaou, George1 aPatel, Sanjay, R1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPress, Michael, F1 aRao, D, C1 aRasmussen-Torvik, Laura, J1 aRedline, Susan1 aReiner, Alex, P1 aRhie, Suhn, K1 aRodriguez-Gil, Jorge, L1 aRotimi, Charles, N1 aRotter, Jerome, I1 aRuiz-Narvaez, Edward, A1 aRybicki, Benjamin, A1 aSalako, Babatunde1 aSale, Michèle, M1 aSanderson, Maureen1 aSchadt, Eric1 aSchreiner, Pamela, J1 aSchurmann, Claudia1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aSiscovick, David, S1 aSmith, Jennifer, A1 aSmith, Shad1 aSpeliotes, Elizabeth1 aSpitz, Margaret1 aStanford, Janet, L1 aStevens, Victoria, L1 aStram, Alex1 aStrom, Sara, S1 aSucheston, Lara1 aSun, Yan, V1 aTajuddin, Salman, M1 aTaylor, Herman1 aTaylor, Kira1 aTayo, Bamidele, O1 aThun, Michael, J1 aTucker, Margaret, A1 aVaidya, Dhananjay1 aVan Den Berg, David, J1 aVedantam, Sailaja1 aVitolins, Mara1 aWang, Zhaoming1 aWare, Erin, B1 aWassertheil-Smoller, Sylvia1 aWeir, David, R1 aWiencke, John, K1 aWilliams, Scott, M1 aWilliams, Keoki1 aWilson, James, G1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYao, Jie1 aZakai, Neil1 aZanetti, Krista1 aZemel, Babette, S1 aZhao, Wei1 aZhao, Jing Hua1 aZheng, Wei1 aZhi, Degui1 aZhou, Jie1 aZhu, Xiaofeng1 aZiegler, Regina, G1 aZmuda, Joe1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aLiu, Ching-Ti1 aHaiman, Christopher, A1 aLoos, Ruth1 aC Y Ng, Maggie1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/870504417nas a2200649 4500008004100000022001400041245006500055210006400120260001500184300001400199490000800213520264800221653000902869653001002878653002402888653002002912653002402932653001602956653001102972653002202983653001103005653001403016653000903030653003703039653001603076653002703092653002003119100002203139700002203161700001503183700001903198700001503217700002403232700003203256700002003288700001903308700002303327700001903350700001903369700002303388700001803411700002103429700002103450700002003471700002003491700002003511700002203531700002403553700002403577700002103601700002103622700002203643700002403665700001903689700002303708856003603731 2021 eng d a1524-453900aEpigenetic Age and the Risk of Incident Atrial Fibrillation.0 aEpigenetic Age and the Risk of Incident Atrial Fibrillation c2021 12 14 a1899-19110 v1443 aBACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.
METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.
RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.
CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.
10aAged10aAging10aAtrial Fibrillation10aDNA Methylation10aEpigenesis, Genetic10aEpigenomics10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aMendelian Randomization Analysis10aMiddle Aged10aModels, Cardiovascular10aModels, Genetic1 aRoberts, Jason, D1 aVittinghoff, Eric1 aLu, Ake, T1 aAlonso, Alvaro1 aWang, Biqi1 aSitlani, Colleen, M1 aMohammadi-Shemirani, Pedrum1 aFornage, Myriam1 aKornej, Jelena1 aBrody, Jennifer, A1 aArking, Dan, E1 aLin, Honghuang1 aHeckbert, Susan, R1 aProkic, Ivana1 aGhanbari, Mohsen1 aSkanes, Allan, C1 aBartz, Traci, M1 aPerez, Marco, V1 aTaylor, Kent, D1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aPankow, James, S1 aParé, Guillaume1 aSotoodehnia, Nona1 aBenjamin, Emelia, J1 aHorvath, Steve1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/900103323nas a2200721 4500008004100000245009700041210006900138260000700207300000900214490000700223520147000230100002101700700002701721700001101748700001101759700002001770700001201790700001501802700001601817700001401833700001901847700001601866700001401882700003101896700002001927700001701947700001501964700002001979700001701999700001802016700001502034700001702049700001702066700001502083700001402098700001602112700001902128700001502147700002502162700002502187700002102212700001802233700001602251700001502267700001902282700001902301700002002320700001702340700001602357700001502373700001502388700001502403700001602418700002102434700002002455700001702475700001202492700001602504700001302520700001502533700001702548856003602565 2021 eng d00a{Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption0 aEpigenomewide association metaanalysis of DNA methylation with c c05 a28300 v123 a10.1038/s41467-021-22752-6Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.1 aKarabegović, I.1 aPortilla-Fernandez, E.1 aLi, Y.1 aMa, J.1 aMaas, S., C. E.1 aSun, D.1 aHu, E., A.1 aKühnel, B.1 aZhang, Y.1 aAmbatipudi, S.1 aFiorito, G.1 aHuang, J.1 aCastillo-Fernandez, J., E.1 aWiggins, K., L.1 ade Klein, N.1 aGrioni, S.1 aSwenson, B., R.1 aPolidoro, S.1 aTreur, J., L.1 aCuenin, C.1 aTsai, P., C.1 aCosteira, R.1 aChajes, V.1 aBraun, K.1 aVerweij, N.1 aKretschmer, A.1 aFranke, L.1 avan Meurs, J., B. J.1 aUitterlinden, A., G.1 ade Knegt, R., J.1 aIkram, M., A.1 aDehghan, A.1 aPeters, A.1 aSchöttker, B.1 aGharib, S., A.1 aSotoodehnia, N.1 aBell, J., T.1 aElliott, P.1 aVineis, P.1 aRelton, C.1 aHerceg, Z.1 aBrenner, H.1 aWaldenberger, M.1 aRebholz, C., M.1 aVoortman, T.1 aPan, Q.1 aFornage, M.1 aLevy, D.1 aKayser, M.1 aGhanbari, M. uhttps://chs-nhlbi.org/node/878305600nas a2201549 4500008004100000022001400041245011600055210006900171260001500240300000900255490000700264520122500271653003501496653001901531653001601550653002001566653001401586653001101600653003801611653003401649653004501683653000901728653001101737653000901748653001401757100001801771700002201789700002901811700002101840700001901861700001601880700001201896700001901908700002101927700003301948700001901981700003202000700002602032700002202058700001902080700001902099700002302118700002102141700002102162700001802183700002702201700002202228700001802250700001802268700001802286700001902304700001802323700002502341700002102366700001902387700002202406700002002428700002102448700001202469700001502481700002102496700002102517700001902538700002202557700002202579700002002601700002102621700001902642700002002661700002202681700001902703700001602722700002002738700002002758700002402778700001802802700002202820700002102842700002202863700002402885700002102909700002702930700002202957700001502979700001302994700002703007700002203034700001503056700002503071700002003096700002503116700002403141700001703165700002503182700002003207700002103227700002003248700002103268700002003289700002303309700002203332700002003354700002003374700001903394700002003413700002303433700002203456700002303478700002303501700002203524700002403546700002603570700003503596700001903631700001703650700002403667700003003691700001403721700001703735700001503752700002003767700002603787700001703813700002203830700002203852700002103874700002203895700001903917710003503936710004303971856003604014 2021 eng d a2041-172300aEpigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.0 aEpigenomewide association study of serum urate reveals insights c2021 12 09 a71730 v123 aElevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
10aAmino Acid Transport System y+10aCohort Studies10aCpG Islands10aDNA Methylation10aEpigenome10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlucose Transport Proteins, Facilitative10aGout10aHumans10aMale10aUric Acid1 aTin, Adrienne1 aSchlosser, Pascal1 aMatias-Garcia, Pamela, R1 aThio, Chris, H L1 aJoehanes, Roby1 aLiu, Hongbo1 aYu, Zhi1 aWeihs, Antoine1 aHoppmann, Anselm1 aGrundner-Culemann, Franziska1 aMin, Josine, L1 aKuhns, Victoria, L Halperin1 aAdeyemo, Adebowale, A1 aAgyemang, Charles1 aArnlöv, Johan1 aAziz, Nasir, A1 aBaccarelli, Andrea1 aBochud, Murielle1 aBrenner, Hermann1 aBressler, Jan1 aBreteler, Monique, M B1 aCarmeli, Cristian1 aChaker, Layal1 aCoresh, Josef1 aCorre, Tanguy1 aCorrea, Adolfo1 aCox, Simon, R1 aDelgado, Graciela, E1 aEckardt, Kai-Uwe1 aEkici, Arif, B1 aEndlich, Karlhans1 aFloyd, James, S1 aFraszczyk, Eliza1 aGao, Xu1 aGào, Xīn1 aGelber, Allan, C1 aGhanbari, Mohsen1 aGhasemi, Sahar1 aGieger, Christian1 aGreenland, Philip1 aGrove, Megan, L1 aHarris, Sarah, E1 aHemani, Gibran1 aHenneman, Peter1 aHerder, Christian1 aHorvath, Steve1 aHou, Lifang1 aHurme, Mikko, A1 aHwang, Shih-Jen1 aKardia, Sharon, L R1 aKasela, Silva1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKronenberg, Florian1 aKuhnel, Brigitte1 aLadd-Acosta, Christine1 aLehtimäki, Terho1 aLind, Lars1 aLiu, Dan1 aLloyd-Jones, Donald, M1 aLorkowski, Stefan1 aLu, Ake, T1 aMarioni, Riccardo, E1 aMärz, Winfried1 aMcCartney, Daniel, L1 aMeeks, Karlijn, A C1 aMilani, Lili1 aMishra, Pashupati, P1 aNauck, Matthias1 aNowak, Christoph1 aPeters, Annette1 aProkisch, Holger1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRatliff, Scott, M1 aReiner, Alex, P1 aSchöttker, Ben1 aSchwartz, Joel1 aSedaghat, Sanaz1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStocker, Hannah, R1 aStringhini, Silvia1 aSundström, Johan1 aSwenson, Brenton, R1 avan Meurs, Joyce, B J1 avan Vliet-Ostaptchouk, Jana, V1 aVenema, Andrea1 aVölker, Uwe1 aWinkelmann, Juliane1 aWolffenbuttel, Bruce, H R1 aZhao, Wei1 aZheng, Yinan1 aLoh, Marie1 aSnieder, Harold1 aWaldenberger, Melanie1 aLevy, Daniel1 aAkilesh, Shreeram1 aWoodward, Owen, M1 aSusztak, Katalin1 aTeumer, Alexander1 aKöttgen, Anna1 aEstonian Biobank Research Team1 aGenetics of DNA Methylation Consortium uhttps://chs-nhlbi.org/node/900603927nas a2200709 4500008004100000022001400041245011200055210006900167260001600236520183400252100002102086700001302107700001702120700002902137700002002166700003002186700002202216700002502238700001702263700001302280700002002293700002202313700002302335700002202358700001802380700002302398700002402421700002902445700002702474700002102501700002902522700001902551700002102570700002302591700002102614700002302635700002802658700001802686700001902704700001902723700002102742700002002763700001802783700002502801700001902826700003202845700002902877700002002906700002102926700002302947700001902970700001802989700002203007700002203029700002403051700002103075700002403096700002003120700001803140700002303158856003603181 2021 eng d a1538-783600aFGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.0 aFGL1 as a modulator of plasma Ddimer levels Exomewide marker ana c2021 Apr 203 aBACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.
OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.
METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.
RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.
CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.
1 aThibord, Florian1 aSong, Ci1 aPattee, Jack1 aRodriguez, Benjamin, A T1 aChen, Ming-Huei1 aO'Donnell, Christopher, J1 aKleber, Marcus, E1 aDelgado, Graciela, E1 aGuo, Xiuqing1 aYao, Jie1 aTaylor, Kent, D1 aOzel, Ayse, Bilge1 aBrody, Jennifer, A1 aMcKnight, Barbara1 aGyorgy, Beata1 aSimonsick, Eleanor1 aLeonard, Hampton, L1 aCarrasquilla, Germán, D1 aGuindo-Martinez, Marta1 aSilveira, Angela1 aTemprano-Sagrera, Gerard1 aYanek, Lisa, R1 aBecker, Diane, M1 aMathias, Rasika, A1 aBecker, Lewis, C1 aRaffield, Laura, M1 aKilpeläinen, Tuomas, O1 aGrarup, Niels1 aPedersen, Oluf1 aHansen, Torben1 aLinneberg, Allan1 aHamsten, Anders1 aWatkins, Hugh1 aSabater-Lleal, Maria1 aNalls, Mike, A1 aTrégouët, David-Alexandre1 aMorange, Pierre-Emmanuel1 aPsaty, Bruce, M1 aTracy, Russel, P1 aSmith, Nicholas, L1 aDesch, Karl, C1 aCushman, Mary1 aRotter, Jerome, I1 ade Vries, Paul, S1 aPankratz, Nathan, D1 aFolsom, Aaron, R1 aMorrison, Alanna, C1 aMärz, Winfried1 aTang, Weihong1 aJohnson, Andrew, D uhttps://chs-nhlbi.org/node/879111212nas a2203445 4500008004100000022001400041245008000055210006900135260001300204300001200217490000800229520148100237100002301718700001801741700001901759700002701778700002401805700001601829700002501845700002301870700001801893700002601911700002901937700002401966700002601990700002302016700001902039700002202058700002002080700001802100700002202118700001502140700003102155700001902186700002802205700002302233700002002256700002002276700002302296700002002319700002502339700001502364700002102379700002502400700002202425700002502447700001802472700002302490700002102513700002402534700002602558700002502584700002602609700002302635700001802658700002602676700002802702700001902730700002102749700002102770700002102791700002202812700002302834700002102857700002302878700001702901700002102918700002102939700002002960700002202980700002003002700002403022700002903046700001903075700001803094700002103112700001603133700002003149700002003169700002103189700001803210700002403228700002403252700002303276700002403299700002303323700001603346700002303362700001703385700002103402700001603423700002303439700002103462700002003483700002303503700002503526700002803551700002403579700003103603700002203634700002103656700002103677700002803698700002403726700002003750700002703770700002303797700001403820700002203834700001603856700001203872700001903884700002303903700002003926700002303946700001403969700001803983700002304001700002404024700002704048700002004075700002004095700001904115700002404134700002704158700002104185700002204206700001804228700002404246700001704270700002304287700002104310700002304331700002404354700002404378700002204402700002104424700002304445700002304468700001604491700002104507700002104528700002204549700001804571700001704589700001504606700001804621700001804639700002704657700002104684700002004705700001804725700002104743700002404764700001804788700002204806700002204828700002304850700002204873700002004895700002104915700001704936700002004953700002504973700002904998700002105027700002205048700001905070700001905089700001705108700002105125700001905146700002005165700002205185700001905207700002205226700001905248700002305267700002305290700002005313700001905333700002305352700001905375700002005394700002005414700001805434700001705452700002105469700002005490700001905510700002305529700001905552700002405571700002105595700001605616700001705632700002205649700002005671700002605691700002105717700001805738700002205756700002105778700002405799700002505823700002605848700002605874700002305900700001905923700002305942700002105965700002005986700002306006700002106029700002406050700002006074700002206094700001906116700001906135700002606154700002406180700002606204700002506230700002006255700002106275700002206296700002806318700002506346700002106371700002106392700002506413700002206438700002106460700002806481700001806509700002206527700002206549700001706571700002406588700001906612700001406631700002506645700002506670700001906695700002106714700002106735700002306756700002106779700003006800700001706830700002006847700001406867700001906881700002006900700001506920700001706935700002106952700002006973700001806993700002907011700002707040700001607067700003107083700002207114700002107136700002407157700002207181700002407203700002307227700002307250700002107273700002107294700002507315700001507340700002407355700001607379700002107395700001707416700001707433700002107450710006007471710002307531710002607554710004707580710002607627710002707653710002407680710002607704856003607730 2021 eng d a1476-468700aGenetic insights into biological mechanisms governing human ovarian ageing.0 aGenetic insights into biological mechanisms governing human ovar c2021 Aug a393-3970 v5963 aReproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
1 aRuth, Katherine, S1 aDay, Felix, R1 aHussain, Jazib1 aMartínez-Marchal, Ana1 aAiken, Catherine, E1 aAzad, Ajuna1 aThompson, Deborah, J1 aKnoblochova, Lucie1 aAbe, Hironori1 aTarry-Adkins, Jane, L1 aGonzalez, Javier, Martin1 aFontanillas, Pierre1 aClaringbould, Annique1 aBakker, Olivier, B1 aSulem, Patrick1 aWalters, Robin, G1 aTerao, Chikashi1 aTuron, Sandra1 aHorikoshi, Momoko1 aLin, Kuang1 aOnland-Moret, Charlotte, N1 aSankar, Aditya1 aHertz, Emil, Peter Thra1 aTimshel, Pascal, N1 aShukla, Vallari1 aBorup, Rehannah1 aOlsen, Kristina, W1 aAguilera, Paula1 aFerrer-Roda, Mònica1 aHuang, Yan1 aStankovic, Stasa1 aTimmers, Paul, R H J1 aAhearn, Thomas, U1 aAlizadeh, Behrooz, Z1 aNaderi, Elnaz1 aAndrulis, Irene, L1 aArnold, Alice, M1 aAronson, Kristan, J1 aAugustinsson, Annelie1 aBandinelli, Stefania1 aBarbieri, Caterina, M1 aBeaumont, Robin, N1 aBecher, Heiko1 aBeckmann, Matthias, W1 aBenonisdottir, Stefania1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBojesen, Stig, E1 aBolla, Manjeet, K1 aBoomsma, Dorret, I1 aBowker, Nicholas1 aBrody, Jennifer, A1 aBroer, Linda1 aBuring, Julie, E1 aCampbell, Archie1 aCampbell, Harry1 aCastelao, Jose, E1 aCatamo, Eulalia1 aChanock, Stephen, J1 aChenevix-Trench, Georgia1 aCiullo, Marina1 aCorre, Tanguy1 aCouch, Fergus, J1 aCox, Angela1 aCrisponi, Laura1 aCross, Simon, S1 aCucca, Francesco1 aCzene, Kamila1 aSmith, George Davey1 ade Geus, Eco, J C N1 ade Mutsert, Renée1 aDe Vivo, Immaculata1 aDemerath, Ellen, W1 aDennis, Joe1 aDunning, Alison, M1 aDwek, Miriam1 aEriksson, Mikael1 aEsko, Tõnu1 aFasching, Peter, A1 aFaul, Jessica, D1 aFerrucci, Luigi1 aFranceschini, Nora1 aFrayling, Timothy, M1 aGago-Dominguez, Manuela1 aMezzavilla, Massimo1 aGarcía-Closas, Montserrat1 aGieger, Christian1 aGiles, Graham, G1 aGrallert, Harald1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aGuénel, Pascal1 aHaiman, Christopher, A1 aHåkansson, Niclas1 aHall, Per1 aHayward, Caroline1 aHe, Chunyan1 aHe, Wei1 aHeiss, Gerardo1 aHøffding, Miya, K1 aHopper, John, L1 aHottenga, Jouke, J1 aHu, Frank1 aHunter, David1 aIkram, Mohammad, A1 aJackson, Rebecca, D1 aJoaquim, Micaella, D R1 aJohn, Esther, M1 aJoshi, Peter, K1 aKarasik, David1 aKardia, Sharon, L R1 aKartsonaki, Christiana1 aKarlsson, Robert1 aKitahara, Cari, M1 aKolcic, Ivana1 aKooperberg, Charles1 aKraft, Peter1 aKurian, Allison, W1 aKutalik, Zoltán1 aLa Bianca, Martina1 aLachance, Genevieve1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLaven, Joop, S E1 aLawlor, Deborah, A1 aLe Marchand, Loïc1 aLi, Jingmei1 aLindblom, Annika1 aLindström, Sara1 aLindstrom, Tricia1 aLinet, Martha1 aLiu, Yongmei1 aLiu, Simin1 aLuan, Jian'an1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMannermaa, Arto1 aMarco, Brumat1 aMarten, Jonathan1 aMartin, Nicholas, G1 aMbarek, Hamdi1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMeisinger, Christa1 aMeitinger, Thomas1 aMenni, Cristina1 aMetspalu, Andres1 aMilani, Lili1 aMilne, Roger, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMulas, Antonella1 aMulligan, Anna, M1 aMurray, Alison1 aNalls, Mike, A1 aNewman, Anne1 aNoordam, Raymond1 aNutile, Teresa1 aNyholt, Dale, R1 aOlshan, Andrew, F1 aOlsson, Håkan1 aPainter, Jodie, N1 aPatel, Alpa, V1 aPedersen, Nancy, L1 aPerjakova, Natalia1 aPeters, Annette1 aPeters, Ulrike1 aPharoah, Paul, D P1 aPolasek, Ozren1 aPorcu, Eleonora1 aPsaty, Bruce, M1 aRahman, Iffat1 aRennert, Gad1 aRennert, Hedy, S1 aRidker, Paul, M1 aRing, Susan, M1 aRobino, Antonietta1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRossouw, Jacques1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aSala, Cinzia, F1 aSaloustros, Emmanouil1 aSandler, Dale, P1 aSanna, Serena1 aSawyer, Elinor, J1 aSarnowski, Chloe1 aSchlessinger, David1 aSchmidt, Marjanka, K1 aSchoemaker, Minouk, J1 aSchraut, Katharina, E1 aScott, Christopher1 aShekari, Saleh1 aShrikhande, Amruta1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSorice, Rossella1 aSouthey, Melissa, C1 aSpector, Tim, D1 aSpinelli, John, J1 aStampfer, Meir1 aStöckl, Doris1 avan Meurs, Joyce, B J1 aStrauch, Konstantin1 aStyrkarsdottir, Unnur1 aSwerdlow, Anthony, J1 aTanaka, Toshiko1 aTeras, Lauren, R1 aTeumer, Alexander1 aÞorsteinsdottir, Unnur1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTraglia, Michela1 aTroester, Melissa, A1 aTruong, Thérèse1 aTyrrell, Jessica1 aUitterlinden, André, G1 aUlivi, Sheila1 aVachon, Celine, M1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVölzke, Henry1 aWang, Qin1 aWareham, Nicholas, J1 aWeinberg, Clarice, R1 aWeir, David, R1 aWilcox, Amber, N1 aDijk, Ko Willems1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWolk, Alicja1 aWood, Andrew, R1 aZhao, Wei1 aZygmunt, Marek1 aChen, Zhengming1 aLi, Liming1 aFranke, Lude1 aBurgess, Stephen1 aDeelen, Patrick1 aPers, Tune, H1 aGrøndahl, Marie, Louise1 aAndersen, Claus, Yding1 aPujol, Anna1 aLopez-Contreras, Andres, J1 aDaniel, Jeremy, A1 aStefansson, Kari1 aChang-Claude, Jenny1 aSchouw, Yvonne, T1 aLunetta, Kathryn, L1 aChasman, Daniel, I1 aEaston, Douglas, F1 aVisser, Jenny, A1 aOzanne, Susan, E1 aNamekawa, Satoshi, H1 aSolc, Petr1 aMurabito, Joanne, M1 aOng, Ken, K1 aHoffmann, Eva, R1 aMurray, Anna1 aRoig, Ignasi1 aPerry, John, R B1 aBiobank-based Integrative Omics Study (BIOS) Consortium1 aeQTLGen Consortium1 aBioBank Japan Project1 aChina Kadoorie Biobank Collaborative Group1 akConFab Investigators1 aLifeLines Cohort Study1 aInterAct Consortium1 a23andMe Research Team uhttps://chs-nhlbi.org/node/883505153nas a2201609 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2021 eng d00a{Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci0 aGenomeWide Association Study of Circulating Interleukin 6 Levels cJan3 aInterleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.1 aAhluwalia, T., S.1 aPrins, B., P.1 aAbdollahi, M.1 aArmstrong, N., J.1 aAslibekyan, S.1 aBain, L.1 aJefferis, B.1 aBaumert, J.1 aBeekman, M.1 aBen-Shlomo, Y.1 aBis, J., C.1 aMitchell, B., D.1 ade Geus, E.1 aDelgado, G., E.1 aMarek, D.1 aEriksson, J.1 aKajantie, E.1 aKanoni, S.1 aKemp, J., P.1 aLu, C.1 aMarioni, R., E.1 aMcLachlan, S.1 aMilaneschi, Y.1 aNolte, I., M.1 aPetrelis, A., M.1 aPorcu, E.1 aSabater-Lleal, M.1 aNaderi, E.1 aSeppälä, I.1 aShah, T.1 aSinghal, G.1 aStandl, M.1 aTeumer, A.1 aThalamuthu, A.1 aThiering, E.1 aTrompet, S.1 aBallantyne, C., M.1 aBenjamin, E., J.1 aCasas, J., P.1 aToben, C.1 aDedoussis, G.1 aDeelen, J.1 aDurda, P.1 aEngmann, J.1 aFeitosa, M., F.1 aGrallert, H.1 aHammarstedt, A.1 aHarris, S., E.1 aHomuth, G.1 aHottenga, J., J.1 aJalkanen, S.1 aJamshidi, Y.1 aJawahar, M., C.1 aJess, T.1 aKivimaki, M.1 aKleber, M., E.1 aLahti, J.1 aLiu, Y.1 aMarques-Vidal, P.1 aMellström, D.1 aMooijaart, S., P.1 aMüller-Nurasyid, M.1 aPenninx, B.1 aRevez, J., A.1 aRossing, P.1 aRäikkönen, K.1 aSattar, N.1 aScharnagl, H.1 aSennblad, B.1 aSilveira, A.1 aPourcain, B., S.1 aTimpson, N., J.1 aTrollor, J.1 avan Dongen, J.1 avan Heemst, D.1 aVisvikis-Siest, S.1 aVollenweider, P.1 aVölker, U.1 aWaldenberger, M.1 aWillemsen, G.1 aZabaneh, D.1 aMorris, R., W.1 aArnett, D., K.1 aBaune, B., T.1 aBoomsma, D., I.1 aChang, Y., C.1 aDeary, I., J.1 aDeloukas, P.1 aEriksson, J., G.1 aEvans, D., M.1 aFerreira, M., A.1 aGaunt, T.1 aGudnason, V.1 aHamsten, A.1 aHeinrich, J.1 aHingorani, A.1 aHumphries, S., E.1 aJukema, J., W.1 aKoeing, W.1 aKumari, M.1 aKutalik, Z.1 aLawlor, D., A.1 aLehtimäki, T.1 aMärz, W.1 aMather, K.1 aNaitza, S.1 aNauck, M.1 aOhlsson, C.1 aPrice, J., F.1 aRaitakari, O.1 aRice, K.1 aSachdev, P., S.1 aSlagboom, E.1 aSørensen, T., I. A.1 aSpector, T.1 aStacey, D.1 aStathopoulou, M., G.1 aTanaka, T.1 aWannamethee, S., G.1 aWhincup, P.1 aRotter, J., I.1 aDehghan, A.1 aBoerwinkle, E.1 aPsaty, B., M.1 aSnieder, H.1 aAlizadeh, B., Z. uhttps://chs-nhlbi.org/node/865703469nas a2200913 4500008004100000245010700041210006900148260000700217300000800224490000700232520108800239100001401327700001901341700002301360700001601383700001601399700001901415700001801434700001401452700001301466700001801479700001301497700001801510700002001528700001501548700002301563700001601586700001801602700001601620700001301636700002201649700001501671700001701686700001401703700002801717700001901745700002001764700001901784700001801803700001401821700001401835700001501849700002201864700002901886700001801915700001801933700001901951700001901970700002001989700001902009700002302028700001602051700001202067700001402079700001902093700001702112700002002129700002002149700002102169700002502190700001602215700001502231700001502246700002602261700002002287700002202307700001302329700001602342700001602358700002102374700001502395700001902410700001702429700001602446700002002462700001702482700002002499856003602519 2021 eng d00a{Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women0 aGenomewide metaanalysis of muscle weakness identifies 15 suscept c01 a6540 v123 aLow muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.1 aJones, G.1 aTrajanoska, K.1 aSantanasto, A., J.1 aStringa, N.1 aKuo, C., L.1 aAtkins, J., L.1 aLewis, J., R.1 aDuong, T.1 aHong, S.1 aBiggs, M., L.1 aLuan, J.1 aSarnowski, C.1 aLunetta, K., L.1 aTanaka, T.1 aWojczynski, M., K.1 aCvejkus, R.1 aNethander, M.1 aGhasemi, S.1 aYang, J.1 aZillikens, M., C.1 aWalter, S.1 aSicinski, K.1 aKague, E.1 aAckert-Bicknell, C., L.1 aArking, D., E.1 aWindham, B., G.1 aBoerwinkle, E.1 aGrove, M., L.1 aGraff, M.1 aSpira, D.1 aDemuth, I.1 aVan der Velde, N.1 ade Groot, L., C. P. G. M1 aPsaty, B., M.1 aOdden, M., C.1 aFohner, A., E.1 aLangenberg, C.1 aWareham, N., J.1 aBandinelli, S.1 avan Schoor, N., M.1 aHuisman, M.1 aTan, Q.1 aZmuda, J.1 aMellström, D.1 aKarlsson, M.1 aBennett, D., A.1 aBuchman, A., S.1 aDe Jager, P., L.1 aUitterlinden, A., G.1 aVölker, U.1 aKocher, T.1 aTeumer, A.1 aRodriguéz-Mañas, L.1 aGarcía, F., J.1 aCarnicero, J., A.1 aHerd, P.1 aBertram, L.1 aOhlsson, C.1 aMurabito, J., M.1 aMelzer, D.1 aKuchel, G., A.1 aFerrucci, L.1 aKarasik, D.1 aRivadeneira, F.1 aKiel, D., P.1 aPilling, L., C. uhttps://chs-nhlbi.org/node/866006020nas a2202185 4500008004100000245008200041210006900123260000800192520049900200100002000699700001300719700001200732700001400744700001400758700002100772700001800793700001800811700001600829700001900845700001700864700001700881700001800898700001500916700001600931700001900947700001600966700002000982700001801002700001801020700001601038700002001054700001801074700002901092700001801121700002001139700002001159700001601179700001301195700001301208700001801221700001601239700002301255700001701278700001701295700001601312700002001328700001601348700001801364700001401382700001901396700001801415700001301433700001801446700001801464700001401482700001301496700002001509700001701529700001701546700001601563700001901579700001901598700002301617700001401640700002601654700001201680700001601692700002101708700002201729700002001751700002001771700001601791700001701807700001401824700001901838700001501857700001501872700001601887700001701903700001901920700001501939700001801954700001401972700002201986700001902008700001302027700002102040700001502061700001802076700002102094700001302115700001802128700001602146700001302162700002202175700002002197700001402217700002402231700001702255700001602272700001802288700001902306700001902325700001902344700002102363700001802384700001902402700002002421700001702441700001702458700001402475700002302489700001802512700002202530700001302552700001502565700002202580700002702602700001802629700001702647700001902664700002302683700001602706700001902722700001702741700002102758700001302779700001602792700001902808700002002827700002002847700001802867700001902885700001602904700001802920700002302938700002102961700001902982700001903001700002103020700001503041700002103056700002503077700002203102700001603124700001703140700001203157700002503169700001403194700001803208700002103226700001603247700001803263700001303281700002003294700001803314700001403332700001803346700002003364700001303384700001303397700001303410700002903423700001103452700001503463700001303478700001703491700001303508700001503521700001903536700002003555700001303575700001703588700001803605700002303623700002203646700001803668700001903686700001703705700002003722700002003742700001803762700001803780856003603798 2021 eng d00a{The genomics of heart failure: design and rationale of the HERMES consortium0 agenomics of heart failure design and rationale of the HERMES con cSep3 aThe HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.\ under an additive genetic model.\ HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.1 aLumbers, R., T.1 aShah, S.1 aLin, H.1 aCzuba, T.1 aHenry, A.1 aSwerdlow, D., I.1 aMalarstig, A.1 aAndersson, C.1 aVerweij, N.1 aHolmes, M., V.1 aÄrnlöv, J.1 aSvensson, P.1 aHemingway, H.1 aSallah, N.1 aAlmgren, P.1 aAragam, K., G.1 aAsselin, G.1 aBackman, J., D.1 aBiggs, M., L.1 aBloom, H., L.1 aBoersma, E.1 aBrandimarto, J.1 aBrown, M., R.1 aLa Rocca, H., P. Brunner1 aCarey, D., J.1 aChaffin, M., D.1 aChasman, D., I.1 aChazara, O.1 aChen, X.1 aChen, X.1 aChung, J., H.1 aChutkow, W.1 aCleland, J., G. F.1 aCook, J., P.1 ade Denus, S.1 aDehghan, A.1 aDelgado, G., E.1 aDenaxas, S.1 aDoney, A., S.1 aDörr, M.1 aDudley, S., C.1 aEngström, G.1 aEsko, T.1 aFatemifar, G.1 aFelix, S., B.1 aFinan, C.1 aFord, I.1 aFougerousse, F.1 aFouodjio, R.1 aGhanbari, M.1 aGhasemi, S.1 aGiedraitis, V.1 aGiulianini, F.1 aGottdiener, J., S.1 aGross, S.1 aGuðbjartsson, D., F.1 aGui, H.1 aGutmann, R.1 aHaggerty, C., M.1 avan der Harst, P.1 aHedman, Å., K.1 aHelgadottir, A.1 aHillege, H.1 aHyde, C., L.1 aJacob, J.1 aJukema, J., W.1 aKamanu, F.1 aKardys, I.1 aKavousi, M.1 aKhaw, K., T.1 aKleber, M., E.1 aKøber, L.1 aKoekemoer, A.1 aKraus, B.1 aKuchenbaecker, K.1 aLangenberg, C.1 aLind, L.1 aLindgren, C., M.1 aLondon, B.1 aLotta, L., A.1 aLovering, R., C.1 aLuan, J.1 aMagnusson, P.1 aMahajan, A.1 aMann, D.1 aMargulies, K., B.1 aMarston, N., A.1 aMärz, W.1 aMcMurray, J., J. V.1 aMelander, O.1 aMelloni, G.1 aMordi, I., R.1 aMorley, M., P.1 aMorris, A., D.1 aMorris, A., P.1 aMorrison, A., C.1 aNagle, M., W.1 aNelson, C., P.1 aNewton-Cheh, C.1 aNiessner, A.1 aNiiranen, T.1 aNowak, C.1 aO'Donoghue, M., L.1 aOwens, A., T.1 aPalmer, C., N. A.1 aPare, G.1 aPerola, M.1 aPerreault, L., L.1 aPortilla-Fernandez, E.1 aPsaty, B., M.1 aRice, K., M.1 aRidker, P., M.1 aRomaine, S., P. R.1 aRoselli, C.1 aRotter, J., I.1 aRuff, C., T.1 aSabatine, M., S.1 aSalo, P.1 aSalomaa, V.1 avan Setten, J.1 aShalaby, A., A.1 aSmelser, D., T.1 aSmith, N., L.1 aStefansson, K.1 aStender, S.1 aStott, D., J.1 aSveinbjornsson, G.1 aTammesoo, M., L.1 aTardif, J., C.1 aTaylor, K., D.1 aTeder-Laving, M.1 aTeumer, A.1 aThorgeirsson, G.1 aThorsteinsdottir, U.1 aTorp-Pedersen, C.1 aTrompet, S.1 aTuckwell, D.1 aTyl, B.1 aUitterlinden, A., G.1 aVaura, F.1 aVeluchamy, A.1 aVisscher, P., M.1 aVölker, U.1 aVoors, A., A.1 aWang, X.1 aWareham, N., J.1 aWeeke, P., E.1 aWeiss, R.1 aWhite, H., D.1 aWiggins, K., L.1 aXing, H.1 aYang, J.1 aYang, Y.1 aYerges-Armstrong, L., M.1 aYu, B.1 aZannad, F.1 aZhao, F.1 aWilk, J., B.1 aHolm, H.1 aSattar, N.1 aLubitz, S., A.1 aLanfear, D., E.1 aShah, S.1 aDunn, M., E.1 aWells, Q., S.1 aAsselbergs, F., W.1 aHingorani, A., D.1 aDubé, M., P.1 aSamani, N., J.1 aLang, C., C.1 aCappola, T., P.1 aEllinor, P., T.1 aVasan, R., S.1 aSmith, J., G. uhttps://chs-nhlbi.org/node/892503037nas a2200409 4500008004100000022001400041245016000055210006900215260001200284300001200296490000700308520181500315100001602130700002002146700002202166700001702188700002102205700002002226700001802246700001302264700002302277700003002300700002202330700001802352700002402370700002802394700001802422700001902440700002302459700002002482700002202502700002102524700002002545700001302565700001302578856003602591 2021 eng d a2574-830000aIdentification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation.0 aIdentification of Functional Genetic Determinants of Cardiac Tro c2021 12 ae0034600 v143 aBACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive.
METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI.
RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in and 3 previously reported loci at , , and . One known locus at was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; =2.80×10). We observed pleiotropic loci located at and . The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with expression in heart tissues and hs-cTnT and with expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI).
CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.
1 aYang, Yunju1 aBartz, Traci, M1 aBrown, Michael, R1 aGuo, Xiuqing1 aZilhão, Nuno, R1 aTrompet, Stella1 aWeiss, Stefan1 aYao, Jie1 aBrody, Jennifer, A1 adeFilippi, Christopher, R1 aHoogeveen, Ron, C1 aLin, Henry, J1 aGudnason, Vilmundur1 aBallantyne, Christie, M1 aDörr, Marcus1 aJukema, Wouter1 aPetersmann, Astrid1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aFornage, Myriam1 aJun, Goo1 aYu, Bing uhttps://chs-nhlbi.org/node/900703417nas a2200493 4500008004100000022001400041245018000055210006900235260000900304300001300313490000700326520180900333100002102142700001402163700001902177700003202196700001802228700002502246700002202271700001902293700002102312700002502333700002002358700002702378700002502405700001702430700002002447700002402467700002102491700002502512700002402537700002602561700002002587700001802607700002102625700002702646700001802673700002102691700002402712700002402736710005302760710007402813856003602887 2021 eng d a1932-620300aIdentification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.0 aIdentification of novel and rare variants associated with handgr c2021 ae02536110 v163 aHandgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.
1 aSarnowski, Chloe1 aChen, Han1 aBiggs, Mary, L1 aWassertheil-Smoller, Sylvia1 aBressler, Jan1 aIrvin, Marguerite, R1 aRyan, Kathleen, A1 aKarasik, David1 aArnett, Donna, K1 aCupples, Adrienne, L1 aFardo, David, W1 aGogarten, Stephanie, M1 aHeavner, Benjamin, D1 aJain, Deepti1 aKang, Hyun, Min1 aKooperberg, Charles1 aMainous, Arch, G1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aO'Connell, Jeffrey, R1 aPsaty, Bruce, M1 aRice, Kenneth1 aSmith, Albert, V1 aVasan, Ramachandran, S1 aWindham, Gwen1 aKiel, Douglas, P1 aMurabito, Joanne, M1 aLunetta, Kathryn, L1 aTOPMed Longevity and Healthy Aging Working Group1 afrom the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/883602579nas a2200241 4500008004100000022001400041245008900055210006900144260001600213520182700229100002402056700002102080700002702101700002302128700001902151700002402170700002302194700002202217700002402239700001802263700002002281856003602301 2021 eng d a1468-201X00aIndividual non-esterified fatty acids and incident atrial fibrillation late in life.0 aIndividual nonesterified fatty acids and incident atrial fibrill c2021 Jan 223 aOBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life.
METHODS: The present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF.
RESULTS: The study sample included 1872 participants (age 77.7±4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95% CI 1.08 to 1.29; p<0.001). Conversely, higher serum concentration of gamma-linolenic acid (GLA) (18:3 n-6), a polyunsaturated n-6 fatty acid, was associated with lower risk of AF (HR per SD: 0.81, 95% CI 0.71 to 0.94; p=0.004). None of the remaining NEFAs was significantly associated with AF.
CONCLUSIONS: Among older adults, serum levels of non-esterified nervonic acid were positively associated, while serum levels of non-esterified GLA were inversely associated, with incident AF. If confirmed, these results could offer new strategies for AF prevention and early intervention in this segment of the population at highest risk.
1 aPellegrini, Cara, N1 aBůzková, Petra1 aLichtenstein, Alice, H1 aMatthan, Nirupa, R1 aIx, Joachim, H1 aSiscovick, David, S1 aHeckbert, Susan, R1 aTracy, Russell, P1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/866503651nas a2200313 4500008004100000022001400041245015000055210006900205260001600274300001200290520265600302100001502958700001502973700001702988700002003005700002903025700002403054700002203078700002203100700002003122700002403142700002203166700002203188700002003210700002403230700002203254700002503276856003603301 2021 eng d a2047-998000aLongitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults.0 aLongitudinal Plasma Measures of Trimethylamine NOxide and Risk o c2021 Aug 16 ae0206463 aBackground Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine, and phosphatidylcholine-rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community-based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community-based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography-tandem mass spectrometry (laboratory coefficient of variation, <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time-varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow-up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95% CI, 1.02-1.42; -trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR-adjusted HR, 1.07; 95% CI, 0.90-1.27), as well as modified by eGFR (-interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1.73 m: HR, 1.56 [95% CI, 1.13-2.14]; -trend=0.007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m: HR, 1.03 [95% CI, 0.85-1.25]; -trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95% CI, 1.01-1.56]; -trend=0.009), without significant modification by eGFR. Conclusions In this large community-based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.
1 aLee, Yujin1 aNemet, Ina1 aWang, Zeneng1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aLemaitre, Rozenn, N1 aFretts, Amanda, M1 aSotoodehnia, Nona1 aBudoff, Matthew1 aDiDonato, Joseph, A1 aMcKnight, Barbara1 aTang, W, H Wilson1 aPsaty, Bruce, M1 aSiscovick, David, S1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/883105906nas a2201705 4500008004100000022001400041245008700055210006900142260001500211300000900226490000700235520117400242653001001416653000901426653001601435653002001451653001101471653003101482653001101513653003401524653001101558653002601569653002401595653000901619653002201628653001601650653003301666653002601699100002201725700001801747700002901765700002101794700001901815700001601834700001901850700001201869700002101881700003301902700001901935700002601954700002201980700001902002700001902021700002302040700002102063700002102084700002702105700002202132700001802154700002202172700002102194700001802215700001802233700001902251700001802270700001902288700002502307700002602332700002102358700001902379700002202398700002202420700002002442700002002462700001702482700002102499700001202520700001502532700002102547700001902568700002202587700002202609700002002631700002102651700001902672700002002691700002202711700001902733700001602752700002002768700002002788700002702808700002402835700001802859700002202877700002102899700002202920700001802942700002402960700002102984700002203005700001503027700001303042700001703055700002703072700001703099700002203116700001503138700002503153700002003178700002503198700002403223700001703247700002503264700002003289700002103309700002103330700002003351700002103371700002003392700002303412700002203435700002003457700002103477700002003498700001903518700002003537700002303557700002203580700002303602700002303625700002203648700002403670700002403694700002603718700003503744700001903779700001803798700002103816700002403837700002403861700003003885700001403915700001703929700001503946700002003961700001703981700002603998700002104024700001904045700002204064710003504086710004304121856003604164 2021 eng d a2041-172300aMeta-analyses identify DNA methylation associated with kidney function and damage.0 aMetaanalyses identify DNA methylation associated with kidney fun c2021 12 09 a71740 v123 aChronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
10aAdult10aAged10aCpG Islands10aDNA Methylation10aFemale10aGlomerular Filtration Rate10aHumans10aInterferon Regulatory Factors10aKidney10aKidney Function Tests10aLIM Domain Proteins10aMale10aMembrane Proteins10aMiddle Aged10aRenal Insufficiency, Chronic10aTranscription Factors1 aSchlosser, Pascal1 aTin, Adrienne1 aMatias-Garcia, Pamela, R1 aThio, Chris, H L1 aJoehanes, Roby1 aLiu, Hongbo1 aWeihs, Antoine1 aYu, Zhi1 aHoppmann, Anselm1 aGrundner-Culemann, Franziska1 aMin, Josine, L1 aAdeyemo, Adebowale, A1 aAgyemang, Charles1 aArnlöv, Johan1 aAziz, Nasir, A1 aBaccarelli, Andrea1 aBochud, Murielle1 aBrenner, Hermann1 aBreteler, Monique, M B1 aCarmeli, Cristian1 aChaker, Layal1 aChambers, John, C1 aCole, Shelley, A1 aCoresh, Josef1 aCorre, Tanguy1 aCorrea, Adolfo1 aCox, Simon, R1 ade Klein, Niek1 aDelgado, Graciela, E1 aDomingo-Relloso, Arce1 aEckardt, Kai-Uwe1 aEkici, Arif, B1 aEndlich, Karlhans1 aEvans, Kathryn, L1 aFloyd, James, S1 aFornage, Myriam1 aFranke, Lude1 aFraszczyk, Eliza1 aGao, Xu1 aGào, Xīn1 aGhanbari, Mohsen1 aGhasemi, Sahar1 aGieger, Christian1 aGreenland, Philip1 aGrove, Megan, L1 aHarris, Sarah, E1 aHemani, Gibran1 aHenneman, Peter1 aHerder, Christian1 aHorvath, Steve1 aHou, Lifang1 aHurme, Mikko, A1 aHwang, Shih-Jen1 aJarvelin, Marjo-Riitta1 aKardia, Sharon, L R1 aKasela, Silva1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKramer, Holly1 aKronenberg, Florian1 aKuhnel, Brigitte1 aLehtimäki, Terho1 aLind, Lars1 aLiu, Dan1 aLiu, Yongmei1 aLloyd-Jones, Donald, M1 aLohman, Kurt1 aLorkowski, Stefan1 aLu, Ake, T1 aMarioni, Riccardo, E1 aMärz, Winfried1 aMcCartney, Daniel, L1 aMeeks, Karlijn, A C1 aMilani, Lili1 aMishra, Pashupati, P1 aNauck, Matthias1 aNavas-Acien, Ana1 aNowak, Christoph1 aPeters, Annette1 aProkisch, Holger1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRatliff, Scott, M1 aReiner, Alex, P1 aRosas, Sylvia, E1 aSchöttker, Ben1 aSchwartz, Joel1 aSedaghat, Sanaz1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStocker, Hannah, R1 aStringhini, Silvia1 aSundström, Johan1 aSwenson, Brenton, R1 aTellez-Plaza, Maria1 avan Meurs, Joyce, B J1 avan Vliet-Ostaptchouk, Jana, V1 aVenema, Andrea1 aVerweij, Niek1 aWalker, Rosie, M1 aWielscher, Matthias1 aWinkelmann, Juliane1 aWolffenbuttel, Bruce, H R1 aZhao, Wei1 aZheng, Yinan1 aLoh, Marie1 aSnieder, Harold1 aLevy, Daniel1 aWaldenberger, Melanie1 aSusztak, Katalin1 aKöttgen, Anna1 aTeumer, Alexander1 aEstonian Biobank Research Team1 aGenetics of DNA Methylation Consortium uhttps://chs-nhlbi.org/node/900203140nas a2200649 4500008004100000022001400041245009100055210006900146260001600215520129400231100003201525700002001557700001701577700001801594700001601612700002201628700002501650700002301675700001901698700002001717700002101737700002001758700002101778700002101799700001701820700002001837700001901857700001801876700001801894700001901912700002201931700002001953700002001973700002001993700002202013700001902035700002002054700002102074700001602095700002102111700002502132700002302157700001902180700002102199700001902220700002302239700002002262700002002282700002302302700001902325700001802344700001702362700002602379700003002405700001902435856003602454 2021 eng d a1573-728400aMeta-analysis of epigenome-wide association studies of carotid intima-media thickness.0 aMetaanalysis of epigenomewide association studies of carotid int c2021 Jun 063 aCommon carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
1 aPortilla-Fernández, Eliana1 aHwang, Shih-Jen1 aWilson, Rory1 aMaddock, Jane1 aHill, David1 aTeumer, Alexander1 aMishra, Pashupati, P1 aBrody, Jennifer, A1 aJoehanes, Roby1 aLigthart, Symen1 aGhanbari, Mohsen1 aKavousi, Maryam1 aRoks, Anton, J M1 aDanser, A, H Jan1 aLevy, Daniel1 aPeters, Annette1 aGhasemi, Sahar1 aSchminke, Ulf1 aDörr, Marcus1 aGrabe, Hans, J1 aLehtimäki, Terho1 aKähönen, Mika1 aHurme, Mikko, A1 aBartz, Traci, M1 aSotoodehnia, Nona1 aBis, Joshua, C1 aThiery, Joachim1 aKoenig, Wolfgang1 aOng, Ken, K1 aBell, Jordana, T1 aMeisinger, Christine1 aWardlaw, Joanna, M1 aStarr, John, M1 aSeissler, Jochen1 aThen, Cornelia1 aRathmann, Wolfgang1 aIkram, Arfan, M1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aVölzke, Henry1 aDeary, Ian, J1 aWong, Andrew1 aWaldenberger, Melanie1 aO'Donnell, Christopher, J1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/878906260nas a2201741 4500008004100000022001400041245015100055210006900206260001600275490000600291520132000297100001601617700002101633700002301654700001801677700002301695700002101718700002001739700001701759700002801776700002001804700002001824700002001844700002401864700002201888700002601910700002501936700002801961700001701989700002202006700002102028700002102049700002102070700002102091700002802112700001902140700002102159700002702180700001602207700001802223700001802241700001702259700001902276700001902295700002102314700001502335700002102350700002102371700002602392700002202418700002502440700002502465700002602490700002302516700002202539700002502561700002202586700001802608700002102626700002202647700002002669700002502689700001602714700002202730700002802752700002002780700002002800700001802820700001902838700002302857700002202880700002202902700002102924700001702945700001702962700001702979700002302996700002003019700002203039700002103061700002303082700002203105700002003127700002403147700002603171700002203197700002003219700001803239700002603257700002403283700002903307700002503336700002203361700002203383700001703405700002003422700001603442700002303458700002203481700002403503700001903527700001703546700002803563700002303591700002603614700001803640700001803658700002003676700001503696700001303711700001803724700001403742700001803756700002303774700002103797700001803818700002203836700001903858700002203877700001903899700002903918700002703947700002003974700001803994700001904012700001504031700002204046700002104068700002404089700002304113700001804136700002904154700002404183700002604207700002004233700001604253700001804269700002404287700001704311700001804328700002204346700002404368700002304392700002004415700002004435710002704455856003604482 2021 eng d a2666-247700aMulti-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.0 aMultiAncestry Genomewide Association Study Accounting for GenePs c2021 Jan 140 v23 aPsychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.
1 aSun, Daokun1 aRichard, Melissa1 aMusani, Solomon, K1 aSung, Yun, Ju1 aWinkler, Thomas, W1 aSchwander, Karen1 aChai, Jin, Fang1 aGuo, Xiuqing1 aKilpeläinen, Tuomas, O1 aVojinovic, Dina1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aBrown, Michael, R1 aChitrala, Kumaraswamy1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLiu, Yongmei1 aManning, Alisa, K1 aNoordam, Raymond1 aSmith, Albert, V1 aHarris, Sarah, E1 aKuhnel, Brigitte1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aRauramaa, Rainer1 avan der Most, Peter, J1 aWang, Rujia1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aArking, Dan, E1 aArnett, Donna, K1 aBarac, Ana1 aBoerwinkle, Eric1 aBroeckel, Ulrich1 aChakravarti, Aravinda1 aChen, Yii-Der Ida1 aCupples, Adrienne, L1 aDavigulus, Martha, L1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Vries, Paul, S1 aDelaney, Joseph, A C1 aRoux, Ana, V Diez1 aDörr, Marcus1 aFaul, Jessica, D1 aFretts, Amanda, M1 aGallo, Linda, C1 aGrabe, Hans, Jörgen1 aGu, Charles1 aHarris, Tamara, B1 aHartman, Catharina, C A1 aHeikkinen, Sami1 aIkram, Arfan, M1 aIsasi, Carmen1 aJohnson, Craig1 aJonas, Jost, Bruno1 aKaplan, Robert, C1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aLevy, Daniel1 aLiu, Jianjun1 aLohman, Kurt1 aLuik, Annemarie, I1 aMartin, Lisa, W1 aMeitinger, Thomas1 aMilaneschi, Yuri1 aO'Connell, Jeff, R1 aPalmas, Walter, R1 aPeters, Annette1 aPeyser, Patricia, A1 aPulkki-Råback, Laura1 aRaffel, Leslie, J1 aReiner, Alex, P1 aRice, Kenneth1 aRobinson, Jennifer, G1 aRosendaal, Frits, R1 aSchmidt, Carsten, Oliver1 aSchreiner, Pamela, J1 aSchwettmann, Lars1 aShikany, James, M1 aShu, Xiao-Ou1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStrauch, Konstantin1 aTai, Shyong, E1 aTaylor, Kent1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aWaldenberger, Melanie1 aWee, Hwee-Lin1 aBin Wei, Wen-1 aWilson, Gregory1 aXuan, Deng1 aYao, Jie1 aZeng, Donglin1 aZhao, Wei1 aZhu, Xiaofeng1 aZonderman, Alan, B1 aBecker, Diane, M1 aDeary, Ian, J1 aGieger, Christian1 aLakka, Timo, A1 aLehtimäki, Terho1 aNorth, Kari, E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aSnieder, Harold1 aWang, Ya-Xing1 aWeir, David, R1 aZheng, Wei1 aEvans, Michele, K1 aGauderman, James1 aGudnason, Vilmundur1 aHorta, Bernardo, L1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aMorrison, Alanna, C1 aPereira, Alexandre, C1 aPsaty, Bruce, M1 aAmin, Najaf1 aFox, Ervin, R1 aKooperberg, Charles1 aSim, Xueling1 aBierut, Laura1 aRotter, Jerome, I1 aKardia, Sharon, L R1 aFranceschini, Nora1 aRao, Dabeeru, C1 aFornage, Myriam1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/900506233nas a2201609 4500008004100000022001400041245009500055210006900150260001600219520178500235100001702020700002102037700001902058700002102077700002302098700001502121700001802136700002002154700002202174700002002196700002802216700001802244700002202262700002402284700002102308700002002329700002002349700001502369700002502384700001702409700003102426700002002457700002302477700002302500700002102523700001702544700002002561700002102581700002702602700001902629700002402648700002602672700002102698700001802719700001702737700001902754700002802773700002002801700002402821700002202845700002202867700001902889700001402908700002102922700002102943700002502964700002002989700002203009700001803031700002203049700002003071700001903091700002303110700002003133700002803153700001603181700001503197700001703212700001403229700002003243700002303263700001903286700001603305700002003321700001703341700002103358700001903379700001303398700001703411700002203428700002403450700002903474700002003503700001503523700002303538700002403561700002203585700002003607700001803627700001703645700002103662700001903683700002103702700001603723700001503739700002603754700002003780700002403800700002203824700002103846700001703867700001803884700001703902700002203919700002203941700002003963700002603983700002204009700001904031700001504050700002004065700002204085700002404107700002404131700002604155700002004181700002004201700002304221700001804244700002104262700002204283700002104305700001804326700002404344700001804368700001904386700001604405700001904421700001804440700002004458700002704478700002104505700002004526700001904546700002204565856003604587 2021 eng d a1476-557800aMulti-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.0 aMultiancestry genomewide genesleep interactions identify novel l c2021 Apr 153 aLong and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
1 aWang, Heming1 aNoordam, Raymond1 aCade, Brian, E1 aSchwander, Karen1 aWinkler, Thomas, W1 aLee, Jiwon1 aSung, Yun, Ju1 aBentley, Amy, R1 aManning, Alisa, K1 aAschard, Hugues1 aKilpeläinen, Tuomas, O1 aIlkov, Marjan1 aBrown, Michael, R1 aHorimoto, Andrea, R1 aRichard, Melissa1 aBartz, Traci, M1 aVojinovic, Dina1 aLim, Elise1 aNierenberg, Jovia, L1 aLiu, Yongmei1 aChitrala, Kumaraswamynaidu1 aRankinen, Tuomo1 aMusani, Solomon, K1 aFranceschini, Nora1 aRauramaa, Rainer1 aAlver, Maris1 aZee, Phyllis, C1 aHarris, Sarah, E1 avan der Most, Peter, J1 aNolte, Ilja, M1 aMunroe, Patricia, B1 aPalmer, Nicholette, D1 aKuhnel, Brigitte1 aWeiss, Stefan1 aWen, Wanqing1 aHall, Kelly, A1 aLyytikäinen, Leo-Pekka1 aO'Connell, Jeff1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 ade Vries, Paul, S1 aArking, Dan, E1 aChen, Han1 aBoerwinkle, Eric1 aKrieger, Jose, E1 aSchreiner, Pamela, J1 aSidney, Stephen1 aShikany, James, M1 aRice, Kenneth1 aChen, Yii-Der Ida1 aGharib, Sina, A1 aBis, Joshua, C1 aLuik, Annemarie, I1 aIkram, Arfan, M1 aUitterlinden, André, G1 aAmin, Najaf1 aXu, Hanfei1 aLevy, Daniel1 aHe, Jiang1 aLohman, Kurt, K1 aZonderman, Alan, B1 aRice, Treva, K1 aSims, Mario1 aWilson, Gregory1 aSofer, Tamar1 aRich, Stephen, S1 aPalmas, Walter1 aYao, Jie1 aGuo, Xiuqing1 aRotter, Jerome, I1 aBiermasz, Nienke, R1 aMook-Kanamori, Dennis, O1 aMartin, Lisa, W1 aBarac, Ana1 aWallace, Robert, B1 aGottlieb, Daniel, J1 aKomulainen, Pirjo1 aHeikkinen, Sami1 aMägi, Reedik1 aMilani, Lili1 aMetspalu, Andres1 aStarr, John, M1 aMilaneschi, Yuri1 aWaken, R, J1 aGao, Chuan1 aWaldenberger, Melanie1 aPeters, Annette1 aStrauch, Konstantin1 aMeitinger, Thomas1 aRoenneberg, Till1 aVölker, Uwe1 aDörr, Marcus1 aShu, Xiao-Ou1 aMukherjee, Sutapa1 aHillman, David, R1 aKähönen, Mika1 aWagenknecht, Lynne, E1 aGieger, Christian1 aGrabe, Hans, J1 aZheng, Wei1 aPalmer, Lyle, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aMorrison, Alanna, C1 aPereira, Alexandre, C1 aFornage, Myriam1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLiu, Ching-Ti1 aKelly, Tanika, N1 aEvans, Michele, K1 aBouchard, Claude1 aFox, Ervin, R1 aKooperberg, Charles1 aZhu, Xiaofeng1 aLakka, Timo, A1 aEsko, Tõnu1 aNorth, Kari, E1 aDeary, Ian, J1 aSnieder, Harold1 aPenninx, Brenda, W J H1 aGauderman, James1 aRao, Dabeeru, C1 aRedline, Susan1 avan Heemst, Diana uhttps://chs-nhlbi.org/node/871403367nas a2200889 4500008004100000245009900041210006900140260000700209300000900216490000700225520112800232100001701360700001801377700001501395700001701410700001701427700001601444700001301460700002101473700001501494700002001509700001401529700002401543700001301567700001801580700001801598700002201616700002201638700001201660700001201672700001901684700001401703700001301717700001601730700001701746700002501763700001801788700001501806700001501821700001301836700001701849700001801866700001401884700001801898700002101916700001801937700001701955700001201972700001901984700001302003700001102016700001202027700002002039700001702059700001602076700002202092700001902114700001602133700001702149700001502166700001802181700002002199700001702219700001802236700001302254700001602267700001902283700002102302700001202323700002002335700001902355700001302374700001602387700001802403700002002421856003602441 2021 eng d00a{A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids0 amultiethnic epigenomewide association study of leukocyte DNA met c06 a39870 v123 a10.1038/s41467-021-23899-yHere we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.1 aJhun, M., A.1 aMendelson, M.1 aWilson, R.1 aGondalia, R.1 aJoehanes, R.1 aSalfati, E.1 aZhao, X.1 aBraun, K., V. E.1 aDo, A., N.1 aHedman, Å., K.1 aZhang, T.1 aCarnero-Montoro, E.1 aShen, J.1 aBartz, T., M.1 aBrody, J., A.1 aMontasser, M., E.1 aO'Connell, J., R.1 aYao, C.1 aXia, R.1 aBoerwinkle, E.1 aGrove, M.1 aGuan, W.1 aLiliane, P.1 aSingmann, P.1 aMüller-Nurasyid, M.1 aMeitinger, T.1 aGieger, C.1 aPeters, A.1 aZhao, W.1 aWare, E., B.1 aSmith, J., A.1 aDhana, K.1 avan Meurs, J.1 aUitterlinden, A.1 aIkram, M., A.1 aGhanbari, M.1 aZhi, D.1 aGustafsson, S.1 aLind, L.1 aLi, S.1 aSun, D.1 aSpector, T., D.1 aChen, Y., I.1 aDamcott, C.1 aShuldiner, A., R.1 aAbsher, D., M.1 aHorvath, S.1 aTsao, P., S.1 aKardia, S.1 aPsaty, B., M.1 aSotoodehnia, N.1 aBell, J., T.1 aIngelsson, E.1 aChen, W.1 aDehghan, A.1 aArnett, D., K.1 aWaldenberger, M.1 aHou, L.1 aWhitsel, E., A.1 aBaccarelli, A.1 aLevy, D.1 aFornage, M.1 aIrvin, M., R.1 aAssimes, T., L. uhttps://chs-nhlbi.org/node/878103781nas a2200637 4500008004100000022001400041245011400055210006900169260001300238300001200251490000700263520196300270100001802233700002402251700002002275700002402295700001902319700002102338700001502359700002002374700002302394700002102417700001602438700001802454700001302472700001502485700002602500700002802526700001602554700002102570700002002591700002002611700002002631700002302651700002302674700003002697700001302727700002302740700002302763700001602786700001702802700001902819700002402838700002102862700002302883700001802906700002802924700002102952700002402973700002702997700002003024700002203044700002203066700001903088856003603107 2021 eng d a2574-830000aMultiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.0 aMultiethnic GenomeWide Association Study of Subclinical Atherosc c2021 Aug ae0032580 v143 aBACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.
METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.
RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).
CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
1 aLu, Yingchang1 aDimitrov, Latchezar1 aChen, Shyh-Huei1 aBielak, Lawrence, F1 aBis, Joshua, C1 aFeitosa, Mary, F1 aLu, Lingyi1 aKavousi, Maryam1 aRaffield, Laura, M1 aSmith, Albert, V1 aWang, Lihua1 aWeiss, Stefan1 aYao, Jie1 aZhu, Jiaxi1 aGudmundsson, Elias, F1 aGudmundsdottir, Valborg1 aBos, Daniel1 aGhanbari, Mohsen1 aIkram, Arfan, M1 aHwang, Shih-Jen1 aTaylor, Kent, D1 aBudoff, Matthew, J1 aGislason, Gauti, K1 aO'Donnell, Christopher, J1 aAn, Ping1 aFranceschini, Nora1 aFreedman, Barry, I1 aFu, Yi-Ping1 aGuo, Xiuqing1 aHeiss, Gerardo1 aKardia, Sharon, L R1 aWilson, James, G1 aLangefeld, Carl, D1 aSchminke, Ulf1 aUitterlinden, André, G1 aLange, Leslie, A1 aPeyser, Patricia, A1 aGudnason, Vilmundur, G1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aBowden, Donald, W1 aC Y Ng, Maggie uhttps://chs-nhlbi.org/node/883202637nas a2200673 4500008004100000022001400041245009500055210006900150260001300219300001200232490000600244520068400250100002400934700002300958700001800981700001900999700002201018700002001040700001701060700002701077700002001104700001901124700001701143700002101160700002401181700002401205700002201229700002001251700002301271700002501294700001801319700002201337700002001359700002501379700001801404700001801422700002001440700002001460700001801480700002001498700002301518700001501541700002501556700001601581700002201597700001701619700002001636700002801656700002001684700002301704700001801727700001401745700002301759700002401782700002301806710006501829710003301894856003601927 2021 eng d a2643-324900ais mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing.0 amutated in clonal hematopoiesis and myelodysplastic syndromes an c2021 Sep a500-5170 v23 aClonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, , as well as in , , and . We also identified these mutations at low frequency in myelodysplastic syndrome patients. edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage and increased genome-wide intron retention. mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.
1 aBeauchamp, Ellen, M1 aLeventhal, Matthew1 aBernard, Elsa1 aHoppe, Emma, R1 aTodisco, Gabriele1 aCreignou, Maria1 aGallì, Anna1 aCastellano, Cecilia, A1 aMcConkey, Marie1 aTarun, Akansha1 aWong, Waihay1 aSchenone, Monica1 aStanclift, Caroline1 aTanenbaum, Benjamin1 aMalolepsza, Edyta1 aNilsson, Björn1 aBick, Alexander, G1 aWeinstock, Joshua, S1 aMiller, Mendy1 aNiroula, Abhishek1 aDunford, Andrew1 aTaylor-Weiner, Amaro1 aWood, Timothy1 aBarbera, Alex1 aAnand, Shankara1 aPsaty, Bruce, M1 aDesai, Pinkal1 aCho, Michael, H1 aJohnson, Andrew, D1 aLoos, Ruth1 aMacArthur, Daniel, G1 aLek, Monkol1 aNeuberg, Donna, S1 aLage, Kasper1 aCarr, Steven, A1 aHellstrom-Lindberg, Eva1 aMalcovati, Luca1 aPapaemmanuil, Elli1 aStewart, Chip1 aGetz, Gad1 aBradley, Robert, K1 aJaiswal, Siddhartha1 aEbert, Benjamin, L1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aExome Aggregation Consortium uhttps://chs-nhlbi.org/node/890802765nas a2200637 4500008004100000245014100041210006900182260000800251300001600259490000700275520106700282100001301349700002601362700001601388700001701404700001501421700002101436700001301457700002001470700001201490700001701502700001801519700001701537700001701554700001901571700001601590700001601606700002101622700001301643700002001656700001601676700002101692700001601713700001301729700001901742700002001761700002101781700002001802700001401822700001801836700001701854700001701871700001901888700001001907700001501917700002201932700001501954700002201969700001801991700001502009700002102024700001402045700002002059700001202079856003602091 2021 eng d00an-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies0 an3 Fatty Acid Biomarkers and Incident Type 2 Diabetes An Individ cMay a1133–11420 v443 a-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.\ For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis.\ 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses.\ Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.1 aQian, F.1 aKorat, A., V. Ardisso1 aImamura, F.1 aMarklund, M.1 aTintle, N.1 aVirtanen, J., K.1 aZhou, X.1 aBassett, J., K.1 aLai, H.1 aHirakawa, Y.1 aChien, K., L.1 aWood, A., C.1 aLankinen, M.1 aMurphy, R., A.1 aSamieri, C.1 aPertiwi, K.1 ade Mello, V., D.1 aGuan, W.1 aForouhi, N., G.1 aWareham, N.1 aHu, I., C. F. B.1 aRiserus, U.1 aLind, L.1 aHarris, W., S.1 aShadyab, A., H.1 aRobinson, J., G.1 aSteffen, L., M.1 aHodge, A.1 aGiles, G., G.1 aNinomiya, T.1 aUusitupa, M.1 aTuomilehto, J.1 am, J.1 aLaakso, M.1 aSiscovick, D., S.1 aHelmer, C.1 aGeleijnse, J., M.1 aWu, J., H. Y.1 aFretts, A.1 aLemaitre, R., N.1 aMicha, R.1 aMozaffarian, D.1 aSun, Q. uhttps://chs-nhlbi.org/node/945802649nas a2200265 4500008004100000022001400041245016700055210006900222260001600291300000700307490000700314520178800321100002502109700001902134700002402153700002202177700002002199700002002219700002302239700002202262700002002284700002002304700002302324856003602347 2021 eng d a1471-226100aNatural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA).0 aNatural killer cells gamma delta T cells and classical monocytes c2021 Jan 22 a450 v213 aBACKGROUND: Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP).
METHODS: We assayed immune cells from cryopreserved samples collected at the baseline examination (2000-2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level.
RESULTS: The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34-3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82-2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14CD16) was associated with 2.01 mmHG (95% CI 0.79-3.24) lower average systolic blood pressure. There were no associations of CD4 T helper cell subsets with average systolic blood pressure.
CONCLUSION: These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.
1 aDelaney, Joseph, A C1 aOlson, Nels, C1 aSitlani, Colleen, M1 aFohner, Alison, E1 aHuber, Sally, A1 aLanday, Alan, L1 aHeckbert, Susan, R1 aTracy, Russell, P1 aPsaty, Bruce, M1 aFeinstein, Matt1 aDoyle, Margaret, F uhttps://chs-nhlbi.org/node/865804049nas a2200253 4500008004100000022001400041245020400055210006900259260001600328300001200344490000600356520318300362100002103545700001803566700001903584700001803603700002703621700002203648700002003670700002103690700002703711700002103738856003603759 2021 eng d a2380-659100aPerformance of the American Heart Association/American College of Cardiology Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Self-reported Physical Activity Levels.0 aPerformance of the American Heart AssociationAmerican College of c2021 Jun 01 a690-6960 v63 aImportance: The American Heart Association/American College of Cardiology pooled cohort equations (PCEs) are used for predicting 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Pooled cohort equation risk prediction capabilities across self-reported leisure-time physical activity (LTPA) levels and the change in model performance with addition of LTPA to the PCE are unclear.
Objective: To evaluate PCE risk prediction performance across self-reported LTPA levels and the change in model performance by adding LTPA to the existing PCE model.
Design, Setting, and Participants: Individual-level pooling of data from 3 longitudinal cohort studies-Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, and Cardiovascular Health Study-was performed. A total of 18 824 participants were stratified into 4 groups based on self-reported LTPA levels: inactive (0 metabolic equivalent of task [MET]-min/wk), less than guideline-recommended (<500 MET-min/wk), guideline-recommended (500-1000 MET-min/week), and greater than guideline-recommended (>1000 MET-min/wk). Pooled cohort equation risk discrimination was studied using the C statistic and reclassification capabilities were studied using the Greenwood Nam-D'Agostino χ2 goodness-of-fit test. Change in risk discrimination and reclassification on adding LTPA to PCEs was evaluated using change in C statistic, integrated discrimination index, and categorical net reclassification index.
Main Outcomes and Measures: Adjudicated ASCVD events during 10-year follow-up.
Results: Among 18 824 participants studied, 10 302 were women (54.7%); mean (SD) age was 57.6 (8.2) years. A total of 5868 participants (31.2%) were inactive, 3849 (20.4%) had less than guideline-recommended LTPA, 3372 (17.9%) had guideline-recommended LTPA, and 5735 (30.5%) had greater than guideline-recommended LTPA level. Higher LTPA levels were associated with a lower risk of ASCVD after adjustment for risk factors (hazard ratio [HR] per 1-SD higher LTPA, 0.91; 95% CI, 0.86-0.96). Across LTPA groups, PCE risk discrimination (C statistic, 0.76-0.78) and risk calibration (all χ2 P > .10) was similar. Addition of LTPA to the PCE model resulted in no significant change in the C statistic (0.0005; 95% CI, -0.0004 to 0.0015; P = .28) and categorical net reclassification index (-0.003; 95% CI, -0.010 to 0.010; P = .95), but a minimal improvement in the integrated discrimination index (0.0008; 95% CI, 0.0002-0.0013; P = .005) was observed. Similar results were noted when cohort-specific coefficients were used for creating the baseline model.
Conclusions and Relevance: Higher self-reported LTPA levels appear to be associated with lower ASCVD risk and increasing LTPA promotes cardiovascular wellness. These findings suggest the American Heart Association/American College of Cardiology PCEs are accurate at estimating the probability of 10-year ASCVD risk regardless of LTPA level. The addition of self-reported LTPA to PCEs does not appear to be associated with improvement in risk prediction model performance.
1 aPandey, Ambarish1 aMehta, Anurag1 aPaluch, Amanda1 aNing, Hongyan1 aCarnethon, Mercedes, R1 aAllen, Norrina, B1 aMichos, Erin, D1 aBerry, Jarett, D1 aLloyd-Jones, Donald, M1 aWilkins, John, T uhttps://chs-nhlbi.org/node/878802876nas a2200337 4500008004100000022001400041245014800055210006900203260000900272300001100281490000700292520184000299100002002139700001802159700002102177700002102198700002202219700002302241700001602264700002202280700002302302700002202325700002402347700002202371700002002393700002302413700001902436700002502455700002202480856003602502 2021 eng d a1663-981200aThe Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction.0 aPharmacogenetics of Statin Therapy on Clinical Events No Evidenc c2021 a6798570 v123 a The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with -values <5.0 × 10 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. In stage-1 meta-analysis (eight studies, = 10,769, 4,212 cases), we observed no genome-wide significant results ( < 5.0 × 10). A total of 144 genetic variants were followed-up in the second stage (three studies, = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.
1 aTrompet, Stella1 aPostmus, Iris1 aWarren, Helen, R1 aNoordam, Raymond1 aSmit, Roelof, A J1 aTheusch, Elizabeth1 aLi, Xiaohui1 aArsenault, Benoit1 aChasman, Daniel, I1 aHitman, Graham, A1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aKrauss, Ron, M1 aCupples, Adrienne, L1 aJukema, Wouter, J uhttps://chs-nhlbi.org/node/898002244nas a2200205 4500008004100000022001400041245011000055210006900165260001600234300001100250490000700261520160000268100002601868700002301894700002001917700002201937700002001959700002301979856003602002 2021 eng d a1872-697600aPhysical Function and Survival in Older Adults: A longitudinal study accounting for time-varying effects.0 aPhysical Function and Survival in Older Adults A longitudinal st c2021 May 24 a1044400 v963 aPURPOSE OF THE STUDY: Variation in physical function in older adults over time raises several methodological challenges in the study of its association with survival, many of which have largely been overlooked in previous studies. The objective of this study is to examine the relationship between time-varying measures of physical function and survival in men and women aged 70 years and over, while accounting for the time-varying effects of health and lifestyle characteristics.
METHODS: 1,846 women and 1,245 men in the Cardiovascular Health Study followed annually for up to 10 years beginning at age 70-74 years were included. We estimated the effect of gait speed and grip strength on survival over the subsequent year, using age as the timescale.
RESULTS: A 0.1m/s higher gait speed was associated with a 12% decrease in the likelihood of death in the subsequent year among women (HR 0.88, 95% CI 0.82-0.94). There was no statistically significant effect of gait speed on survival among men (HR 0.97, 95% CI 0.91 to 1.03), or of grip strength on survival among women (HR 0.97, 95% CI 0.95-1.00) or men (HR 0.99, 95% CI 0.97-1.01), over one year.
CONCLUSIONS: Upon using time-varying measures of physical function while accounting for time-varying effects of health and lifestyle characteristics, higher gait speed was associated with increased survival among the women in our study. We found no evidence of an association between gait speed and one-year survival in men, or between grip strength and one-year survival in women or men.
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2021 eng d00a{The power of genetic diversity in genome-wide association studies of lipids0 apower of genetic diversity in genomewide association studies of cDec a675–6790 v6003 aapplication of polygenic scores in clinical practice.1 aGraham, S., E.1 aClarke, S., L.1 aWu, K., H.1 aKanoni, S.1 aZajac, G., J. 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H. J.1 aArbeeva, L.1 aDorajoo, R.1 aLange, L., A.1 aChai, X.1 aPrasad, G.1 aLorés-Motta, L.1 aPauper, M.1 aLong, J.1 aLi, X.1 aTheusch, E.1 aTakeuchi, F.1 aSpracklen, C., N.1 aLoukola, A.1 aBollepalli, S.1 aWarner, S., C.1 aWang, Y., X.1 aWei, W., B.1 aNutile, T.1 aRuggiero, D.1 aSung, Y., J.1 aHung, Y., J.1 aChen, S.1 aLiu, F.1 aYang, J.1 aKentistou, K., A.1 aGorski, M.1 aBrumat, M.1 aMeidtner, K.1 aBielak, L., F.1 aSmith, J., A.1 aHebbar, P.1 aFarmaki, A., E.1 aHofer, E.1 aLin, M.1 aXue, C.1 aZhang, J.1 aConcas, M., P.1 aVaccargiu, S.1 avan der Most, P., J.1 aPitkänen, N.1 aCade, B., E.1 aLee, J.1 avan der Laan, S., W.1 aChitrala, K., N.1 aWeiss, S.1 aZimmermann, M., E.1 aLee, J., Y.1 aChoi, H., S.1 aNethander, M.1 aFreitag-Wolf, S.1 aSoutham, L.1 aRayner, N., W.1 aWang, C., A.1 aLin, S., Y.1 aWang, J., S.1 aCouture, C.1 aLyytikäinen, L., P.1 aNikus, K.1 aCuellar-Partida, G.1 aVestergaard, H.1 aHildalgo, B.1 aGiannakopoulou, O.1 aCai, Q.1 aObura, M., O.1 avan Setten, J.1 aLi, X.1 aSchwander, K.1 aTerzikhan, N.1 aShin, J., H.1 aJackson, R., D.1 aReiner, A., P.1 aMartin, L., W.1 aChen, Z.1 aLi, L.1 aHighland, H., M.1 aYoung, K., L.1 aKawaguchi, T.1 aThiery, J.1 aBis, J., C.1 aNadkarni, G., N.1 aLauner, L., J.1 aLi, H.1 aNalls, M., A.1 aRaitakari, O., T.1 aIchihara, S.1 aWild, S., H.1 aNelson, C., P.1 aCampbell, H.1 aJäger, S.1 aNabika, T.1 aAl-Mulla, F.1 aNiinikoski, H.1 aBraund, P., S.1 aKolcic, I.1 aKovacs, P.1 aGiardoglou, T.1 aKatsuya, T.1 aBhatti, K., F.1 ade Kleijn, D.1 ade Borst, G., J.1 aKim, E., K.1 aAdams, H., H. H.1 aIkram, M., A.1 aZhu, X.1 aAsselbergs, F., W.1 aKraaijeveld, A., O.1 aBeulens, J., W. J.1 aShu, X., O.1 aRallidis, L., S.1 aPedersen, O.1 aHansen, T.1 aMitchell, P.1 aHewitt, A., W.1 aKähönen, M.1 aPérusse, L.1 aBouchard, C.1 aTonjes, A.1 aChen, Y., I.1 aPennell, C., E.1 aMori, T., A.1 aLieb, W.1 aFranke, A.1 aOhlsson, C.1 aMellström, D.1 aCho, Y., S.1 aLee, H.1 aYuan, J., M.1 aKoh, W., P.1 aRhee, S., Y.1 aWoo, J., T.1 aHeid, I., M.1 aStark, K., J.1 aVölzke, H.1 aHomuth, G.1 aEvans, M., K.1 aZonderman, A., B.1 aPolasek, O.1 aPasterkamp, G.1 aHoefer, I., E.1 aRedline, S.1 aPahkala, K.1 aOldehinkel, A., J.1 aSnieder, H.1 aBiino, G.1 aSchmidt, R.1 aSchmidt, H.1 aChen, Y., E.1 aBandinelli, S.1 aDedoussis, G.1 aThanaraj, T., A.1 aKardia, S., L. R.1 aKato, N.1 aSchulze, M., B.1 aGirotto, G.1 aJung, B.1 aBöger, C., A.1 aJoshi, P., K.1 aBennett, D., A.1 aDe Jager, P., L.1 aLu, X.1 aMamakou, V.1 aBrown, M.1 aCaulfield, M., J.1 aMunroe, P., B.1 aGuo, X.1 aCiullo, M.1 aJonas, J., B.1 aSamani, N., J.1 aKaprio, J.1 aPajukanta, P.1 aAdair, L., S.1 aBechayda, S., A.1 ade Silva, H., J.1 aWickremasinghe, A., R.1 aKrauss, R., M.1 aWu, J., Y.1 aZheng, W.1 aHollander, A., I. den1 aBharadwaj, D.1 aCorrea, A.1 aWilson, J., G.1 aLind, L.1 aHeng, C., K.1 aNelson, A., E.1 aGolightly, Y., M.1 aWilson, J., F.1 aPenninx, B.1 aKim, H., L.1 aAttia, J.1 aScott, R., J.1 aRao, D., C.1 aArnett, D., K.1 aWalker, M.1 aKoistinen, H., A.1 aChandak, G., R.1 aYajnik, C., S.1 aMercader, J., M.1 aTusié-Luna, T.1 aAguilar-Salinas, C., A.1 aVillalpando, C., G.1 aOrozco, L.1 aFornage, M.1 aTai, E., S.1 avan Dam, R., M.1 aLehtimäki, T.1 aChaturvedi, N.1 aYokota, M.1 aLiu, J.1 aReilly, D., F.1 aMcKnight, A., J.1 aKee, F.1 aJöckel, K., H.1 aMcCarthy, M., I.1 aPalmer, C., N. A.1 aVitart, V.1 aHayward, C.1 aSimonsick, E.1 avan Duijn, C., M.1 aLu, F.1 aQu, J.1 aHishigaki, H.1 aLin, X.1 aMärz, W.1 aParra, E., J.1 aCruz, M.1 aGudnason, V.1 aTardif, J., C.1 aLettre, G.1 aHart, L., M. 't1 aElders, P., J. M.1 aDamrauer, S., M.1 aKumari, M.1 aKivimaki, M.1 avan der Harst, P.1 aSpector, T., D.1 aLoos, R., J. F.1 aProvince, M., A.1 aPsaty, B., M.1 aBrandslund, I.1 aPramstaller, P., P.1 aChristensen, K.1 aRipatti, S.1 aWidén, E.1 aHakonarson, H.1 aGrant, S., F. A.1 aKiemeney, L., A. L. M.1 ade Graaf, J.1 aLoeffler, M.1 aKronenberg, F.1 aGu, D.1 aErdmann, J.1 aSchunkert, H.1 aFranks, P., W.1 aLinneberg, A.1 aJukema, J., W.1 aKhera, A., V.1 aMännikkö, M.1 aJarvelin, M., R.1 aKutalik, Z.1 aCucca, F.1 aMook-Kanamori, D., O.1 avan Dijk, K., W.1 aWatkins, H.1 aStrachan, D., P.1 aGrarup, N.1 aSever, P.1 aPoulter, N.1 aRotter, J., I.1 aDantoft, T., M.1 aKarpe, F.1 aNeville, M., J.1 aTimpson, N., J.1 aCheng, C., Y.1 aWong, T., Y.1 aKhor, C., C.1 aSabanayagam, C.1 aPeters, A.1 aGieger, C.1 aHattersley, A., T.1 aPedersen, N., L.1 aMagnusson, P., K. E.1 aBoomsma, D., I.1 ade Geus, E., J. C.1 aCupples, L., A.1 avan Meurs, J., B. J.1 aGhanbari, M.1 aGordon-Larsen, P.1 aHuang, W.1 aKim, Y., J.1 aTabara, Y.1 aWareham, N., J.1 aLangenberg, C.1 aZeggini, E.1 aKuusisto, J.1 aLaakso, M.1 aIngelsson, E.1 aAbecasis, G.1 aChambers, J., C.1 aKooner, J., S.1 ade Vries, P., S.1 aMorrison, A., C.1 aNorth, K., E.1 aDaviglus, M.1 aKraft, P.1 aMartin, N., G.1 aWhitfield, J., B.1 aAbbas, S.1 aSaleheen, D.1 aWalters, R., G.1 aHolmes, M., V.1 aBlack, C.1 aSmith, B., H.1 aJustice, A., E.1 aBaras, A.1 aBuring, J., E.1 aRidker, P., M.1 aChasman, D., I.1 aKooperberg, C.1 aWei, W., Q.1 aJarvik, G., P.1 aNamjou, B.1 aHayes, M., G.1 aRitchie, M., D.1 aJousilahti, P.1 aSalomaa, V.1 aHveem, K.1 aÅsvold, B., O.1 aKubo, M.1 aKamatani, Y.1 aOkada, Y.1 aMurakami, Y.1 aThorsteinsdottir, U.1 aStefansson, K.1 aHo, Y., L.1 aLynch, J., A.1 aRader, D., J.1 aTsao, P., S.1 aChang, K., M.1 aCho, K.1 aO'Donnell, C., J.1 aGaziano, J., M.1 aWilson, P.1 aRotimi, C., N.1 aHazelhurst, S.1 aRamsay, M.1 aTrembath, R., C.1 avan Heel, D., A.1 aTamiya, G.1 aYamamoto, M.1 aKim, B., J.1 aMohlke, K., L.1 aFrayling, T., M.1 aHirschhorn, J., N.1 aKathiresan, S.1 aBoehnke, M.1 aNatarajan, P.1 aPeloso, G., M.1 aBrown, C., D.1 aMorris, A., P.1 aAssimes, T., L.1 aDeloukas, P.1 aSun, Y., V.1 aWiller, C., J. uhttps://chs-nhlbi.org/node/899202672nas a2200289 4500008004100000022001400041245010200055210006900157260001600226520178900242100002702031700002302058700002202081700002102103700001702124700002002141700002402161700002002185700002202205700002002227700002202247700002102269700001302290700002002303700002302323856003602346 2021 eng d a1468-201X00aPremature ventricular complexes and development of heart failure in a community-based population.0 aPremature ventricular complexes and development of heart failure c2021 Sep 073 aOBJECTIVE: A higher premature ventricular complex (PVC) frequency is associated with incident congestive heart failure (CHF) and death. While certain PVC characteristics may contribute to that risk, the current literature stems from patients in medical settings and is therefore prone to referral bias. This study aims to identify PVC characteristics associated with incident CHF in a community-based setting.
METHODS: The Cardiovascular Health Study is a cohort of community-dwelling individuals who underwent prospective evaluation and follow-up. We analysed 24-hour Holter data to assess PVC characteristics and used multivariable logistic and Cox proportional hazards models to identify predictors of a left ventricular ejection fraction (LVEF) decline and incident CHF, respectively.
RESULTS: Of 871 analysed participants, 316 participants exhibited at least 10 PVCs during the 24-hour recording. For participants with PVCs, the average age was 72±5 years, 41% were women and 93% were white. Over a median follow-up of 11 years, 34% developed CHF. After adjusting for demographics, cardiovascular comorbidities, antiarrhythmic drug use and PVC frequency, a greater heterogeneity of the PVC coupling interval was associated with an increased risk of LVEF decline and incident CHF. Of note, neither PVC duration nor coupling interval duration exhibited a statistically significant relationship with either outcome.
CONCLUSIONS: In this first community-based study to identify Holter-based features of PVCs that are associated with LVEF reduction and incident CHF, the fact that coupling interval heterogeneity was an independent risk factor suggests that the mechanism of PVC generation may influence the risk of heart failure.
1 aLimpitikul, Worawan, B1 aDewland, Thomas, A1 aVittinghoff, Eric1 aSoliman, Elsayed1 aNah, Gregory1 aFang, Christina1 aSiscovick, David, S1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aHeckbert, Susan1 aStein, Phyllis, K1 aGottdiener, John1 aHu, Xiao1 aHempfling, Ralf1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/892301911nas a2200685 4500008004100000245009900041210006900140260000700209300001000216490000700226520014700233100001300380700002000393700001800413700001300431700001800444700002000462700001800482700001900500700002100519700001500540700001100555700001500566700001200581700002400593700002000617700001700637700001500654700001700669700001500686700001500701700001900716700001800735700001800753700002000771700002000791700001700811700001900828700001700847700001900864700002600883700001600909700001500925700002100940700001800961700001800979700001700997700001801014700001401032700001401046700001601060700001501076700001501091700001701106700001401123700001901137700001201156700002101168856003601189 2021 eng d00a{Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function0 aRare and lowfrequency exonic variants and genebysmoking interact c09 a193650 v113 a. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.1 aYang, T.1 aJackson, V., E.1 aSmith, A., V.1 aChen, H.1 aBartz, T., M.1 aSitlani, C., M.1 aPsaty, B., M.1 aGharib, S., A.1 aO'Connor, G., T.1 aDupuis, J.1 aXu, J.1 aLohman, K.1 aLiu, Y.1 aKritchevsky, S., B.1 aCassano, P., A.1 aFlexeder, C.1 aGieger, C.1 aKarrasch, S.1 aPeters, A.1 aSchulz, H.1 aHarris, S., E.1 aStarr, J., M.1 aDeary, I., J.1 aManichaikul, A.1 aOelsner, E., C.1 aBarr, R., G.1 aTaylor, K., D.1 aRich, S., S.1 aBonten, T., N.1 aMook-Kanamori, D., O.1 aNoordam, R.1 aLi-Gao, R.1 aJarvelin, M., R.1 aWielscher, M.1 aTerzikhan, N.1 aLahousse, L.1 aBrusselle, G.1 aWeiss, S.1 aEwert, R.1 aGläser, S.1 aHomuth, G.1 aShrine, N.1 aHall, I., P.1 aTobin, M.1 aLondon, S., J.1 aWei, P.1 aMorrison, A., C. uhttps://chs-nhlbi.org/node/891703136nas a2200697 4500008004100000245015100041210006900192260000800261300001200269490000700281520125300288100001701541700002001558700002101578700001701599700002001616700002001636700001701656700001701673700001701690700001801707700001201725700001601737700001501753700002001768700001501788700001201803700001601815700002101831700001801852700002001870700001701890700001201907700001901919700001801938700002001956700001601976700001701992700001602009700001602025700002102041700002002062700001802082700002102100700002002121700001802141700002102159700001502180700001902195700001902214700001902233700001702252700002002269700001402289700001902303700002102322700002002343700002002363700001902383856003602402 2021 eng d00a{Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis0 aRare Coding Variants Associated With Electrocardiographic Interv cAug ae0033000 v143 aAlterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.\ Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).\ ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.\ Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.1 aChoi, S., H.1 aJurgens, S., J.1 aHaggerty, C., M.1 aHall, A., W.1 aHalford, J., L.1 aMorrill, V., N.1 aWeng, L., C.1 aLagerman, B.1 aMirshahi, T.1 aPettinger, M.1 aGuo, X.1 aLin, H., J.1 aAlonso, A.1 aSoliman, E., Z.1 aKornej, J.1 aLin, H.1 aMoscati, A.1 aNadkarni, G., N.1 aBrody, J., A.1 aWiggins, K., L.1 aCade, B., E.1 aLee, J.1 aAustin-Tse, C.1 aBlackwell, T.1 aChaffin, M., D.1 aLee, C., J.1 aRehm, H., L.1 aRoselli, C.1 aRedline, S.1 aMitchell, B., D.1 aSotoodehnia, N.1 aPsaty, B., M.1 aHeckbert, S., R.1 aLoos, R., J. F.1 aVasan, R., S.1 aBenjamin, E., J.1 aCorrea, A.1 aBoerwinkle, E.1 aArking, D., E.1 aRotter, J., I.1 aRich, S., S.1 aWhitsel, E., A.1 aPerez, M.1 aKooperberg, C.1 aFornwalt, B., K.1 aLunetta, K., L.1 aEllinor, P., T.1 aLubitz, S., A. uhttps://chs-nhlbi.org/node/882908483nas a2202413 4500008004100000022001400041245007200055210006900127260001200196300001200208490000800220520169100228100001901919700002201938700002401960700002201984700002402006700001702030700003002047700002002077700002702097700002002124700003002144700002202174700002002196700001802216700002302234700001802257700002202275700002102297700002302318700002002341700002502361700002102386700001702407700001802424700002402442700001802466700002002484700002202504700001902526700002302545700001902568700002302587700001802610700001802628700001702646700001902663700002102682700002102703700002402724700002402748700001902772700002102791700002202812700002302834700002502857700001902882700002202901700002202923700002302945700002202968700002002990700002203010700001903032700002003051700001903071700002203090700001803112700001903130700001903149700002303168700001903191700002203210700002403232700002103256700001703277700001803294700002103312700001703333700002003350700002303370700002703393700002803420700001803448700002103466700002403487700001703511700002103528700001403549700002603563700002303589700002503612700002103637700002303658700001903681700002403700700001803724700001903742700002103761700002103782700002003803700002303823700002403846700001903870700002103889700002203910700001703932700001603949700001803965700001603983700002003999700001704019700002104036700002204057700002404079700001904103700002104122700002204143700002304165700002204188700002504210700002004235700002304255700002204278700002204300700002504322700002504347700002204372700002504394700002404419700002404443700001904467700002304486700002104509700001904530700002604549700002604575700002104601700002004622700002404642700002004666700001904686700002004705700001404725700001904739700002504758700001504783700002204798700002004820700002104840700002604861700002304887700001904910700002004929700002304949700001904972700002404991700002305015700002305038700002205061700002305083700001805106700002005124700001905144700002505163700002205188700002705210700002705237700003005264700001805294700002105312700001905333700002005352700001805372700002305390700001805413700001705431700002105448700002805469700002405497700002105521700002005542700001905562700002105581700002105602700002405623700001805647700001605665700002805681700002605709700002405735700002105759700002405780700002105804700002505825700002105850700002405871700002305895700002505918700002505943710006505968856003606033 2021 eng d a1476-468700aSequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.0 aSequencing of 53831 diverse genomes from the NHLBI TOPMed Progra c2021 02 a290-2990 v5903 aThe Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
1 aTaliun, Daniel1 aHarris, Daniel, N1 aKessler, Michael, D1 aCarlson, Jedidiah1 aSzpiech, Zachary, A1 aTorres, Raul1 aTaliun, Sarah, A Gagliano1 aCorvelo, André1 aGogarten, Stephanie, M1 aKang, Hyun, Min1 aPitsillides, Achilleas, N1 aLeFaive, Jonathon1 aLee, Seung-Been1 aTian, Xiaowen1 aBrowning, Brian, L1 aDas, Sayantan1 aEmde, Anne-Katrin1 aClarke, Wayne, E1 aLoesch, Douglas, P1 aShetty, Amol, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aWong, Quenna1 aLiu, Xiaoming1 aConomos, Matthew, P1 aBobo, Dean, M1 aAguet, Francois1 aAlbert, Christine1 aAlonso, Alvaro1 aArdlie, Kristin, G1 aArking, Dan, E1 aAslibekyan, Stella1 aAuer, Paul, L1 aBarnard, John1 aBarr, Graham1 aBarwick, Lucas1 aBecker, Lewis, C1 aBeer, Rebecca, L1 aBenjamin, Emelia, J1 aBielak, Lawrence, F1 aBlangero, John1 aBoehnke, Michael1 aBowden, Donald, W1 aBrody, Jennifer, A1 aBurchard, Esteban, G1 aCade, Brian, E1 aCasella, James, F1 aChalazan, Brandon1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aCho, Michael, H1 aChoi, Seung, Hoan1 aChung, Mina, K1 aClish, Clary, B1 aCorrea, Adolfo1 aCurran, Joanne, E1 aCuster, Brian1 aDarbar, Dawood1 aDaya, Michelle1 ade Andrade, Mariza1 aDeMeo, Dawn, L1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aEng, Celeste1 aFatkin, Diane1 aFingerlin, Tasha1 aForer, Lukas1 aFornage, Myriam1 aFranceschini, Nora1 aFuchsberger, Christian1 aFullerton, Stephanie, M1 aGermer, Soren1 aGladwin, Mark, T1 aGottlieb, Daniel, J1 aGuo, Xiuqing1 aHall, Michael, E1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHeckbert, Susan, R1 aIrvin, Marguerite, R1 aJohnsen, Jill, M1 aJohnson, Andrew, D1 aKaplan, Robert1 aKardia, Sharon, L R1 aKelly, Tanika1 aKelly, Shannon1 aKenny, Eimear, E1 aKiel, Douglas, P1 aKlemmer, Robert1 aKonkle, Barbara, A1 aKooperberg, Charles1 aKöttgen, Anna1 aLange, Leslie, A1 aLasky-Su, Jessica1 aLevy, Daniel1 aLin, Xihong1 aLin, Keng-Han1 aLiu, Chunyu1 aLoos, Ruth, J F1 aGarman, Lori1 aGerszten, Robert1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aC Y Mak, Angel1 aManichaikul, Ani1 aManning, Alisa, K1 aMathias, Rasika, A1 aMcManus, David, D1 aMcGarvey, Stephen, T1 aMeigs, James, B1 aMeyers, Deborah, A1 aMikulla, Julie, L1 aMinear, Mollie, A1 aMitchell, Braxton, D1 aMohanty, Sanghamitra1 aMontasser, May, E1 aMontgomery, Courtney1 aMorrison, Alanna, C1 aMurabito, Joanne, M1 aNatale, Andrea1 aNatarajan, Pradeep1 aNelson, Sarah, C1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPankratz, Nathan1 aPeloso, Gina, M1 aPeyser, Patricia, A1 aPleiness, Jacob1 aPost, Wendy, S1 aPsaty, Bruce, M1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRoden, Dan1 aRotter, Jerome, I1 aRuczinski, Ingo1 aSarnowski, Chloe1 aSchoenherr, Sebastian1 aSchwartz, David, A1 aSeo, Jeong-Sun1 aSeshadri, Sudha1 aSheehan, Vivien, A1 aSheu, Wayne, H1 aShoemaker, Benjamin1 aSmith, Nicholas, L1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStilp, Adrienne, M1 aTang, Weihong1 aTaylor, Kent, D1 aTelen, Marilyn1 aThornton, Timothy, A1 aTracy, Russell, P1 aVan Den Berg, David, J1 aVasan, Ramachandran, S1 aViaud-Martinez, Karine, A1 aVrieze, Scott1 aWeeks, Daniel, E1 aWeir, Bruce, S1 aWeiss, Scott, T1 aWeng, Lu-Chen1 aWiller, Cristen, J1 aZhang, Yingze1 aZhao, Xutong1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBoerwinkle, Eric1 aGabriel, Stacey1 aGibbs, Richard1 aRice, Kenneth, M1 aRich, Stephen, S1 aSilverman, Edwin, K1 aQasba, Pankaj1 aGan, Weiniu1 aPapanicolaou, George, J1 aNickerson, Deborah, A1 aBrowning, Sharon, R1 aZody, Michael, C1 aZöllner, Sebastian1 aWilson, James, G1 aCupples, Adrienne, L1 aLaurie, Cathy, C1 aJaquish, Cashell, E1 aHernandez, Ryan, D1 aO'Connor, Timothy, D1 aAbecasis, Goncalo, R1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/866603103nas a2200421 4500008004100000022001400041245015900055210006900214260001600283490000700299520182900306653000902135653002202144653002002166653001502186653002002201653002702221653003502248653001502283653003302298653003102331653001102362653001102373653001802384653000902402653002402411653001702435653002002452100001902472700002102491700002302512700001802535700002002553700002402573700002102597700002702618856003602645 2021 eng d a2072-664300aSerum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS).0 aSerum NonEsterified Fatty Acids Carotid Artery IntimaMedia Thick c2021 Aug 310 v133 a Elevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with ( = 255 for carotid IMT, 301 for FMD) or without ( = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. In multivariable adjusted linear regression models per SD increment, the non-esterified fatty acid conjugated linoleic acid (-18:2 CLA) was positively associated with carotid IMT [β (95% CI): 44.8 (19.2, 70.4), = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), = 1.000]. Non-esterified -palmitoleic acid (16:1n-7) was positively associated with FMD [19.7 (8.34, 31.0), = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.
10aAged10aAged, 80 and over10aAtherosclerosis10aBiomarkers10aBrachial Artery10aCarotid Artery, Common10aCarotid Intima-Media Thickness10aDilatation10aFatty Acids, Monounsaturated10aFatty Acids, Nonesterified10aFemale10aHumans10aLinoleic Acid10aMale10aRegional Blood Flow10aRisk Factors10aUltrasonography1 aHuang, Neil, K1 aBůzková, Petra1 aMatthan, Nirupa, R1 aDjoussé, Luc1 aKizer, Jorge, R1 aMukamal, Kenneth, J1 aPolak, Joseph, F1 aLichtenstein, Alice, H uhttps://chs-nhlbi.org/node/891107711nas a2202569 4500008004100000245009400041210006900135260000700204300000700211490000700218520124200225100001401467700001301481700002101494700001701515700002101532700002101553700001601574700001401590700001501604700001601619700001801635700001501653700001501668700001801683700001401701700001601715700001801731700001601749700002501765700001501790700002001805700001601825700001501841700002001856700002201876700002201898700001901920700002001939700001501959700002101974700002101995700002002016700001302036700001702049700001302066700001802079700001102097700001602108700001302124700001302137700002302150700001602173700001402189700002102203700002402224700002902248700001302277700001702290700001302307700001902320700001602339700001502355700001902370700001902389700002002408700001402428700002402442700001402466700001802480700001402498700001602512700001302528700001802541700001102559700001402570700001802584700001902602700001802621700001602639700001902655700001502674700001902689700001702708700001802725700001702743700001602760700001602776700001302792700001402805700001802819700001702837700001502854700001802869700001802887700001702905700001902922700001602941700001202957700001802969700001302987700001403000700001503014700001803029700001703047700001503064700002003079700001903099700001503118700002203133700001703155700001403172700002203186700001703208700002203225700001903247700001503266700001403281700001603295700001903311700001903330700002203349700001303371700001603384700002603400700001503426700002903441700002103470700002103491700001803512700002003530700001803550700001903568700001903587700002203606700002203628700002303650700001503673700002303688700001803711700001303729700001703742700001803759700001703777700001503794700001803809700003403827700002103861700002003882700001903902700002003921700001903941700001703960700001903977700001603996700001504012700001504027700002304042700001504065700001804080700001404098700001704112700001704129700002204146700001504168700001404183700001704197700002104214700002404235700001604259700002104275700002204296700001904318700002204337700001904359700002004378700001604398700001904414700001404433700001804447700001804465700002004483700002004503700001604523700001604539700002004555700001404575700001404589700001504603700001904618700001704637700002204654700001604676700001604692700002104708700002404729700001704753700002104770700001904791700001604810700001804826700001404844700002404858700002104882700002104903700001604924700002104940700001704961700002104978700001804999700001905017700001505036700001605051700001905067700001905086856003605105 2021 eng d00a{Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability0 aSexdimorphic genetic effects and novel loci for fasting glucose c01 a240 v123 aDifferences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.1 aLagou, V.1 aM?gi, R.1 aHottenga, J., J.1 aGrallert, H.1 aPerry, J., R. B.1 aBouatia-Naji, N.1 aMarullo, L.1 aRybin, D.1 aJansen, R.1 aMin, J., L.1 aDimas, A., S.1 aUlrich, A.1 aZudina, L.1 aG?din, J., R.1 aJiang, L.1 aFaggian, A.1 aBonnefond, A.1 aFadista, J.1 aStathopoulou, M., G.1 aIsaacs, A.1 aWillems, S., M.1 aNavarro, P.1 aTanaka, T.1 aJackson, A., U.1 aMontasser, M., E.1 aO'Connell, J., R.1 aBielak, L., F.1 aWebster, R., J.1 aSaxena, R.1 aStafford, J., M.1 aPourcain, B., S.1 aTimpson, N., J.1 aSalo, P.1 aShin, S., Y.1 aAmin, N.1 aSmith, A., V.1 aLi, G.1 aVerweij, N.1 aGoel, A.1 aFord, I.1 aJohnson, P., C. D.1 aJohnson, T.1 aKapur, K.1 aThorleifsson, G.1 aStrawbridge, R., J.1 aRasmussen-Torvik, L., J.1 aEsko, T.1 aMihailov, E.1 aFall, T.1 aFraser, R., M.1 aMahajan, A.1 aKanoni, S.1 aGiedraitis, V.1 aKleber, M., E.1 aSilbernagel, G.1 aMeyer, J.1 aM?ller-Nurasyid, M.1 aGanna, A.1 aSarin, A., P.1 aYengo, L.1 aShungin, D.1 aLuan, J.1 aHorikoshi, M.1 aAn, P.1 aSanna, S.1 aBoettcher, Y.1 aRayner, N., W.1 aNolte, I., M.1 aZemunik, T.1 aIperen, E., V.1 aKovacs, P.1 aHastie, N., D.1 aWild, S., H.1 aMcLachlan, S.1 aCampbell, S.1 aPolasek, O.1 aCarlson, O.1 aEgan, J.1 aKiess, W.1 aWillemsen, G.1 aKuusisto, J.1 aLaakso, M.1 aDimitriou, M.1 aHicks, A., A.1 aRauramaa, R.1 aBandinelli, S.1 aThorand, B.1 aLiu, Y.1 aMiljkovic, I.1 aLind, L.1 aDoney, A.1 aPerola, M.1 aHingorani, A.1 aKivimaki, M.1 aKumari, M.1 aBennett, A., J.1 aGroves, C., J.1 aHerder, C.1 aKoistinen, H., A.1 aKinnunen, L.1 aFaire, U.1 aBakker, S., J. L.1 aUusitupa, M.1 aPalmer, C., N. A.1 aJukema, J., W.1 aSattar, N.1 aPouta, A.1 aSnieder, H.1 aBoerwinkle, E.1 aPankow, J., S.1 aMagnusson, P., K.1 aKrus, U.1 aScapoli, C.1 ade Geus, E., J. C. N.1 aBl?her, M.1 aWolffenbuttel, B., H. R.1 aProvince, M., A.1 aAbecasis, G., R.1 aMeigs, J., B.1 aHovingh, G., K.1 aLindstr?m, J.1 aWilson, J., F.1 aWright, A., F.1 aDedoussis, G., V.1 aBornstein, S., R.1 aSchwarz, P., E. H.1 aT?njes, A.1 aWinkelmann, B., R.1 aBoehm, B., O.1 aM?rz, W.1 aMetspalu, A.1 aPrice, J., F.1 aDeloukas, P.1 aK?rner, A.1 aLakka, T., A.1 aKeinanen-Kiukaanniemi, S., M.1 aSaaristo, T., E.1 aBergman, R., N.1 aTuomilehto, J.1 aWareham, N., J.1 aLangenberg, C.1 aM?nnist?, S.1 aFranks, P., W.1 aHayward, C.1 aVitart, V.1 aKaprio, J.1 aVisvikis-Siest, S.1 aBalkau, B.1 aAltshuler, D.1 aRudan, I.1 aStumvoll, M.1 aCampbell, H.1 avan Duijn, C., M.1 aGieger, C.1 aIllig, T.1 aFerrucci, L.1 aPedersen, N., L.1 aPramstaller, P., P.1 aBoehnke, M.1 aFrayling, T., M.1 aShuldiner, A., R.1 aPeyser, P., A.1 aKardia, S., L. R.1 aPalmer, L., J.1 aPenninx, B., W.1 aMeneton, P.1 aHarris, T., B.1 aNavis, G.1 aHarst, P., V.1 aSmith, G., D.1 aForouhi, N., G.1 aLoos, R., J. F.1 aSalomaa, V.1 aSoranzo, N.1 aBoomsma, D., I.1 aGroop, L.1 aTuomi, T.1 aHofman, A.1 aMunroe, P., B.1 aGudnason, V.1 aSiscovick, D., S.1 aWatkins, H.1 aLecoeur, C.1 aVollenweider, P.1 aFranco-Cereceda, A.1 aEriksson, P.1 aJarvelin, M., R.1 aStefansson, K.1 aHamsten, A.1 aNicholson, G.1 aKarpe, F.1 aDermitzakis, E., T.1 aLindgren, C., M.1 aMcCarthy, M., I.1 aFroguel, P.1 aKaakinen, M., A.1 aLyssenko, V.1 aWatanabe, R., M.1 aIngelsson, E.1 aFlorez, J., C.1 aDupuis, J.1 aBarroso, I.1 aMorris, A., P.1 aProkopenko, I. uhttps://chs-nhlbi.org/node/861807720nas a2202569 4500008004100000245009400041210006900135260000700204300000700211490000700218520124200225100001401467700001401481700002101495700001701516700002101533700002101554700001601575700001401591700001501605700001601620700001801636700001501654700001501669700001901684700001401703700001601717700001801733700001601751700002501767700001501792700002001807700001601827700001501843700002001858700002201878700002201900700001901922700002001941700001501961700002101976700002101997700002002018700001302038700001702051700001302068700001802081700001102099700001602110700001302126700001302139700002302152700001602175700001402191700002102205700002402226700002902250700001302279700001702292700001302309700001902322700001602341700001502357700001902372700001902391700002002410700001402430700002502444700001402469700001802483700001402501700001602515700001302531700001802544700001102562700001402573700001802587700001902605700001802624700001602642700001902658700001502677700001902692700001702711700001802728700001702746700001602763700001602779700001302795700001402808700001802822700001702840700001502857700001802872700001802890700001702908700001902925700001602944700001202960700001802972700001302990700001403003700001503017700001803032700001703050700001503067700002003082700001903102700001503121700002203136700001703158700001403175700002203189700001703211700002203228700001903250700001503269700001403284700001603298700001903314700001903333700002203352700001303374700001603387700002603403700001603429700002903445700002103474700002103495700001803516700002003534700001903554700001903573700001903592700002203611700002203633700002303655700001503678700002303693700001803716700001403734700001703748700001803765700001703783700001603800700001803816700003403834700002103868700002003889700001903909700002003928700001903948700001903967700001903986700001604005700001504021700001504036700002304051700001504074700001804089700001404107700001704121700001704138700002204155700001504177700001404192700001704206700002104223700002404244700001604268700002104284700002204305700001904327700002204346700001904368700002004387700001604407700001904423700001404442700001804456700001804474700002004492700002004512700001604532700001604548700002004564700001404584700001404598700001504612700001904627700001704646700002204663700001604685700001604701700002104717700002404738700001704762700002104779700001904800700001604819700001804835700001404853700002404867700002104891700002104912700001604933700002104949700001704970700002104987700001805008700001905026700001505045700001605060700001905076700001905095856003605114 2021 eng d00a{Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability0 aSexdimorphic genetic effects and novel loci for fasting glucose c01 a240 v123 aDifferences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.1 aLagou, V.1 aMägi, R.1 aHottenga, J., J.1 aGrallert, H.1 aPerry, J., R. B.1 aBouatia-Naji, N.1 aMarullo, L.1 aRybin, D.1 aJansen, R.1 aMin, J., L.1 aDimas, A., S.1 aUlrich, A.1 aZudina, L.1 aGådin, J., R.1 aJiang, L.1 aFaggian, A.1 aBonnefond, A.1 aFadista, J.1 aStathopoulou, M., G.1 aIsaacs, A.1 aWillems, S., M.1 aNavarro, P.1 aTanaka, T.1 aJackson, A., U.1 aMontasser, M., E.1 aO'Connell, J., R.1 aBielak, L., F.1 aWebster, R., J.1 aSaxena, R.1 aStafford, J., M.1 aPourcain, B., S.1 aTimpson, N., J.1 aSalo, P.1 aShin, S., Y.1 aAmin, N.1 aSmith, A., V.1 aLi, G.1 aVerweij, N.1 aGoel, A.1 aFord, I.1 aJohnson, P., C. D.1 aJohnson, T.1 aKapur, K.1 aThorleifsson, G.1 aStrawbridge, R., J.1 aRasmussen-Torvik, L., J.1 aEsko, T.1 aMihailov, E.1 aFall, T.1 aFraser, R., M.1 aMahajan, A.1 aKanoni, S.1 aGiedraitis, V.1 aKleber, M., E.1 aSilbernagel, G.1 aMeyer, J.1 aMüller-Nurasyid, M.1 aGanna, A.1 aSarin, A., P.1 aYengo, L.1 aShungin, D.1 aLuan, J.1 aHorikoshi, M.1 aAn, P.1 aSanna, S.1 aBoettcher, Y.1 aRayner, N., W.1 aNolte, I., M.1 aZemunik, T.1 aIperen, E., V.1 aKovacs, P.1 aHastie, N., D.1 aWild, S., H.1 aMcLachlan, S.1 aCampbell, S.1 aPolasek, O.1 aCarlson, O.1 aEgan, J.1 aKiess, W.1 aWillemsen, G.1 aKuusisto, J.1 aLaakso, M.1 aDimitriou, M.1 aHicks, A., A.1 aRauramaa, R.1 aBandinelli, S.1 aThorand, B.1 aLiu, Y.1 aMiljkovic, I.1 aLind, L.1 aDoney, A.1 aPerola, M.1 aHingorani, A.1 aKivimaki, M.1 aKumari, M.1 aBennett, A., J.1 aGroves, C., J.1 aHerder, C.1 aKoistinen, H., A.1 aKinnunen, L.1 aFaire, U.1 aBakker, S., J. L.1 aUusitupa, M.1 aPalmer, C., N. A.1 aJukema, J., W.1 aSattar, N.1 aPouta, A.1 aSnieder, H.1 aBoerwinkle, E.1 aPankow, J., S.1 aMagnusson, P., K.1 aKrus, U.1 aScapoli, C.1 ade Geus, E., J. C. N.1 aBlüher, M.1 aWolffenbuttel, B., H. R.1 aProvince, M., A.1 aAbecasis, G., R.1 aMeigs, J., B.1 aHovingh, G., K.1 aLindström, J.1 aWilson, J., F.1 aWright, A., F.1 aDedoussis, G., V.1 aBornstein, S., R.1 aSchwarz, P., E. H.1 aTonjes, A.1 aWinkelmann, B., R.1 aBoehm, B., O.1 aMärz, W.1 aMetspalu, A.1 aPrice, J., F.1 aDeloukas, P.1 aKörner, A.1 aLakka, T., A.1 aKeinanen-Kiukaanniemi, S., M.1 aSaaristo, T., E.1 aBergman, R., N.1 aTuomilehto, J.1 aWareham, N., J.1 aLangenberg, C.1 aMännistö, S.1 aFranks, P., W.1 aHayward, C.1 aVitart, V.1 aKaprio, J.1 aVisvikis-Siest, S.1 aBalkau, B.1 aAltshuler, D.1 aRudan, I.1 aStumvoll, M.1 aCampbell, H.1 avan Duijn, C., M.1 aGieger, C.1 aIllig, T.1 aFerrucci, L.1 aPedersen, N., L.1 aPramstaller, P., P.1 aBoehnke, M.1 aFrayling, T., M.1 aShuldiner, A., R.1 aPeyser, P., A.1 aKardia, S., L. R.1 aPalmer, L., J.1 aPenninx, B., W.1 aMeneton, P.1 aHarris, T., B.1 aNavis, G.1 aHarst, P., V.1 aSmith, G., D.1 aForouhi, N., G.1 aLoos, R., J. F.1 aSalomaa, V.1 aSoranzo, N.1 aBoomsma, D., I.1 aGroop, L.1 aTuomi, T.1 aHofman, A.1 aMunroe, P., B.1 aGudnason, V.1 aSiscovick, D., S.1 aWatkins, H.1 aLecoeur, C.1 aVollenweider, P.1 aFranco-Cereceda, A.1 aEriksson, P.1 aJarvelin, M., R.1 aStefansson, K.1 aHamsten, A.1 aNicholson, G.1 aKarpe, F.1 aDermitzakis, E., T.1 aLindgren, C., M.1 aMcCarthy, M., I.1 aFroguel, P.1 aKaakinen, M., A.1 aLyssenko, V.1 aWatanabe, R., M.1 aIngelsson, E.1 aFlorez, J., C.1 aDupuis, J.1 aBarroso, I.1 aMorris, A., P.1 aProkopenko, I. uhttps://chs-nhlbi.org/node/866302456nas a2200229 4500008004100000022001400041245010000055210006900155260001600224520173300240100002601973700002001999700001802019700002402037700002102061700002002082700001902102700002302121700002602144700002002170856003602190 2021 eng d a1526-632X00aSilent Myocardial Infarction and Subsequent Ischemic Stroke in the Cardiovascular Health Study.0 aSilent Myocardial Infarction and Subsequent Ischemic Stroke in t c2021 May 243 aOBJECTIVE: To test the hypothesis that silent MI is a risk factor for ischemic stroke, we evaluated the association between silent MI and subsequent ischemic stroke in the Cardiovascular Health Study.
METHODS: The Cardiovascular Health Study prospectively enrolled community-dwelling individuals ≥65 years of age. We included participants without prevalent stroke or baseline evidence of MI. Our exposures were silent and clinically apparent, overt MI. Silent MI was defined as new evidence of Q-wave MI, without clinical symptoms of MI, on ECGs performed during annual study visits from 1989-1999. The primary outcome was incident ischemic stroke. Secondary outcomes were ischemic stroke subtypes: non-lacunar, lacunar, and other/unknown. Cox proportional hazards analysis was used to model the association between time-varying MI status (silent, overt, or no MI) and stroke after adjustment for baseline demographics and vascular risk factors.
RESULTS: Among 4,224 participants, 362 (8.6%) had an incident silent MI, 421 (10.0%) an incident overt MI, and 377 (8.9%) an incident ischemic stroke during a median follow-up of 9.8 years. After adjustment for demographics and comorbidities, silent MI was independently associated with subsequent ischemic stroke (HR, 1.51; 95% CI, 1.03-2.21). Overt MI was associated with ischemic stroke both in the short term (HR, 80; 95% CI, 53-119) and long term (HR, 1.60; 95% CI, 1.04-2.44). In secondary analyses, the association between silent MI and stroke was limited to non-lacunar ischemic stroke (HR 2.40; 95% CI, 1.36-4.22).
CONCLUSION: In a community-based sample, we found an association between silent MI and ischemic stroke.
1 aMerkler, Alexander, E1 aBartz, Traci, M1 aKamel, Hooman1 aSoliman, Elsayed, Z1 aHoward, Virginia1 aPsaty, Bruce, M1 aOkin, Peter, M1 aSafford, Monika, M1 aElkind, Mitchell, S V1 aLongstreth, W T uhttps://chs-nhlbi.org/node/878504415nas a2200805 4500008004100000022001400041245024200055210006900297260001300366300001200379490000700391520195900398100002402357700002002381700002202401700002102423700002002444700003002464700001902494700002002513700002102533700002102554700002202575700002202597700002002619700002002639700001802659700002002677700003202697700002102729700001902750700002402769700002902793700001602822700001902838700002902857700002202886700002002908700002202928700001902950700002202969700002402991700002003015700002803035700002003063700002503083700002203108700002003130700002203150700002303172700002403195700002003219700002103239700002103260700002303281700002003304700002103324700001603345700002003361700001803381700002003399700002203419700002303441700002703464700002003491700001903511700002003530700002303550856003603573 2021 eng d a2574-830000aSugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations.0 aSugarSweetened Beverage Consumption May Modify Associations Betw c2021 Aug ae0032880 v143 aBACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia.
METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.
RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).
CONCLUSIONS: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.
1 aHaslam, Danielle, E1 aPeloso, Gina, M1 aGuirette, Melanie1 aImamura, Fumiaki1 aBartz, Traci, M1 aPitsillides, Achilleas, N1 aWang, Carol, A1 aLi-Gao, Ruifang1 aWestra, Jason, M1 aPitkänen, Niina1 aYoung, Kristin, L1 aGraff, Mariaelisa1 aWood, Alexis, C1 aBraun, Kim, V E1 aLuan, Jian'an1 aKähönen, Mika1 ade Jong, Jessica, C Kiefte-1 aGhanbari, Mohsen1 aTintle, Nathan1 aLemaitre, Rozenn, N1 aMook-Kanamori, Dennis, O1 aNorth, Kari1 aHelminen, Mika1 aMossavar-Rahmani, Yasmin1 aSnetselaar, Linda1 aMartin, Lisa, W1 aViikari, Jorma, S1 aOddy, Wendy, H1 aPennell, Craig, E1 aRosendall, Frits, R1 aIkram, Arfan, M1 aUitterlinden, André, G1 aPsaty, Bruce, M1 aMozaffarian, Dariush1 aRotter, Jerome, I1 aTaylor, Kent, D1 aLehtimäki, Terho1 aRaitakari, Olli, T1 aLivingston, Kara, A1 aVoortman, Trudy1 aForouhi, Nita, G1 aWareham, Nick, J1 ade Mutsert, Renée1 aRich, Steven, S1 aManson, JoAnn, E1 aMora, Samia1 aRidker, Paul, M1 aMerino, Jordi1 aMeigs, James, B1 aDashti, Hassan, S1 aChasman, Daniel, I1 aLichtenstein, Alice, H1 aSmith, Caren, E1 aDupuis, Josée1 aHerman, Mark, A1 aMcKeown, Nicola, M uhttps://chs-nhlbi.org/node/883003856nas a2200673 4500008004100000022001400041245008300055210006900138260001500207300001000222490000700232520192100239653000902160653002502169653002402194653001502218653002502233653001102258653001802269653001102287653001902298653000902317653001602326653001302342653003202355653002802387653002302415653001702438653001802455653003402473653002702507100001302534700002102547700002302568700002902591700002602620700001902646700002202665700002102687700001802708700001902726700002402745700001802769700002202787700002202809700002602831700002302857700002002880700002102900700002102921700002402942700002302966700002802989700002003017700002303037700002203060710006403082856003603146 2021 eng d a1558-359700aSupplemental Association of Clonal Hematopoiesis With Incident Heart Failure.0 aSupplemental Association of Clonal Hematopoiesis With Incident H c2021 07 06 a42-520 v783 aBACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).
OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF.
METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.
RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.
CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.
10aAged10aClonal Hematopoiesis10aCorrelation of Data10aDemography10aDNA-Binding Proteins10aFemale10aHeart Failure10aHumans10aJanus Kinase 210aMale10aMiddle Aged10aMutation10aProportional Hazards Models10aProto-Oncogene Proteins10aRepressor Proteins10aRisk Factors10aStroke Volume10aVentricular Dysfunction, Left10aWhole Exome Sequencing1 aYu, Bing1 aRoberts, Mary, B1 aRaffield, Laura, M1 aZekavat, Seyedeh, Maryam1 aNguyen, Ngoc, Quynh H1 aBiggs, Mary, L1 aBrown, Michael, R1 aGriffin, Gabriel1 aDesai, Pinkal1 aCorrea, Adolfo1 aMorrison, Alanna, C1 aShah, Amil, M1 aNiroula, Abhishek1 aUddin, Md, Mesbah1 aHonigberg, Michael, C1 aEbert, Benjamin, L1 aPsaty, Bruce, M1 aWhitsel, Eric, A1 aManson, JoAnn, E1 aKooperberg, Charles1 aBick, Alexander, G1 aBallantyne, Christie, M1 aReiner, Alex, P1 aNatarajan, Pradeep1 aEaton, Charles, B1 aNational Heart, Lung, and Blood Institute TOPMed Consortium uhttps://chs-nhlbi.org/node/883904296nas a2200973 4500008004100000022001400041245010700055210006900162260001600231520147300247100002301720700002101743700001901764700001801783700001901801700002301820700001901843700001701862700001901879700003001898700002601928700002801954700002801982700002102010700001702031700002202048700002302070700002202093700002202115700002102137700002402158700002302182700002002205700002402225700002002249700002102269700002302290700002402313700002402337700001902361700001902380700002002399700001902419700002502438700002302463700002402486700002002510700002302530700001602553700002202569700002002591700002002611700001702631700002202648700001802670700002402688700002402712700002302736700002402759700001902783700001502802700002302817700002502840700002502865700002202890700002402912700001902936700002602955700002602981700002103007700002103028700002203049700002303071700002003094700002703114700002103141700002003162700002103182700001903203700002003222700002303242700002103265856003603286 2021 eng d a1476-625600aA System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.0 aSystem for Phenotype Harmonization in the NHLBI TransOmics for P c2021 Apr 163 aGenotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
1 aStilp, Adrienne, M1 aEmery, Leslie, S1 aBroome, Jai, G1 aButh, Erin, J1 aKhan, Alyna, T1 aLaurie, Cecelia, A1 aWang, Fei, Fei1 aWong, Quenna1 aChen, Dongquan1 aD'Augustine, Catherine, M1 aHeard-Costa, Nancy, L1 aHohensee, Chancellor, R1 aJohnson, William, Craig1 aJuarez, Lucia, D1 aLiu, Jingmin1 aMutalik, Karen, M1 aRaffield, Laura, M1 aWiggins, Kerri, L1 ade Vries, Paul, S1 aKelly, Tanika, N1 aKooperberg, Charles1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aPeyser, Patricia, A1 aReiner, Alex, P1 aArnett, Donna, K1 aAslibekyan, Stella1 aBarnes, Kathleen, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aCade, Brian, E1 aChen, Ming-Huei1 aCorrea, Adolfo1 aCupples, Adrienne, L1 ade Andrade, Mariza1 aEllinor, Patrick, T1 aFornage, Myriam1 aFranceschini, Nora1 aGan, Weiniu1 aGanesh, Santhi, K1 aGraffelman, Jan1 aGrove, Megan, L1 aGuo, Xiuqing1 aHawley, Nicola, L1 aHsu, Wan-Ling1 aJackson, Rebecca, D1 aJaquish, Cashell, E1 aJohnson, Andrew, D1 aKardia, Sharon, L R1 aKelly, Shannon1 aLee, Jiwon1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNorth, Kari, E1 aNouraie, Seyed, Mehdi1 aOelsner, Elizabeth, C1 aPankratz, Nathan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aWeeks, Daniel, E1 aWeiss, Scott, T1 aWilson, Carla, G1 aYanek, Lisa, R1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aLaurie, Cathy, C uhttps://chs-nhlbi.org/node/871313921nas a2205113 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2021 eng d00a{The trans-ancestral genomic architecture of glycemic traits0 atransancestral genomic architecture of glycemic traits c06 a840–8600 v533 a10.1038/s41588-021-00852-9Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.1 aChen, J.1 aSpracklen, C., N.1 aMarenne, G.1 aVarshney, A.1 aCorbin, L., J.1 aLuan, J.1 aWillems, S., M.1 aWu, Y.1 aZhang, X.1 aHorikoshi, M.1 aBoutin, T., S.1 aMägi, R.1 aWaage, J.1 aLi-Gao, R.1 aChan, K., H. K.1 aYao, J.1 aAnasanti, M., D.1 aChu, A., Y.1 aClaringbould, A.1 aHeikkinen, J.1 aHong, J.1 aHottenga, J., J.1 aHuo, S.1 aKaakinen, M., A.1 aLouie, T.1 aMärz, W.1 aMoreno-Macias, H.1 aNdungu, A.1 aNelson, S., C.1 aNolte, I., M.1 aNorth, K., E.1 aRaulerson, C., K.1 aRay, D.1 aRohde, R.1 aRybin, D.1 aSchurmann, C.1 aSim, X.1 aSoutham, L.1 aStewart, I., D.1 aWang, C., A.1 aWang, Y.1 aWu, P.1 aZhang, W.1 aAhluwalia, T., S.1 aAppel, E., V. R.1 aBielak, L., F.1 aBrody, J., A.1 aBurtt, N., P.1 aCabrera, C., P.1 aCade, B., E.1 aChai, J., F.1 aChai, X.1 aChang, L., C.1 aChen, C., H.1 aChen, B., H.1 aChitrala, K., N.1 aChiu, Y., F.1 ade Haan, H., G.1 aDelgado, G., E.1 aDemirkan, A.1 aDuan, Q.1 aEngmann, J.1 aFatumo, S., A.1 aGayán, J.1 aGiulianini, F.1 aGong, J., H.1 aGustafsson, S.1 aHai, Y.1 aHartwig, F., P.1 aHe, J.1 aHeianza, Y.1 aHuang, T.1 aHuerta-Chagoya, A.1 aHwang, M., Y.1 aJensen, R., A.1 aKawaguchi, T.1 aKentistou, K., A.1 aKim, Y., J.1 aKleber, M., E.1 aKooner, I., K.1 aLai, S.1 aLange, L., A.1 aLangefeld, C., D.1 aLauzon, M.1 aLi, M.1 aLigthart, S.1 aLiu, J.1 aLoh, M.1 aLong, J.1 aLyssenko, V.1 aMangino, M.1 aMarzi, C.1 aMontasser, M., E.1 aNag, A.1 aNakatochi, M.1 aNoce, D.1 aNoordam, R.1 aPistis, G.1 aPreuss, M.1 aRaffield, L.1 aRasmussen-Torvik, L., J.1 aRich, S., S.1 aRobertson, N., R.1 aRueedi, R.1 aRyan, K.1 aSanna, S.1 aSaxena, R.1 aSchraut, K., E.1 aSennblad, B.1 aSetoh, K.1 aSmith, A., V.1 aSparsø, T.1 aStrawbridge, R., J.1 aTakeuchi, F.1 aTan, J.1 aTrompet, S.1 avan den Akker, E.1 avan der Most, P., J.1 aVerweij, N.1 aVogel, M.1 aWang, H.1 aWang, C.1 aWang, N.1 aWarren, H., R.1 aWen, W.1 aWilsgaard, T.1 aWong, A.1 aWood, A., R.1 aXie, T.1 aZafarmand, M., H.1 aZhao, J., H.1 aZhao, W.1 aAmin, N.1 aArzumanyan, Z.1 aAstrup, A.1 aBakker, S., J. L.1 aBaldassarre, D.1 aBeekman, M.1 aBergman, R., N.1 aBertoni, A.1 aBlüher, M.1 aBonnycastle, L., L.1 aBornstein, S., R.1 aBowden, D., W.1 aCai, Q.1 aCampbell, A.1 aCampbell, H.1 aChang, Y., C.1 ade Geus, E., J. C.1 aDehghan, A.1 aDu, S.1 aEiriksdottir, G.1 aFarmaki, A., E.1 aFrånberg, M.1 aFuchsberger, C.1 aGao, Y.1 aGjesing, A., P.1 aGoel, A.1 aHan, S.1 aHartman, C., A.1 aHerder, C.1 aHicks, A., A.1 aHsieh, C., H.1 aHsueh, W., A.1 aIchihara, S.1 aIgase, M.1 aIkram, M., A.1 aJohnson, W., C.1 aJørgensen, M., E.1 aJoshi, P., K.1 aKalyani, R., R.1 aKandeel, F., R.1 aKatsuya, T.1 aKhor, C., C.1 aKiess, W.1 aKolcic, I.1 aKuulasmaa, T.1 aKuusisto, J.1 aLäll, K.1 aLam, K.1 aLawlor, D., A.1 aLee, N., R.1 aLemaitre, R., N.1 aLi, H.1 aLin, S., Y.1 aLindström, J.1 aLinneberg, A.1 aLiu, J.1 aLorenzo, C.1 aMatsubara, T.1 aMatsuda, F.1 aMingrone, G.1 aMooijaart, S.1 aMoon, S.1 aNabika, T.1 aNadkarni, G., N.1 aNadler, J., L.1 aNelis, M.1 aNeville, M., J.1 aNorris, J., M.1 aOhyagi, Y.1 aPeters, A.1 aPeyser, P., A.1 aPolasek, O.1 aQi, Q.1 aRaven, D.1 aReilly, D., F.1 aReiner, A.1 aRivideneira, F.1 aRoll, K.1 aRudan, I.1 aSabanayagam, C.1 aSandow, K.1 aSattar, N.1 aSchürmann, A.1 aShi, J.1 aStringham, H., M.1 aTaylor, K., D.1 aTeslovich, T., M.1 aThuesen, B.1 aTimmers, P., R. H. J.1 aTremoli, E.1 aTsai, M., Y.1 aUitterlinden, A.1 avan Dam, R., M.1 avan Heemst, D.1 aVlieg, van, Hylckama1 aVan Vliet-Ostaptchouk, J., V.1 aVangipurapu, J.1 aVestergaard, H.1 aWang, T.1 avan Dijk, Willems1 aZemunik, T.1 aAbecasis, G., R.1 aAdair, L., S.1 aAguilar-Salinas, C., A.1 aAlarcón-Riquelme, M., E.1 aAn, P.1 aAviles-Santa, L.1 aBecker, D., M.1 aBeilin, L., J.1 aBergmann, S.1 aBisgaard, H.1 aBlack, C.1 aBoehnke, M.1 aBoerwinkle, E.1 aBöhm, B., O.1 aBønnelykke, K.1 aBoomsma, D., I.1 aBottinger, E., P.1 aBuchanan, T., A.1 aCanouil, M.1 aCaulfield, M., J.1 aChambers, J., C.1 aChasman, D., I.1 aChen, Y., I.1 aCheng, C., Y.1 aCollins, F., S.1 aCorrea, A.1 aCucca, F.1 ade Silva, H., J.1 aDedoussis, G.1 aElmståhl, S.1 aEvans, M., K.1 aFerrannini, E.1 aFerrucci, L.1 aFlorez, J., C.1 aFranks, P., W.1 aFrayling, T., M.1 aFroguel, P.1 aGigante, B.1 aGoodarzi, M., O.1 aGordon-Larsen, P.1 aGrallert, H.1 aGrarup, N.1 aGrimsgaard, S.1 aGroop, L.1 aGudnason, V.1 aGuo, X.1 aHamsten, A.1 aHansen, T.1 aHayward, C.1 aHeckbert, S., R.1 aHorta, B., L.1 aHuang, W.1 aIngelsson, E.1 aJames, P., S.1 aJarvelin, M., R.1 aJonas, J., B.1 aJukema, J., W.1 aKaleebu, P.1 aKaplan, R.1 aKardia, S., L. R.1 aKato, N.1 aKeinanen-Kiukaanniemi, S., M.1 aKim, B., J.1 aKivimaki, M.1 aKoistinen, H., A.1 aKooner, J., S.1 aKörner, A.1 aKovacs, P.1 aKuh, D.1 aKumari, M.1 aKutalik, Z.1 aLaakso, M.1 aLakka, T., A.1 aLauner, L., J.1 aLeander, K.1 aLi, H.1 aLin, X.1 aLind, L.1 aLindgren, C.1 aLiu, S.1 aLoos, R., J. F.1 aMagnusson, P., K. E.1 aMahajan, A.1 aMetspalu, A.1 aMook-Kanamori, D., O.1 aMori, T., A.1 aMunroe, P., B.1 aNjølstad, I.1 aO'Connell, J., R.1 aOldehinkel, A., J.1 aOng, K., K.1 aPadmanabhan, S.1 aPalmer, C., N. A.1 aPalmer, N., D.1 aPedersen, O.1 aPennell, C., E.1 aPorteous, D., J.1 aPramstaller, P., P.1 aProvince, M., A.1 aPsaty, B., M.1 aQi, L.1 aRaffel, L., J.1 aRauramaa, R.1 aRedline, S.1 aRidker, P., M.1 aRosendaal, F., R.1 aSaaristo, T., E.1 aSandhu, M.1 aSaramies, J.1 aSchneiderman, N.1 aSchwarz, P.1 aScott, L., J.1 aSelvin, E.1 aSever, P.1 aShu, X., O.1 aSlagboom, P., E.1 aSmall, K., S.1 aSmith, B., H.1 aSnieder, H.1 aSofer, T.1 aSørensen, T., I. A.1 aSpector, T., D.1 aStanton, A.1 aSteves, C., J.1 aStumvoll, M.1 aSun, L.1 aTabara, Y.1 aTai, E., S.1 aTimpson, N., J.1 aTonjes, A.1 aTuomilehto, J.1 aTusie, T.1 aUusitupa, M.1 avan der Harst, P.1 avan Duijn, C.1 aVitart, V.1 aVollenweider, P.1 aVrijkotte, T., G. M.1 aWagenknecht, L., E.1 aWalker, M.1 aWang, Y., X.1 aWareham, N., J.1 aWatanabe, R., M.1 aWatkins, H.1 aWei, W., B.1 aWickremasinghe, A., R.1 aWillemsen, G.1 aWilson, J., F.1 aWong, T., Y.1 aWu, J., Y.1 aXiang, A., H.1 aYanek, L., R.1 aYengo, L.1 aYokota, M.1 aZeggini, E.1 aZheng, W.1 aZonderman, A., B.1 aRotter, J., I.1 aGloyn, A., L.1 aMcCarthy, M., I.1 aDupuis, J.1 aMeigs, J., B.1 aScott, R., A.1 aProkopenko, I.1 aLeong, A.1 aLiu, C., T.1 aParker, S., C. J.1 aMohlke, K., L.1 aLangenberg, C.1 aWheeler, E.1 aMorris, A., P.1 aBarroso, I.1 ade Haan, H., G.1 avan den Akker, E.1 avan der Most, P., J.1 ade Geus, E., J. C.1 avan Dam, R., M.1 avan Heemst, D.1 aVlieg, van, Hylckama1 avan Dijk, van, Willems1 ade Silva, H., J.1 avan der Harst, P.1 avan Duijn, C. uhttps://chs-nhlbi.org/node/877203425nas a2200577 4500008004100000022001400041245020400055210006900259260001500328300001400343490000700357520172900364653000902093653001102102653000902113653001102122653002302133653000902156653002402165653001502189653001202204653001802216100002202234700002102256700002802277700002002305700002102325700002102346700002402367700001602391700002402407700002002431700002202451700001802473700001902491700002002510700002402530700002002554700001902574700002102593700001702614700002302631700002202654700002202676700002302698700001902721700002902740700002202769700002002791856003602811 2021 eng d a1758-535X00aWhat Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium.0 aWhat CutPoint in Gait Speed Best Discriminates CommunityDwelling c2021 09 13 ae321-e3270 v763 aBACKGROUND: Cut-points to define slow walking speed have largely been derived from expert opinion.
METHODS: Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.
RESULTS: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.
CONCLUSIONS: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.
10aAged10aFemale10aGait10aHumans10aIndependent Living10aMale10aMobility Limitation10aSarcopenia10aWalking10aWalking Speed1 aCawthon, Peggy, M1 aPatel, Sheena, M1 aKritchevsky, Stephen, B1 aNewman, Anne, B1 aSantanasto, Adam1 aKiel, Douglas, P1 aTravison, Thomas, G1 aLane, Nancy1 aCummings, Steven, R1 aOrwoll, Eric, S1 aDuchowny, Kate, A1 aKwok, Timothy1 aHirani, Vasant1 aSchousboe, John1 aKarlsson, Magnus, K1 aMellström, Dan1 aOhlsson, Claes1 aLjunggren, Osten1 aXue, Qian-Li1 aShardell, Michelle1 aJordan, Joanne, M1 aPencina, Karol, M1 aFielding, Roger, A1 aMagaziner, Jay1 aCorrea-de-Araujo, Rosaly1 aBhasin, Shalender1 aManini, Todd, M uhttps://chs-nhlbi.org/node/898904364nas a2200997 4500008004100000022001400041245016200055210006900217260001300286300001100299490000700310520151100317100002001828700002201848700002301870700002301893700002301916700002601939700002501965700002001990700002102010700002602031700001702057700002502074700002202099700001702121700001702138700002002155700002002175700002302195700001702218700002102235700001802256700001802274700001902292700001202311700001802323700001502341700002302356700002802379700001802407700002002425700002002445700002102465700002302486700002002509700002102529700002302550700001802573700002202591700002302613700002202636700001802658700002002676700002302696700002302719700001902742700002002761700001402781700002002795700002202815700002002837700002102857700002102878700001702899700002402916700001902940700002502959700001402984700002302998700002403021700002303045700002503068700002603093700002103119700002703140700002203167700001703189700002103206700001903227700002103246700001603267700002403283700002303307856003603330 2021 eng d a2352-396400aWhole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.0 aWhole genome sequence analyses of eGFR in 23732 people represent c2021 Jan a1031570 v633 aBACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.
METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.
FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.
INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
1 aLin, Bridget, M1 aGrinde, Kelsey, E1 aBrody, Jennifer, A1 aBreeze, Charles, E1 aRaffield, Laura, M1 aMychaleckyj, Josyf, C1 aThornton, Timothy, A1 aPerry, James, A1 aBaier, Leslie, J1 aFuentes, Lisa, de Las1 aGuo, Xiuqing1 aHeavner, Benjamin, D1 aHanson, Robert, L1 aHung, Yi-Jen1 aQian, Huijun1 aHsiung, Chao, A1 aHwang, Shih-Jen1 aIrvin, Margaret, R1 aJain, Deepti1 aKelly, Tanika, N1 aKobes, Sayuko1 aLange, Leslie1 aLash, James, P1 aLi, Yun1 aLiu, Xiaoming1 aMi, Xuenan1 aMusani, Solomon, K1 aPapanicolaou, George, J1 aParsa, Afshin1 aReiner, Alex, P1 aSalimi, Shabnam1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aTaylor, Kent, D1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTin, Adrienne1 aVaidya, Dhananjay1 aWallace, Robert, B1 aYamamoto, Kenichi1 aSakaue, Saori1 aMatsuda, Koichi1 aKamatani, Yoichiro1 aMomozawa, Yukihide1 aYanek, Lisa, R1 aYoung, Betsi, A1 aZhao, Wei1 aOkada, Yukinori1 aAbecasis, Gonzalo1 aPsaty, Bruce, M1 aArnett, Donna, K1 aBoerwinkle, Eric1 aCai, Jianwen1 aDer Chen, Ida, Yii-1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aHe, Jiang1 aKardia, Sharon, Lr1 aKooperberg, Charles1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aNickerson, Deborah, A1 aTurner, Steve, T1 aVasan, Ramachandran, S1 aRotter, Jerome, I1 aLevy, Daniel1 aKramer, Holly, J1 aKöttgen, Anna1 aRich, Stephen, S1 aLin, Dan-Yu1 aBrowning, Sharon, R1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/866404419nas a2200925 4500008004100000022001400041245011400055210006900169260001600238520175700254100002002011700001202031700001402043700001702057700001602074700002002090700002102110700002002131700002302151700002502174700002302199700001902222700002002241700001902261700002002280700002302300700002002323700002102343700002002364700002302384700001902407700001402426700002002440700001902460700002502479700001802504700002002522700002102542700001902563700002102582700002502603700002002628700001902648700002202667700002002689700002002709700002002729700001602749700002002765700002402785700002102809700002702830700002002857700001502877700002502892700002402917700002202941700001902963700002602982700002103008700002003029700002703049700002103076700002203097700002103119700002303140700001403163700002203177700002403199700002303223700002303246700001203269700001803281700002203299700002503321700002303346700002303369710006503392856003603457 2021 eng d a1460-208300aWhole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.0 aWhole genome sequence analysis of platelet traits in the NHLBI t c2021 Sep 063 aPlatelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.
1 aLittle, Amarise1 aHu, Yao1 aSun, Quan1 aJain, Deepti1 aBroome, Jai1 aChen, Ming-Huei1 aThibord, Florian1 aMcHugh, Caitlin1 aSurendran, Praveen1 aBlackwell, Thomas, W1 aBrody, Jennifer, A1 aBhan, Arunoday1 aChami, Nathalie1 aVries, Paul, S1 aEkunwe, Lynette1 aHeard-Costa, Nancy1 aHobbs, Brian, D1 aManichaikul, Ani1 aMoon, Jee-Young1 aPreuss, Michael, H1 aRyan, Kathleen1 aWang, Zhe1 aWheeler, Marsha1 aYanek, Lisa, R1 aAbecasis, Goncalo, R1 aAlmasy, Laura1 aBeaty, Terri, H1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aButterworth, Adam, S1 aChoquet, Helene1 aCorrea, Adolfo1 aCurran, Joanne, E1 aFaraday, Nauder1 aFornage, Myriam1 aGlahn, David, C1 aHou, Lifang1 aJorgenson, Eric1 aKooperberg, Charles1 aLewis, Joshua, P1 aLloyd-Jones, Donald, M1 aLoos, Ruth, J F1 aMin, Nancy1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aNickerson, Debbie1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPankratz, Nathan1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Albert, V1 aSmith, Nicholas, L1 aTang, Hua1 aTracy, Russell, P1 aConomos, Matthew, P1 aLaurie, Cecelia, A1 aMathias, Rasika, A1 aLi, Yun1 aAuer, Paul, L1 aThornton, Timothy1 aReiner, Alexander, P1 aJohnson, Andrew, D1 aRaffield, Laura, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/891303828nas a2200625 4500008004100000022001400041245010800055210006900163260001500232300000800247490000700255520201900262100001902281700001502300700001702315700001702332700001502349700001402364700002002378700002402398700001702422700002402439700002002463700001602483700001302499700002102512700002202533700001802555700001902573700002102592700002002613700002202633700002202655700002002677700002002697700002302717700002502740700002402765700001902789700002502808700002202833700002602855700001902881700002002900700002202920700002102942700002202963700002702985700002103012700001803033700001903051710006503070710003103135856003603166 2021 eng d a1756-994X00aWhole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.0 aWholegenome association analyses of sleepdisordered breathing ph c2021 08 26 a1360 v133 aBACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.
METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.
RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.
CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.
1 aCade, Brian, E1 aLee, Jiwon1 aSofer, Tamar1 aWang, Heming1 aZhang, Man1 aChen, Han1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aGuo, Xiuqing1 aLane, Jacqueline, M1 aLiang, Jingjing1 aLin, Xihong1 aMei, Hao1 aPatel, Sanjay, R1 aPurcell, Shaun, M1 aSaxena, Richa1 aShah, Neomi, A1 aEvans, Daniel, S1 aHanis, Craig, L1 aHillman, David, R1 aMukherjee, Sutapa1 aPalmer, Lyle, J1 aStone, Katie, L1 aTranah, Gregory, J1 aAbecasis, Goncalo, R1 aBoerwinkle, Eric, A1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aKaplan, Robert, C1 aNickerson, Deborah, A1 aNorth, Kari, E1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aRich, Stephen, S1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aWilson, James, G1 aZhu, Xiaofeng1 aRedline, Susan1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Sleep Working Group uhttps://chs-nhlbi.org/node/892005743nas a2201309 4500008004100000022001400041245011800055210006900173260001500242300001200257490000800269520205100277653001002328653000902338653003202347653002202379653001702401653001102418653001702429653002202446653003402468653001702502653001102519653000902530653001602539653005302555653001402608653002002622653003102642653001802673100001202691700002302703700002302726700001702749700001702766700001802783700001502801700003602816700002302852700002002875700001902895700002002914700001302934700001702947700001602964700002002980700002203000700002003022700001403042700002303056700002303079700002503102700002003127700001903147700002803166700002303194700001403217700002003231700002303251700001503274700002003289700002103309700001803330700002003348700002203368700001803390700001803408700002103426700002003447700002203467700002003489700002703509700002703536700002303563700001903586700002103605700002103626700002103647700002503668700001603693700002603709700002403735700002003759700001903779700001903798700001903817700002003836700002003856700002403876700002303900700002903923700001403952700002003966700002003986700002504006700002204031700002104053700002504074700002304099700001804122700001204140700002304152700002204175700002104197700002104218700002304239700002104262700002404283700002504307710006504332856003604397 2021 eng d a1537-660500aWhole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.0 aWholegenome sequencing association analysis of quantitative red c2021 05 06 a874-8930 v1083 aWhole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
10aAdult10aAged10aChromosomes, Human, Pair 1610aDatasets as Topic10aErythrocytes10aFemale10aGene Editing10aGenetic Variation10aGenome-Wide Association Study10aHEK293 Cells10aHumans10aMale10aMiddle Aged10aNational Heart, Lung, and Blood Institute (U.S.)10aPhenotype10aQuality Control10aReproducibility of Results10aUnited States1 aHu, Yao1 aStilp, Adrienne, M1 aMcHugh, Caitlin, P1 aRao, Shuquan1 aJain, Deepti1 aZheng, Xiuwen1 aLane, John1 ade Bellefon, Sébastian, Méric1 aRaffield, Laura, M1 aChen, Ming-Huei1 aYanek, Lisa, R1 aWheeler, Marsha1 aYao, Yao1 aRen, Chunyan1 aBroome, Jai1 aMoon, Jee-Young1 ade Vries, Paul, S1 aHobbs, Brian, D1 aSun, Quan1 aSurendran, Praveen1 aBrody, Jennifer, A1 aBlackwell, Thomas, W1 aChoquet, Helene1 aRyan, Kathleen1 aDuggirala, Ravindranath1 aHeard-Costa, Nancy1 aWang, Zhe1 aChami, Nathalie1 aPreuss, Michael, H1 aMin, Nancy1 aEkunwe, Lynette1 aLange, Leslie, A1 aCushman, Mary1 aFaraday, Nauder1 aCurran, Joanne, E1 aAlmasy, Laura1 aKundu, Kousik1 aSmith, Albert, V1 aGabriel, Stacey1 aRotter, Jerome, I1 aFornage, Myriam1 aLloyd-Jones, Donald, M1 aVasan, Ramachandran, S1 aSmith, Nicholas, L1 aNorth, Kari, E1 aBoerwinkle, Eric1 aBecker, Lewis, C1 aLewis, Joshua, P1 aAbecasis, Goncalo, R1 aHou, Lifang1 aO'Connell, Jeffrey, R1 aMorrison, Alanna, C1 aBeaty, Terri, H1 aKaplan, Robert1 aCorrea, Adolfo1 aBlangero, John1 aJorgenson, Eric1 aPsaty, Bruce, M1 aKooperberg, Charles1 aWalton, Russell, T1 aKleinstiver, Benjamin, P1 aTang, Hua1 aLoos, Ruth, J F1 aSoranzo, Nicole1 aButterworth, Adam, S1 aNickerson, Debbie1 aRich, Stephen, S1 aMitchell, Braxton, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aLi, Yun1 aMathias, Rasika, A1 aLettre, Guillaume1 aPankratz, Nathan1 aLaurie, Cathy, C1 aLaurie, Cecelia, A1 aBauer, Daniel, E1 aConomos, Matthew, P1 aReiner, Alexander, P1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/877905763nas a2201477 4500008004100000022001400041245012500055210006900180260001500249300001400264490000800278520153200286653001101818653001501829653002301844653003801867653001801905653003401923653001101957653001501968653005301983653001402036653003602050653001402086653001302100653004302113653002802156653001902184653001802203653002802221100002402249700002302273700002102296700002302317700002902340700002502369700002302394700001602417700002002433700002002453700002402473700001502497700002202512700001902534700002002553700002002573700002302593700002502616700002002641700001802661700001702679700002102696700002802717700001502745700002002760700002302780700002002803700001902823700002102842700001402863700002302877700002202900700002002922700001402942700002002956700001902976700001502995700002503010700001803035700002403053700002003077700002103097700001903118700002103137700002503158700001903183700002003202700002003222700001903242700001503261700001903276700002003295700002003315700002403335700001603359700002303375700002003398700001903418700002403437700001803461700002303479700002203502700002103524700001703545700001203562700002703574700002003601700002103621700002303642700002503665700002403690700001503714700002603729700002303755700001903778700002603797700002203823700002103845700002003866700002003886700002103906700002003927700002203947700002403969700002303993700001404016700002204030700002504052700002704077700001404104700002304118700002504141700001804166710006504184856003604249 2021 eng d a1537-660500aWhole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.0 aWholegenome sequencing in diverse subjects identifies genetic co c2021 10 07 a1836-18510 v1083 aMany common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
10aAsthma10aBiomarkers10aDermatitis, Atopic10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLeukocytes10aNational Heart, Lung, and Blood Institute (U.S.)10aPhenotype10aPolymorphism, Single Nucleotide10aPrognosis10aProteome10aPulmonary Disease, Chronic Obstructive10aQuantitative Trait Loci10aUnited Kingdom10aUnited States10aWhole Genome Sequencing1 aMikhaylova, Anna, V1 aMcHugh, Caitlin, P1 aPolfus, Linda, M1 aRaffield, Laura, M1 aBoorgula, Meher, Preethi1 aBlackwell, Thomas, W1 aBrody, Jennifer, A1 aBroome, Jai1 aChami, Nathalie1 aChen, Ming-Huei1 aConomos, Matthew, P1 aCox, Corey1 aCurran, Joanne, E1 aDaya, Michelle1 aEkunwe, Lynette1 aGlahn, David, C1 aHeard-Costa, Nancy1 aHighland, Heather, M1 aHobbs, Brian, D1 aIlboudo, Yann1 aJain, Deepti1 aLange, Leslie, A1 aMiller-Fleming, Tyne, W1 aMin, Nancy1 aMoon, Jee-Young1 aPreuss, Michael, H1 aRosen, Jonathon1 aRyan, Kathleen1 aSmith, Albert, V1 aSun, Quan1 aSurendran, Praveen1 ade Vries, Paul, S1 aWalter, Klaudia1 aWang, Zhe1 aWheeler, Marsha1 aYanek, Lisa, R1 aZhong, Xue1 aAbecasis, Goncalo, R1 aAlmasy, Laura1 aBarnes, Kathleen, C1 aBeaty, Terri, H1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aButterworth, Adam, S1 aChavan, Sameer1 aCho, Michael, H1 aChoquet, Helene1 aCorrea, Adolfo1 aCox, Nancy1 aDeMeo, Dawn, L1 aFaraday, Nauder1 aFornage, Myriam1 aGerszten, Robert, E1 aHou, Lifang1 aJohnson, Andrew, D1 aJorgenson, Eric1 aKaplan, Robert1 aKooperberg, Charles1 aKundu, Kousik1 aLaurie, Cecelia, A1 aLettre, Guillaume1 aLewis, Joshua, P1 aLi, Bingshan1 aLi, Yun1 aLloyd-Jones, Donald, M1 aLoos, Ruth, J F1 aManichaikul, Ani1 aMeyers, Deborah, A1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aNgo, Debby1 aNickerson, Deborah, A1 aNongmaithem, Suraj1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOrtega, Victor, E1 aPankratz, Nathan1 aPerry, James, A1 aPsaty, Bruce, M1 aRich, Stephen, S1 aSoranzo, Nicole1 aRotter, Jerome, I1 aSilverman, Edwin, K1 aSmith, Nicholas, L1 aTang, Hua1 aTracy, Russell, P1 aThornton, Timothy, A1 aVasan, Ramachandran, S1 aZein, Joe1 aMathias, Rasika, A1 aReiner, Alexander, P1 aAuer, Paul, L1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/891403404nas a2200757 4500008004100000022001400041245011100055210006900166260001300235300001200248490000700260520115000267100002601417700001701443700001701460700002501477700002401502700002201526700002701548700002501575700002001600700002401620700001801644700002501662700001501687700002301702700001901725700002701744700002101771700002401792700002101816700002201837700002601859700001901885700002301904700002401927700002801951700001901979700002001998700002002018700002302038700002402061700002702085700002302112700002002135700002102155700002202176700002302198700001902221700001702240700002002257700002302277700002302300700002502323700002402348700002102372700001902393700002102412700001902433700001602452700001502468700002302483710003902506710006502545856003602610 2022 eng d a1546-171800aAssessing the contribution of rare variants to complex trait heritability from whole-genome sequence data.0 aAssessing the contribution of rare variants to complex trait her c2022 Mar a263-2730 v543 aAnalyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.
1 aWainschtein, Pierrick1 aJain, Deepti1 aZheng, Zhili1 aCupples, Adrienne, L1 aShadyab, Aladdin, H1 aMcKnight, Barbara1 aShoemaker, Benjamin, M1 aMitchell, Braxton, D1 aPsaty, Bruce, M1 aKooperberg, Charles1 aLiu, Ching-Ti1 aAlbert, Christine, M1 aRoden, Dan1 aChasman, Daniel, I1 aDarbar, Dawood1 aLloyd-Jones, Donald, M1 aArnett, Donna, K1 aRegan, Elizabeth, A1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aO'Connell, Jeffrey, R1 aYanek, Lisa, R1 ade Andrade, Mariza1 aAllison, Matthew, A1 aMcDonald, Merry-Lynn, N1 aChung, Mina, K1 aFornage, Myriam1 aChami, Nathalie1 aSmith, Nicholas, L1 aEllinor, Patrick, T1 aVasan, Ramachandran, S1 aMathias, Rasika, A1 aLoos, Ruth, J F1 aRich, Stephen, S1 aLubitz, Steven, A1 aHeckbert, Susan, R1 aRedline, Susan1 aGuo, Xiuqing1 aChen, Y, -D Ida1 aLaurie, Cecelia, A1 aHernandez, Ryan, D1 aMcGarvey, Stephen, T1 aGoddard, Michael, E1 aLaurie, Cathy, C1 aNorth, Kari, E1 aLange, Leslie, A1 aWeir, Bruce, S1 aYengo, Loic1 aYang, Jian1 aVisscher, Peter, M1 aTOPMed Anthropometry Working Group1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/904202915nas a2200241 4500008004100000022001400041245022000055210006900275260001600344520204900360100001802409700002402427700002102451700002002472700002102492700002102513700002702534700001902561700002002580700002002600700001702620856003602637 2022 eng d a1097-679500aThe association of aortic valve sclerosis, aortic annulus increased reflectivity, and mitral annular calcification with subsequent aortic stenosis in older individuals. Findings from the Cardiovascular Health Study.0 aassociation of aortic valve sclerosis aortic annulus increased r c2022 Sep 093 aBACKGROUND: While aortic valve sclerosis (AVS) is well-described as preceding aortic stenosis (AS), the association of AS with antecedent mitral aortic annular calcification and aortic annulus increased reflectivity (MAC and AAIR, respectively) has not been characterized. In a population-based prospective study, we evaluated whether MAC, AAIR, and AVS are associated with the risk of incident AS.
METHODS: Among participants of the Cardiovascular Health Study (CHS) free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three were evaluated in 3041 participants. Cox proportional hazards regression was used to assess the association between the presence of calcification and the incidence of moderate/severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS.
RESULTS: Over a median follow-up of 11.5 years (IQR 6.7 to 17.0), 110 cases of incident moderate/severe AS were ascertained. Strong positive associations with incident moderate/severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (HR=2.90, 95% CI=[1.95, 4.32], p<0.0005), AVS (HR=2.20, 95% CI=[1.44, 3.37], p<0.0005), MAC (HR=1.67, 95% CI=[1.14, 2.45], p=0.008), and the combination of MAC, AAIR, and AVS (HR=2.50, 95% CI=[1.65, 3.78], p<0.0005). In a secondary analysis, the risk of AS increased with the number of sites at which calcification was present.
CONCLUSIONS: In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of MAC, AAIR, and AVS with incident moderate/severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS, and potential inclusion in the routine assessment by transthoracic echocardiography.
1 aBarasch, Eddy1 aGottdiener, John, S1 aTressel, William1 aBartz, Traci, M1 aBůzková, Petra1 aMassera, Daniele1 aDeFilippi, Christopher1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aKizer, Jorge, R1 aOwens, David uhttps://chs-nhlbi.org/node/915402510nas a2200277 4500008004100000022001400041245012700055210006900182260001600251490000700267520171300274653000901987653001501996653001102011653001702022653001102039653000902050653001602059653002202075100002302097700001902120700001802139700001602157700002302173856003602196 2022 eng d a1468-283400aThe association of hearing problems with social network strength and depressive symptoms: the cardiovascular health study.0 aassociation of hearing problems with social network strength and c2022 Aug 020 v513 aBACKGROUND: research on the association between hearing impairment and psychosocial outcomes is not only limited but also yielded mixed results.
METHODS: we investigated associations between annual self-reports of hearing problems, depressive symptoms and social network strength among 5,888 adults from the Cardiovascular Health Study over a period of 9 years. Social network strength and depressive symptoms were defined using the Lubben Social Network Scale (LSNS), and the Center for Epidemiological Studies Depression Scale (CES-D).
RESULTS: hearing problems were associated with weaker social networks and more depressive symptoms. These association differed for prevalent versus incident hearing problems. Participants with prevalent hearing problems scored an adjusted 0.47 points lower (95% CI: -2.20, -0.71) on the LSNS and 0.71 points higher (95% CI: 0.23, 1.19) on the CES-D than those without hearing problems. Participants with incident hearing problems had a greater decline of 0.12 points (95% CI: -0.12, -0.03) per year in social network score than individuals with no hearing problems after adjusting for confounders. Females appeared to be more vulnerable to changes in social network strength than males (P-value for interaction = 0.02), but not for changes in depressive score. Accounting for social network score did not appear to attenuate the association between hearing problems and depressive score.
CONCLUSION: findings suggest that older adults with prevalent hearing problems may be more at risk for depression, but individuals with incident hearing problems may be at greater risk for a winnowing of their social network.
10aAged10aDepression10aFemale10aHearing Loss10aHumans10aMale10aSelf Report10aSocial Networking1 aDobrota, Sylvie, D1 aBiggs, Mary, L1 aPratt, Sheila1 aPopat, Rita1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/915902657nas a2200289 4500008004100000022001400041245010000055210006900155260001600224520177800240100001702018700002402035700002302059700002202082700002102104700002002125700002002145700001902165700002202184700002002206700002302226700002002249700002202269700001702291700002302308856003602331 2022 eng d a2055-582200aAssociation of immune cell subsets with incident heart failure in two population-based cohorts.0 aAssociation of immune cell subsets with incident heart failure i c2022 Sep 123 aAIMS: Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)].
METHODS AND RESULTS: Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 4.4 years with 62% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95% CI 0.83-0.99), P = 0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF.
CONCLUSIONS: We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.
1 aSinha, Arjun1 aSitlani, Colleen, M1 aDoyle, Margaret, F1 aFohner, Alison, E1 aBůzková, Petra1 aFloyd, James, S1 aHuber, Sally, A1 aOlson, Nels, C1 aNjoroge, Joyce, N1 aKizer, Jorge, R1 aDelaney, Joseph, A1 aShah, Sanjiv, S1 aTracy, Russell, P1 aPsaty, Bruce1 aFeinstein, Matthew uhttps://chs-nhlbi.org/node/917502923nas a2200289 4500008004100000022001400041245013200055210006900187260001600256300001400272490000700286520203000293100002202323700002002345700002202365700002202387700001902409700001802428700002602446700002002472700002002492700002402512700002102536700002002557700002002577856003602597 2022 eng d a1526-632X00aAssociation of Serum Neurofilament Light Chain Concentration and MRI Findings in Older Adults: The Cardiovascular Health Study.0 aAssociation of Serum Neurofilament Light Chain Concentration and c2022 Mar 01 ae903-e9110 v983 aBACKGROUND AND OBJECTIVES: Neurofilament light chain (NfL) in blood is a sensitive but nonspecific marker of brain injury. This study sought to evaluate associations between NfL concentration and MRI findings of vascular brain injury in older adults.
METHODS: A longitudinal cohort study included 2 cranial MRI scans performed about 5 years apart and assessed for white matter hyperintensities (WMH) and infarcts. About 1 year before their second MRI, 1,362 participants (median age 77 years, 61.4% women) without a history of TIA or stroke had measurement of 4 biomarkers: NfL, total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1. Most (n = 1,279) also had the first MRI scan, and some (n = 633) had quantitative measurements of hippocampal and WMH. In primary analyses, we assessed associations of NfL with a 10-point white matter grade (WMG) and prevalent infarcts on second MRI and with worsening WMG and incident infarct comparing the 2 scans. A value <0.0125 (0.05/4) was considered significant for these analyses. We also assessed associations with hippocampal and WMH volume.
RESULTS: In fully adjusted models, log(NfL) concentration was associated with WMG (β = 0.27; = 2.3 × 10) and worsening WMG (relative risk [RR] 1.24; = 0.0022), but less strongly with prevalent brain infarcts (RR 1.18; = 0.013) and not with incident brain infarcts (RR 1.18; = 0.18). Associations were also present with WMH volume (β = 2,242.9, = 0.0036). For the other 3 biomarkers, the associations for log (GFAP) concentration with WMG and worsening WMG were significant.
DISCUSSION: Among older adults without a history of stroke, higher serum NfL concentration was associated with covert MRI findings of vascular brain injury, especially the burden of WMH and its worsening. Whether these results offer opportunities for the use of NfL as a noninvasive biomarker of WMH or to control vascular risk factors remains to be determined.
1 aFohner, Alison, E1 aBartz, Traci, M1 aTracy, Russell, P1 aAdams, Hieab, H H1 aBis, Joshua, C1 aDjoussé, Luc1 aSatizabal, Claudia, L1 aLopez, Oscar, L1 aSeshadri, Sudha1 aMukamal, Kenneth, J1 aKuller, Lewis, H1 aPsaty, Bruce, M1 aLongstreth, W T uhttps://chs-nhlbi.org/node/899004438nas a2200457 4500008004100000022001400041245009000055210006900145260001500214300001300229490000600242520319000248653000903438653001203447653002803459653001403487653001203501653001903513653001103532653001103543653000903554653001703563653002403580100002203604700002203626700001703648700002003665700002403685700001503709700002903724700002403753700001503777700002003792700002403812700002203836700002203858700001503880700002403895700002503919856003603944 2022 eng d a2574-380500aAssociation of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults.0 aAssociation of Trimethylamine NOxide and Metabolites With Mortal c2022 05 02 ae22132420 v53 aImportance: Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population.
Objective: To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US.
Design, Setting, and Participants: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021.
Exposures: Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry.
Main Outcomes and Measures: Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models.
Results: Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3%) were male, 3184 (59.7%) were female, 848 (15.9%) were African American, 4450 (83.4%) were White, and 35 (0.01%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95% CI, 1.17-1.44) for TMAO, 1.19 (95% CI, 1.08-1.32) for choline, 1.26 (95% CI, 1.15-1.40) for carnitine, and 1.26 (95% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality.
Conclusions and Relevance: In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.
10aAged10aBetaine10aCardiovascular Diseases10aCarnitine10aCholine10aCohort Studies10aFemale10aHumans10aMale10aMethylamines10aProspective Studies1 aFretts, Amanda, M1 aHazen, Stanley, L1 aJensen, Paul1 aBudoff, Matthew1 aSitlani, Colleen, M1 aWang, Meng1 aOtto, Marcia, C de Olive1 aDiDonato, Joseph, A1 aLee, Yujin1 aPsaty, Bruce, M1 aSiscovick, David, S1 aSotoodehnia, Nona1 aTang, W, H Wilson1 aLai, Heidi1 aLemaitre, Rozenn, N1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/909101272nas a2200349 4500008004100000245015300041210006900194260000700263300001400270490000700284520024000291100001200531700001800543700001600561700001600577700001600593700002800609700002000637700001800657700001500675700001800690700002500708700001500733700001700748700001900765700002600784700001900810700001900829700002100848700001700869856003600886 2022 eng d00a{An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns0 aassociation test of the spatial distribution of rare missense va c04 a778–7900 v323 ais a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.1 aJin, B.1 aCapra, J., A.1 aBenchek, P.1 aWheeler, N.1 aNaj, A., C.1 aHamilton-Nelson, K., L.1 aFarrell, J., J.1 aLeung, Y., Y.1 aKunkle, B.1 aVadarajan, B.1 aSchellenberg, G., D.1 aMayeux, R.1 aWang, L., S.1 aFarrer, L., A.1 aPericak-Vance, M., A.1 aMartin, E., R.1 aHaines, J., L.1 aCrawford, D., C.1 aBush, W., S. uhttps://chs-nhlbi.org/node/909803642nas a2200589 4500008004100000022001400041245009900055210006900154260001600223520192000239100002002159700001702179700002602196700002402222700002202246700001702268700002002285700002402305700001802329700002402347700001602371700002002387700002202407700002402429700002602453700002002479700002202499700002202521700002502543700002002568700002002588700002702608700002102635700002602656700002202682700002502704700001802729700002002747700002702767700002302794700001902817700002202836700001302858700002102871700002402892700001902916700002002935700002202955700001902977700002002996856003603016 2022 eng d a1875-890800aAssociations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis.0 aAssociations of Pulmonary Function with MRI Brain Volumes A Coor c2022 Oct 033 aBACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.
OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.
METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.
RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.
CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.
1 aFrenzel, Stefan1 aBis, Josh, C1 aGudmundsson, Elias, F1 aO'Donnell, Adrienne1 aSimino, Jeannette1 aYaqub, Amber1 aBartz, Traci, M1 aBrusselle, Guy, G O1 aBülow, Robin1 aDeCarli, Charles, S1 aEwert, Ralf1 aGharib, Sina, A1 aGhosh, Saptaparni1 aGireud-Goss, Monica1 aGottesman, Rebecca, F1 aIkram, Arfan, M1 aKnopman, David, S1 aLauner, Lenore, J1 aLondon, Stephanie, J1 aLongstreth, W T1 aLopez, Oscar, L1 avan Lent, Debora, Melo1 aO'Connor, George1 aSatizabal, Claudia, L1 aShrestha, Srishti1 aSigurdsson, Sigurdur1 aStubbe, Beate1 aTalluri, Rajesh1 aVasan, Ramachandran, S1 aVernooij, Meike, W1 aVölzke, Henry1 aWiggins, Kerri, L1 aYu, Bing1 aBeiser, Alexa, S1 aGudnason, Vilmundur1 aMosley, Thomas1 aPsaty, Bruce, M1 aWolters, Frank, J1 aGrabe, Hans, J1 aSeshadri, Sudha uhttps://chs-nhlbi.org/node/916303278nas a2200457 4500008004100000022001400041245011800055210006900173260001300242300001400255490000700269520192900276653001202205653001902217653001502236653002102251653002702272653003002299653001102329653001902340653000902359653001502368653002602383653003302409653001902442653003002461100002402491700002502515700002502540700002002565700002302585700002002608700002102628700002202649700002802671700002302699700002202722700002102744700001902765856003602784 2022 eng d a1535-566700aCD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer.0 aCD133 as a Biomarker for an AutoantibodytoImmunoPET Paradigm for c2022 Nov a1701-17070 v633 aSmall cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged using near-infrared fluorescence (NIRF) immunoimaging, and Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both and NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted Zr-immunoPET could be an effective early detection screening strategy for SCLC.
10aAnimals10aAutoantibodies10aBiomarkers10aCell Line, Tumor10aDisease Models, Animal10aEarly Detection of Cancer10aHumans10aLung Neoplasms10aMice10aMice, Nude10aNeuroendocrine Tumors10aPositron-Emission Tomography10aRNA, Messenger10aSmall Cell Lung Carcinoma1 aKunihiro, Andrew, G1 aSarrett, Samantha, M1 aLastwika, Kristin, J1 aSolan, Joell, L1 aPisarenko, Tatyana1 aKeinänen, Outi1 aRodriguez, Cindy1 aTaverne, Lydia, R1 aFitzpatrick, Annette, L1 aLi, Christopher, I1 aHoughton, McGarry1 aZeglis, Brian, M1 aLampe, Paul, D uhttps://chs-nhlbi.org/node/925203432nas a2200457 4500008004100000022001400041245018200055210006900237260001300306300001200319490000700331520203700338653000902375653001702384653004602401653003202447653001502479653002802494653001102522653003402533653001802567653001102585653002502596653000902621100001702630700002302647700002002670700001902690700002502709700001802734700002202752700001802774700001802792700001902810700002602829700002002855700002002875700002202895700002102917856003602938 2022 eng d a2047-998000aCirculating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study.0 aCirculating Soluble CD163 Associations With Cardiovascular Outco c2022 Nov ae0243740 v113 aBackground Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near (top result rs62165726, =3.3×10),19 variants near chromosome 17 gene (rs55714927, =1.5×10), and 18 variants near chromosome 11 gene . These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 =7.1×10) in the region, and 3 variants (rs115391969 =4.3×10) near the chromosome 16 gene Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.
10aAged10aAntigens, CD10aAntigens, Differentiation, Myelomonocytic10aAsialoglycoprotein Receptor10aBiomarkers10aCardiovascular Diseases10aFemale10aGenome-Wide Association Study10aHeart Failure10aHumans10aLongitudinal Studies10aMale1 aDurda, Peter1 aRaffield, Laura, M1 aLange, Ethan, M1 aOlson, Nels, C1 aJenny, Nancy, Swords1 aCushman, Mary1 aDeichgraeber, Pia1 aGrarup, Niels1 aJonsson, Anna1 aHansen, Torben1 aMychaleckyj, Josyf, C1 aPsaty, Bruce, M1 aReiner, Alex, P1 aTracy, Russell, P1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/924503135nas a2200529 4500008004100000022001400041245006700055210006600122260001300188300001200201490000700213520159100220100002401811700002401835700002201859700002001881700002001901700002201921700002301943700002201966700001301988700002402001700002102025700002402046700002002070700002702090700001902117700002102136700002202157700002202179700001902201700002002220700002002240700002202260700002402282700002102306700002802327700002402355700002302379700002402402700002102426700002102447700002302468700002502491710005302516856003602569 2022 eng d a1524-462800aClonal Hematopoiesis Is Associated With Higher Risk of Stroke.0 aClonal Hematopoiesis Is Associated With Higher Risk of Stroke c2022 Mar a788-7970 v533 aBACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.
METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (, , and ) with any stroke, ischemic stroke, and hemorrhagic stroke.
RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, showed the strongest association with total stroke and ischemic stroke, whereas and were each associated with increased risk of hemorrhagic stroke.
CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.
1 aBhattacharya, Romit1 aZekavat, Seyedeh, M1 aHaessler, Jeffrey1 aFornage, Myriam1 aRaffield, Laura1 aUddin, Md, Mesbah1 aBick, Alexander, G1 aNiroula, Abhishek1 aYu, Bing1 aGibson, Christopher1 aGriffin, Gabriel1 aMorrison, Alanna, C1 aPsaty, Bruce, M1 aLongstreth, William, T1 aBis, Joshua, C1 aRich, Stephen, S1 aRotter, Jerome, I1 aTracy, Russell, P1 aCorrea, Adolfo1 aSeshadri, Sudha1 aJohnson, Andrew1 aCollins, Jason, M1 aHayden, Kathleen, M1 aMadsen, Tracy, E1 aBallantyne, Christie, M1 aJaiswal, Siddhartha1 aEbert, Benjamin, L1 aKooperberg, Charles1 aManson, JoAnn, E1 aWhitsel, Eric, A1 aNatarajan, Pradeep1 aReiner, Alexander, P1 aNHLBI Trans-Omics for Precision Medicine Program uhttps://chs-nhlbi.org/node/898603145nas a2200253 4500008004100000022001400041245010700055210006900162260001600231520233000247100002202577700002302599700002502622700002102647700002502668700002302693700002402716700002302740700002002763700001902783700002302802700003002825856003602855 2022 eng d a1523-683800aClonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population.0 aClonal Hematopoiesis of Indeterminate Potential and Kidney Funct c2022 Oct 113 aRATIONALE & OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.
STUDY DESIGN: Cohort study.
SETTING & PARTICIPANTS: 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.
EXPOSURE: CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.
OUTCOME: Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.
ANALYTICAL APPROACH: Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.
RESULTS: The median baseline eGFR was 84mL/min/1.73m. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m, of age above or below 60 years, or with or without diabetes.
LIMITATIONS: Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.
CONCLUSIONS: We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.
1 aKestenbaum, Bryan1 aBick, Alexander, G1 aVlasschaert, Caitlyn1 aRauh, Michael, J1 aLanktree, Matthew, B1 aFranceschini, Nora1 aShoemaker, Moore, B1 aHarris, Raymond, C1 aPsaty, Bruce, M1 aKöttgen, Anna1 aNatarajan, Pradeep1 aRobinson-Cohen, Cassianne uhttps://chs-nhlbi.org/node/925102382nas a2200505 4500008004100000245010800041210006900149260000800218300000900226490000700235520100900242100002101251700002201272700001101294700001801305700001601323700001401339700001601353700001701369700002001386700002201406700002201428700001501450700002101465700002001486700001601506700001801522700001901540700001201559700002301571700002001594700002001614700001701634700002101651700001901672700001801691700001601709700001801725700001701743700002301760700001801783700001801801700002101819856003601840 2022 eng d00a{Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease0 aClonal hematopoiesis of indeterminate potential DNA methylation cSep a53500 v133 aAge-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.1 aUddin, M., D. M.1 aNguyen, N., Q. H.1 aYu, B.1 aBrody, J., A.1 aPampana, A.1 aNakao, T.1 aFornage, M.1 aBressler, J.1 aSotoodehnia, N.1 aWeinstock, J., S.1 aHonigberg, M., C.1 aNachun, D.1 aBhattacharya, R.1 aGriffin, G., K.1 aChander, V.1 aGibbs, R., A.1 aRotter, J., I.1 aLiu, C.1 aBaccarelli, A., A.1 aChasman, D., I.1 aWhitsel, E., A.1 aKiel, D., P.1 aMurabito, J., M.1 aBoerwinkle, E.1 aEbert, B., L.1 aJaiswal, S.1 aFloyd, J., S.1 aBick, A., G.1 aBallantyne, C., M.1 aPsaty, B., M.1 aNatarajan, P.1 aConneely, K., N. uhttps://chs-nhlbi.org/node/918102548nas a2200469 4500008004100000022001400041245010300055210006900158260001600227300001100243490000600254520119300260653001101453653002301464653001101487653000901498653001401507100002001521700002401541700001801565700001401583700002401597700002201621700001601643700002401659700001701683700002301700700002001723700002101743700002201764700002701786700002001813700001901833700002601852700002701878700002001905700002201925700001901947700001701966710005901983856003602042 2022 eng d a2666-379100aCorrelations between complex human phenotypes vary by genetic background, gender, and environment.0 aCorrelations between complex human phenotypes vary by genetic ba c2022 Dec 20 a1008440 v33 aWe develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.
10aFemale10aGenetic Background10aHumans10aMale10aPhenotype1 aElgart, Michael1 aGoodman, Matthew, O1 aIsasi, Carmen1 aChen, Han1 aMorrison, Alanna, C1 ade Vries, Paul, S1 aXu, Huichun1 aManichaikul, Ani, W1 aGuo, Xiuqing1 aFranceschini, Nora1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRotter, Jerome, I1 aLloyd-Jones, Donald, M1 aFornage, Myriam1 aCorrea, Adolfo1 aHeard-Costa, Nancy, L1 aVasan, Ramachandran, S1 aHernandez, Ryan1 aKaplan, Robert, C1 aRedline, Susan1 aSofer, Tamar1 aTrans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/924606322nas a2201285 4500008004100000022001400041245007900055210006900134260001600203300001400219490000800233520251800241653003802759653003402797653001302831653001102844653003602855653002802891653001502919653002702934100002102961700001802982700002303000700002003023700002203043700002303065700002003088700002003108700002403128700002603152700001803178700002503196700001503221700002303236700002203259700002403281700002203305700002903327700002303356700002003379700002403399700002403423700002003447700001803467700001903485700002003504700001903524700002203543700001403565700003003579700002003609700002303629700002303652700002203675700001703697700002603714700002003740700002203760700001203782700002503794700001403819700001403833700002403847700002403871700002103895700002203916700002303938700002403961700002203985700001804007700002204025700002004047700002004067700002304087700002504110700001804135700002104153700001904174700001804193700002604211700002004237700002304257700002504280700002104305700002504326700002204351700002004373700003004393700002704423700001704450700002104467700002004488700002004508700002604528700002104554700001904575700002104594700001704615700001804632700002404650700002404674700002904698700002504727700003204752700002304784700002304807700002304830710014704853856003605000 2022 eng d a1524-453900aCross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.0 aCrossAncestry Investigation of Venous Thromboembolism Genomic Pr c2022 Oct 18 a1225-12420 v1463 aBACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.
METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.
RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.
CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.
10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenomics10aHumans10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aThrombosis10aVenous Thromboembolism1 aThibord, Florian1 aKlarin, Derek1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aLevin, Michael, G1 aChasman, Daniel, I1 aGoode, Ellen, L1 aHveem, Kristian1 aTeder-Laving, Maris1 aMartinez-Perez, Angel1 aAïssi, Dylan1 aDaian-Bacq, Delphine1 aIto, Kaoru1 aNatarajan, Pradeep1 aLutsey, Pamela, L1 aNadkarni, Girish, N1 ade Vries, Paul, S1 aCuellar-Partida, Gabriel1 aWolford, Brooke, N1 aPattee, Jack, W1 aKooperberg, Charles1 aBraekkan, Sigrid, K1 aLi-Gao, Ruifang1 aSaut, Noémie1 aSept, Corriene1 aGermain, Marine1 aJudy, Renae, L1 aWiggins, Kerri, L1 aKo, Darae1 aO'Donnell, Christopher, J1 aTaylor, Kent, D1 aGiulianini, Franco1 ade Andrade, Mariza1 aNøst, Therese, H1 aBoland, Anne1 aEmpana, Jean-Philippe1 aKoyama, Satoshi1 aGilliland, Thomas1 aDo, Ron1 aHuffman, Jennifer, E1 aWang, Xin1 aZhou, Wei1 aSoria, Jose, Manuel1 aSouto, Juan, Carlos1 aPankratz, Nathan1 aHaessler, Jeffery1 aHindberg, Kristian1 aRosendaal, Frits, R1 aTurman, Constance1 aOlaso, Robert1 aKember, Rachel, L1 aBartz, Traci, M1 aLynch, Julie, A1 aHeckbert, Susan, R1 aArmasu, Sebastian, M1 aBrumpton, Ben1 aSmadja, David, M1 aJouven, Xavier1 aKomuro, Issei1 aClapham, Katharine, R1 aLoos, Ruth, J F1 aWiller, Cristen, J1 aSabater-Lleal, Maria1 aPankow, James, S1 aReiner, Alexander, P1 aMorelli, Vania, M1 aRidker, Paul, M1 aVlieg, Astrid, van Hylcka1 aDeleuze, Jean-Francois1 aKraft, Peter1 aRader, Daniel, J1 aLee, Kyung, Min1 aPsaty, Bruce, M1 aSkogholt, Anne, Heidi1 aEmmerich, Joseph1 aSuchon, Pierre1 aRich, Stephen, S1 aVy, Ha, My T1 aTang, Weihong1 aJackson, Rebecca, D1 aHansen, John-Bjarne1 aMorange, Pierre-Emmanuel1 aKabrhel, Christopher1 aTrégouët, David-Alexandre1 aDamrauer, Scott, M1 aJohnson, Andrew, D1 aSmith, Nicholas, L1 aGlobal Biobank Meta-Analysis Initiative; Estonian Biobank Research Team; 23andMe Research Team; Biobank Japan; CHARGE Hemostasis Working Group uhttps://chs-nhlbi.org/node/919404032nas a2200397 4500008004100000022001400041245017800055210006900233260001500302300001200317490000800329520282300337653000903160653001903169653002203188653001103210653001803221653001103239653000903250653005303259653001203312653001703324653001803341100002203359700002203381700001903403700002103422700002003443700002303463700002103486700002303507700001803530700002903548700002103577856003603598 2022 eng d a1524-453900aDiabetes Status Modifies the Association Between Different Measures of Obesity and Heart Failure Risk Among Older Adults: A Pooled Analysis of Community-Based NHLBI Cohorts.0 aDiabetes Status Modifies the Association Between Different Measu c2022 01 25 a268-2780 v1453 aBACKGROUND: Obesity and diabetes are associated with a higher risk of heart failure (HF). The interrelationships between different measures of adiposity-overall obesity, central obesity, fat mass (FM)-and diabetes status for HF risk are not well-established.
METHODS: Participant-level data from the ARIC study (Atherosclerosis Risk in Communities; visit 5) and the CHS (Cardiovascular Health Study; visit 1) cohorts were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center, harmonized, and pooled for the present analysis, excluding individuals with prevalent HF. FM was estimated in all participants using established anthropometric prediction equations additionally validated using the bioelectrical impedance-based FM in the ARIC subgroup. Incident HF events on follow-up were captured across both cohorts using similar adjudication methods. Multivariable-adjusted Fine-Gray models were created to evaluate the associations of body mass index (BMI), waist circumference (WC), and FM with risk of HF in the overall cohort as well as among those with versus without diabetes at baseline. The population attributable risk of overall obesity (BMI≥30 kg/m), abdominal obesity (WC>88 and 102 cm in women and men, respectively), and high FM (above sex-specific median) for incident HF was evaluated among participants with and without diabetes.
RESULTS: The study included 10 387 participants (52.9% ARIC; 25.1% diabetes; median age, 74 years). The correlation between predicted and bioelectrical impedance-based FM was high (=0.90; n=5038). During a 5-year follow-up, 447 participants developed HF (4.3%). Higher levels of each adiposity measure were significantly associated with higher HF risk (hazard ratio [95% CI] per 1 SD higher BMI=1.15 [1.05, 1.27], WC=1.22 [1.10, 1.36]; FM=1.13 [1.02, 1.25]). A significant interaction was noted between diabetes status and measures of BMI ( interaction=0.04) and WC ( interaction=0.004) for the risk of HF. In stratified analysis, higher measures of each adiposity parameter were significantly associated with higher HF risk in individuals with diabetes (hazard ratio [95% CI] per 1 SD higher BMI=1.29 [1.14-1.47]; WC=1.48 [1.29-1.70]; FM=1.25 [1.09-1.43]) but not those without diabetes, including participants with prediabetes and euglycemia. The population attributable risk percentage of overall obesity, abdominal obesity, and high FM for incident HF was higher among participants with diabetes (12.8%, 29.9%, and 13.7%, respectively) versus those without diabetes (≤1% for each).
CONCLUSIONS: Higher BMI, WC, and FM are strongly associated with greater risk of HF among older adults, particularly among those with prevalent diabetes.
10aAged10aCohort Studies10aDiabetes Mellitus10aFemale10aHeart Failure10aHumans10aMale10aNational Heart, Lung, and Blood Institute (U.S.)10aObesity10aRisk Factors10aUnited States1 aPatel, Kershaw, V1 aSegar, Matthew, W1 aLavie, Carl, J1 aKondamudi, Nitin1 aNeeland, Ian, J1 aAlmandoz, Jaime, P1 aMartin, Corby, K1 aCarbone, Salvatore1 aButler, Javed1 aPowell-Wiley, Tiffany, M1 aPandey, Ambarish uhttps://chs-nhlbi.org/node/897603344nas a2200421 4500008004100000022001400041245015100055210006900206260001200275300001400287490000700301520211000308653001202418653002002430653002802450653001402478653001102492653000902503653001702512653001702529100001502546700001702561700001502578700002002593700002902613700002402642700001902666700002202685700002002707700002402727700002202751700002202773700002002795700002402815700002202839700002502861856003602886 2022 eng d a1524-463600aDietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study.0 aDietary Meat Trimethylamine NOxideRelated Metabolites and Incide c2022 09 ae273-e2880 v423 aBACKGROUND: Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways.
METHODS: Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways.
RESULTS: After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95% CI) of 10.6% (1.0-114.5), 7.8% (1.0-32.7), and 9.2% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association.
CONCLUSIONS: In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.
10aAnimals10aAtherosclerosis10aCardiovascular Diseases10aCarnitine10aHumans10aMeat10aMethylamines10aRisk Factors1 aWang, Meng1 aWang, Zeneng1 aLee, Yujin1 aLai, Heidi, T M1 aOtto, Marcia, C de Olive1 aLemaitre, Rozenn, N1 aFretts, Amanda1 aSotoodehnia, Nona1 aBudoff, Matthew1 aDiDonato, Joseph, A1 aMcKnight, Barbara1 aTang, W, H Wilson1 aPsaty, Bruce, M1 aSiscovick, David, S1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/918212282nas a2204021 4500008004100000022001400041245011000055210006900165260001600234300000800250490000600258520108400264653001501348653002201363653002701385653003401412653003101446653001101477653001101488100002301499700002101522700002201543700002001565700002001585700002201605700002301627700001801650700002101668700001901689700001901708700002101727700001801748700001901766700002301785700001701808700001201825700001901837700002401856700002101880700002701901700001601928700001901944700001901963700001301982700002001995700002002015700001902035700001902054700001802073700002002091700002402111700002302135700002102158700002902179700002602208700002902234700001802263700001802281700002102299700002102320700002202341700001802363700001702381700002402398700002002422700001902442700002002461700002102481700002302502700002402525700001702549700002002566700001802586700002002604700002502624700001802649700002602667700002002693700001702713700002702730700002602757700002002783700002502803700002302828700002202851700002802873700003002901700002602931700002502957700001902982700002803001700002003029700002003049700002203069700002003091700002703111700002203138700002603160700003203186700002303218700002303241700002803264700002203292700002103314700002003335700002303355700002403378700002403402700002903426700002203455700001703477700001703494700002103511700001703532700002403549700001803573700002003591700002003611700001403631700002603645700002303671700002703694700001703721700002003738700001903758700002103777700002003798700002403818700002503842700002503867700002003892700002003912700002103932700001203953700002603965700002003991700001704011700002104028700001604049700002004065700001804085700001604103700001904119700002104138700002304159700001804182700001904200700002104219700002004240700002104260700001904281700002204300700002804322700002304350700002204373700001704395700001204412700002004424700001904444700002204463700002604485700002204511700002204533700002304555700002104578700002104599700001804620700001904638700002604657700002304683700002104706700002104727700002204748700002204770700002204792700002104814700002004835700001404855700001704869700002004886700002404906700001904930700002004949700001504969700002004984700003105004700002305035700002605058700002205084700002805106700002105134700002105155700001905176700002005195700001805215700002205233700002905255700002405284700001905308700001905327700002505346700001905371700002105390700001905411700002405430700002005454700002305474700002105497700002105518700001905539700002405558700002005582700002005602700002005622700002105642700002005663700002605683700001805709700002005727700002105747700002305768700002205791700002505813700002205838700002805860700001905888700002005907700002105927700001905948700002105967700002105988700002106009700002706030700002406057700002306081700002606104700002006130700001906150700001806169700002606187700001806213700001806231700002106249700001906270700002306289700001906312700001906331700002106350700002506371700001906396700002706415700001806442700002006460700001706480700002106497700002006518700001806538700002606556700001906582700002406601700001506625700002206640700002106662700002106683700001306704700002106717700001806738700002206756700002306778700001706801700002006818700002306838700002306861700002006884700002706904700002006931700002506951700002506976700002607001700002107027700002107048700002007069700001907089700002207108700002107130700001807151700002507169700001607194700001907210700002407229700001907253700001807272700002807290700002207318700002307340700002207363700001907385700002007404700002107424700001607445700001907461700002807480700001707508700002807525700002007553700002207573700002607595700002407621700002507645700001507670700001807685700001707703700001907720700002007739700002107759700001907780700001507799700001707814700001907831700002507850700002007875700002307895700002007918700002107938700001207959700002007971700002107991700002308012700002108035700002408056700001908080700002208099700001808121710002708139710002708166710003108193856003608224 2022 eng d a2399-364200aDifferential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.0 aDifferential and shared genetic effects on kidney function betwe c2022 Jun 13 a5800 v53 aReduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
10aCreatinine10aDiabetes Mellitus10aDiabetic Nephropathies10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney1 aWinkler, Thomas, W1 aRasheed, Humaira1 aTeumer, Alexander1 aGorski, Mathias1 aRowan, Bryce, X1 aStanzick, Kira, J1 aThomas, Laurent, F1 aTin, Adrienne1 aHoppmann, Anselm1 aChu, Audrey, Y1 aTayo, Bamidele1 aThio, Chris, H L1 aCusi, Daniele1 aChai, Jin-Fang1 aSieber, Karsten, B1 aHorn, Katrin1 aLi, Man1 aScholz, Markus1 aCocca, Massimiliano1 aWuttke, Matthias1 avan der Most, Peter, J1 aYang, Qiong1 aGhasemi, Sahar1 aNutile, Teresa1 aLi, Yong1 aPontali, Giulia1 aGünther, Felix1 aDehghan, Abbas1 aCorrea, Adolfo1 aParsa, Afshin1 aFeresin, Agnese1 ade Vries, Aiko, P J1 aZonderman, Alan, B1 aSmith, Albert, V1 aOldehinkel, Albertine, J1 aDe Grandi, Alessandro1 aRosenkranz, Alexander, R1 aFranke, Andre1 aTeren, Andrej1 aMetspalu, Andres1 aHicks, Andrew, A1 aMorris, Andrew, P1 aTönjes, Anke1 aMorgan, Anna1 aPodgornaia, Anna, I1 aPeters, Annette1 aKörner, Antje1 aMahajan, Anubha1 aCampbell, Archie1 aFreedman, Barry, I1 aSpedicati, Beatrice1 aPonte, Belen1 aSchöttker, Ben1 aBrumpton, Ben1 aBanas, Bernhard1 aKrämer, Bernhard, K1 aJung, Bettina1 aÅsvold, Bjørn, Olav1 aSmith, Blair, H1 aNing, Boting1 aPenninx, Brenda, W J H1 aVanderwerff, Brett, R1 aPsaty, Bruce, M1 aKammerer, Candace, M1 aLangefeld, Carl, D1 aHayward, Caroline1 aSpracklen, Cassandra, N1 aRobinson-Cohen, Cassianne1 aHartman, Catharina, A1 aLindgren, Cecilia, M1 aWang, Chaolong1 aSabanayagam, Charumathi1 aHeng, Chew-Kiat1 aLanzani, Chiara1 aKhor, Chiea-Chuen1 aCheng, Ching-Yu1 aFuchsberger, Christian1 aGieger, Christian1 aShaffer, Christian, M1 aSchulz, Christina-Alexandra1 aWiller, Cristen, J1 aChasman, Daniel, I1 aGudbjartsson, Daniel, F1 aRuggiero, Daniela1 aToniolo, Daniela1 aCzamara, Darina1 aPorteous, David, J1 aWaterworth, Dawn, M1 aMascalzoni, Deborah1 aMook-Kanamori, Dennis, O1 aReilly, Dermot, F1 aDaw, Warwick1 aHofer, Edith1 aBoerwinkle, Eric1 aSalvi, Erika1 aBottinger, Erwin, P1 aTai, E-Shyong1 aCatamo, Eulalia1 aRizzi, Federica1 aGuo, Feng1 aRivadeneira, Fernando1 aGuilianini, Franco1 aSveinbjornsson, Gardar1 aEhret, Georg1 aWaeber, Gérard1 aBiino, Ginevra1 aGirotto, Giorgia1 aPistis, Giorgio1 aNadkarni, Girish, N1 aDelgado, Graciela, E1 aMontgomery, Grant, W1 aSnieder, Harold1 aCampbell, Harry1 aWhite, Harvey, D1 aGao, He1 aStringham, Heather, M1 aSchmidt, Helena1 aLi, Hengtong1 aBrenner, Hermann1 aHolm, Hilma1 aKirsten, Holgen1 aKramer, Holly1 aRudan, Igor1 aNolte, Ilja, M1 aTzoulaki, Ioanna1 aOlafsson, Isleifur1 aMartins, Jade1 aCook, James, P1 aWilson, James, F1 aHalbritter, Jan1 aFelix, Janine, F1 aDivers, Jasmin1 aKooner, Jaspal, S1 aLee, Jeannette, Jen-Mai1 aO'Connell, Jeffrey1 aRotter, Jerome, I1 aLiu, Jianjun1 aXu, Jie1 aThiery, Joachim1 aArnlöv, Johan1 aKuusisto, Johanna1 aJakobsdottir, Johanna1 aTremblay, Johanne1 aChambers, John, C1 aWhitfield, John, B1 aGaziano, John, M1 aMarten, Jonathan1 aCoresh, Josef1 aJonas, Jost, B1 aMychaleckyj, Josyf, C1 aChristensen, Kaare1 aEckardt, Kai-Uwe1 aMohlke, Karen, L1 aEndlich, Karlhans1 aDittrich, Katalin1 aRyan, Kathleen, A1 aRice, Kenneth, M1 aTaylor, Kent, D1 aHo, Kevin1 aNikus, Kjell1 aMatsuda, Koichi1 aStrauch, Konstantin1 aMiliku, Kozeta1 aHveem, Kristian1 aLind, Lars1 aWallentin, Lars1 aYerges-Armstrong, Laura, M1 aRaffield, Laura, M1 aPhillips, Lawrence, S1 aLauner, Lenore, J1 aLyytikäinen, Leo-Pekka1 aLange, Leslie, A1 aCitterio, Lorena1 aKlaric, Lucija1 aIkram, Arfan, M1 aIsing, Marcus1 aKleber, Marcus, E1 aFrancescatto, Margherita1 aConcas, Maria, Pina1 aCiullo, Marina1 aPiratsu, Mario1 aOrho-Melander, Marju1 aLaakso, Markku1 aLoeffler, Markus1 aPerola, Markus1 ade Borst, Martin, H1 aGögele, Martin1 aLa Bianca, Martina1 aLukas, Mary, Ann1 aFeitosa, Mary, F1 aBiggs, Mary, L1 aWojczynski, Mary, K1 aKavousi, Maryam1 aKanai, Masahiro1 aAkiyama, Masato1 aYasuda, Masayuki1 aNauck, Matthias1 aWaldenberger, Melanie1 aChee, Miao-Li1 aChee, Miao-Ling1 aBoehnke, Michael1 aPreuss, Michael, H1 aStumvoll, Michael1 aProvince, Michael, A1 aEvans, Michele, K1 aO'Donoghue, Michelle, L1 aKubo, Michiaki1 aKähönen, Mika1 aKastarinen, Mika1 aNalls, Mike, A1 aKuokkanen, Mikko1 aGhanbari, Mohsen1 aBochud, Murielle1 aJosyula, Navya, Shilpa1 aMartin, Nicholas, G1 aTan, Nicholas, Y Q1 aPalmer, Nicholette, D1 aPirastu, Nicola1 aSchupf, Nicole1 aVerweij, Niek1 aHutri-Kähönen, Nina1 aMononen, Nina1 aBansal, Nisha1 aDevuyst, Olivier1 aMelander, Olle1 aRaitakari, Olli, T1 aPolasek, Ozren1 aManunta, Paolo1 aGasparini, Paolo1 aMishra, Pashupati, P1 aSulem, Patrick1 aMagnusson, Patrik, K E1 aElliott, Paul1 aRidker, Paul, M1 aHamet, Pavel1 aSvensson, Per, O1 aJoshi, Peter, K1 aKovacs, Peter1 aPramstaller, Peter, P1 aRossing, Peter1 aVollenweider, Peter1 aHarst, Pim1 aDorajoo, Rajkumar1 aSim, Ralene, Z H1 aBurkhardt, Ralph1 aTao, Ran1 aNoordam, Raymond1 aMägi, Reedik1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aRueedi, Rico1 avan Dam, Rob, M1 aCarroll, Robert, J1 aGansevoort, Ron, T1 aLoos, Ruth, J F1 aFelicita, Sala, Cinzia1 aSedaghat, Sanaz1 aPadmanabhan, Sandosh1 aFreitag-Wolf, Sandra1 aPendergrass, Sarah, A1 aGraham, Sarah, E1 aGordon, Scott, D1 aHwang, Shih-Jen1 aKerr, Shona, M1 aVaccargiu, Simona1 aPatil, Snehal, B1 aHallan, Stein1 aBakker, Stephan, J L1 aLim, Su-Chi1 aLucae, Susanne1 aVogelezang, Suzanne1 aBergmann, Sven1 aCorre, Tanguy1 aAhluwalia, Tarunveer, S1 aLehtimäki, Terho1 aBoutin, Thibaud, S1 aMeitinger, Thomas1 aWong, Tien-Yin1 aBergler, Tobias1 aRabelink, Ton, J1 aEsko, Tõnu1 aHaller, Toomas1 aThorsteinsdottir, Unnur1 aVölker, Uwe1 aFoo, Valencia, Hui Xian1 aSalomaa, Veikko1 aVitart, Veronique1 aGiedraitis, Vilmantas1 aGudnason, Vilmundur1 aJaddoe, Vincent, W V1 aHuang, Wei1 aZhang, Weihua1 aBin Wei, Wen1 aKiess, Wieland1 aMärz, Winfried1 aKoenig, Wolfgang1 aLieb, Wolfgang1 aGào, Xīn1 aSim, Xueling1 aWang, Ya, Xing1 aFriedlander, Yechiel1 aTham, Yih-Chung1 aKamatani, Yoichiro1 aOkada, Yukinori1 aMilaneschi, Yuri1 aYu, Zhi1 aStark, Klaus, J1 aStefansson, Kari1 aBöger, Carsten, A1 aHung, Adriana, M1 aKronenberg, Florian1 aKöttgen, Anna1 aPattaro, Cristian1 aHeid, Iris, M1 aLifeLines Cohort Study1 aDiscovEHR/MyCode study1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/911203859nas a2201189 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2022 eng d00a{DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases0 aDNA methylation signature of chronic lowgrade inflammation and i c05 a24080 v133 aWe performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.1 aWielscher, M.1 aMandaviya, P., R.1 aKuehnel, B.1 aJoehanes, R.1 aMustafa, R.1 aRobinson, O.1 aZhang, Y.1 aBodinier, B.1 aWalton, E.1 aMishra, P., P.1 aSchlosser, P.1 aWilson, R.1 aTsai, P., C.1 aPalaniswamy, S.1 aMarioni, R., E.1 aFiorito, G.1 aCugliari, G.1 aKarhunen, V.1 aGhanbari, M.1 aPsaty, B., M.1 aLoh, M.1 aBis, J., C.1 aLehne, B.1 aSotoodehnia, N.1 aDeary, I., J.1 aChadeau-Hyam, M.1 aBrody, J., A.1 aCardona, A.1 aSelvin, E.1 aSmith, A., K.1 aMiller, A., H.1 aTorres, M., A.1 aMarouli, E.1 aGào, X.1 avan Meurs, J., B. J.1 aGraf-Schindler, J.1 aRathmann, W.1 aKoenig, W.1 aPeters, A.1 aWeninger, W.1 aFarlik, M.1 aZhang, T.1 aChen, W.1 aXia, Y.1 aTeumer, A.1 aNauck, M.1 aGrabe, H., J.1 aDoerr, M.1 aLehtimäki, T.1 aGuan, W.1 aMilani, L.1 aTanaka, T.1 aFisher, K.1 aWaite, L., L.1 aKasela, S.1 aVineis, P.1 aVerweij, N.1 avan der Harst, P.1 aIacoviello, L.1 aSacerdote, C.1 aPanico, S.1 aKrogh, V.1 aTumino, R.1 aTzala, E.1 aMatullo, G.1 aHurme, M., A.1 aRaitakari, O., T.1 aColicino, E.1 aBaccarelli, A., A.1 aKähönen, M.1 aHerzig, K., H.1 aLi, S.1 aConneely, K., N.1 aKooner, J., S.1 aKöttgen, A.1 aHeijmans, B., T.1 aDeloukas, P.1 aRelton, C.1 aOng, K., K.1 aBell, J., T.1 aBoerwinkle, E.1 aElliott, P.1 aBrenner, H.1 aBeekman, M.1 aLevy, D.1 aWaldenberger, M.1 aChambers, J., C.1 aDehghan, A.1 aJarvelin, M., R. uhttps://chs-nhlbi.org/node/911102519nas a2200217 4500008004100000022001400041245010400055210006900159260001600228520182600244100002402070700002102094700001902115700002302134700002202157700002402179700002402203700001802227700002002245856003602265 2022 eng d a1468-201X00aDysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age.0 aDysregulated carbohydrate and lipid metabolism and risk of atria c2022 Dec 223 aOBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently.
METHODS: We assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed.
RESULTS: The study included 1876 participants (age 77.7±4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (β per SD increment=138 μV·ms, 95% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (p=0.044) and postload glucose (p=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men.
CONCLUSIONS: Among older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF.
1 aPellegrini, Cara, N1 aBůzková, Petra1 aOesterle, Adam1 aHeckbert, Susan, R1 aTracy, Russell, P1 aSiscovick, David, S1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/925903248nas a2200733 4500008004100000022001400041245010400055210006900159260001500228300000900243490000700252520109600259653002701355653001901382653001101401653002101412653001401433100002501447700002401472700002201496700002101518700002101539700002501560700001801585700002001603700002001623700001701643700002901660700002601689700002001715700001901735700002401754700002101778700002301799700001901822700002501841700001901866700002901885700002201914700002301936700002101959700002401980700001802004700002002022700002502042700002402067700001602091700002002107700001902127700002102146700002102167700002202188700002202210700002402232700002202256700002002278700002202298700002302320700002402343700002402367700002202391710006502413856003602478 2022 eng d a2041-172300aEndophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.0 aEndophenotype effect sizes support variant pathogenicity in mono c2022 08 30 a51060 v133 aAccurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.
10aDisease Susceptibility10aEndophenotypes10aHumans10aLong QT Syndrome10aVirulence1 aHalford, Jennifer, L1 aMorrill, Valerie, N1 aChoi, Seung, Hoan1 aJurgens, Sean, J1 aMelloni, Giorgio1 aMarston, Nicholas, A1 aWeng, Lu-Chen1 aNauffal, Victor1 aHall, Amelia, W1 aGunn, Sophia1 aAustin-Tse, Christina, A1 aPirruccello, James, P1 aKhurshid, Shaan1 aRehm, Heidi, L1 aBenjamin, Emelia, J1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aCorrea, Adolfo1 aFornwalt, Brandon, K1 aGupta, Namrata1 aHaggerty, Christopher, M1 aHarris, Stephanie1 aHeckbert, Susan, R1 aHong, Charles, C1 aKooperberg, Charles1 aLin, Henry, J1 aLoos, Ruth, J F1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPost, Wendy1 aPsaty, Bruce, M1 aRedline, Susan1 aRice, Kenneth, M1 aRich, Stephen, S1 aRotter, Jerome, I1 aSchnatz, Peter, F1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aWong, Eugene, K1 aSabatine, Marc, S1 aRuff, Christian, T1 aLunetta, Kathryn, L1 aEllinor, Patrick, T1 aLubitz, Steven, A1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/916704975nas a2200733 4500008004100000022001400041245010200055210006900157260001600226520287800242100001603120700001903136700001603155700001903171700001303190700002203203700002203225700002203247700001903269700001703288700001303305700002203318700002303340700002003363700002103383700002303404700002003427700002603447700002003473700001603493700002403509700002003533700002103553700002803574700002603602700002403628700003303652700002303685700002303708700002403731700001603755700001403771700002103785700001703806700001803823700001803841700002103859700002203880700002003902700002603922700002303948700002203971700002403993700002704017700001704044700001904061700002004080700002004100700002204120700002004142700002304162700002004185856003604205 2022 eng d a1460-215600aEpigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.0 aEpigenetic and integrative crossomics analyses of cerebral white c2022 Aug 093 aCerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.
1 aYang, Yunju1 aKnol, Maria, J1 aWang, Ruiqi1 aMishra, Aniket1 aLiu, Dan1 aLuciano, Michelle1 aTeumer, Alexander1 aArmstrong, Nicola1 aBis, Joshua, C1 aJhun, Min, A1 aLi, Shuo1 aAdams, Hieab, H H1 aAziz, Nasir, Ahmad1 aBastin, Mark, E1 aBourgey, Mathieu1 aBrody, Jennifer, A1 aFrenzel, Stefan1 aGottesman, Rebecca, F1 aHosten, Norbert1 aHou, Lifang1 aKardia, Sharon, L R1 aLohner, Valerie1 aMarquis, Pascale1 aManiega, Susana, Muñoz1 aSatizabal, Claudia, L1 aSorond, Farzaneh, A1 aHernández, Maria, C Valdés1 aDuijn, Cornelia, M1 aVernooij, Meike, W1 aWittfeld, Katharina1 aYang, Qiong1 aZhao, Wei1 aBoerwinkle, Eric1 aLevy, Daniel1 aDeary, Ian, J1 aJiang, Jiyang1 aMather, Karen, A1 aMosley, Thomas, H1 aPsaty, Bruce, M1 aSachdev, Perminder, S1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aDeCarli, Charles, S1 aBreteler, Monique, M B1 aIkram, Arfan1 aGrabe, Hans, J1 aWardlaw, Joanna1 aLongstreth, W T1 aLauner, Lenore, J1 aSeshadri, Sudha1 aDebette, Stephanie1 aFornage, Myriam uhttps://chs-nhlbi.org/node/918402585nas a2200217 4500008004100000022001400041245012500055210006900180260001600249520188200265100001902147700002102166700002102187700001902208700002202227700002402249700001802273700002002291700002002311856003602331 2022 eng d a1758-535X00aFasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and its Subtypes in Older Adults.0 aFasting and PostLoad Glucose and NonEsterified Fatty Acids and R c2022 Nov 143 aBACKGROUND: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and post-prandial levels are under different homeostatic regulation. The relationships of fasting and post-load glucose and NEFA with incident heart failure (HF) remain incompletely defined.
METHODS: Serum glucose and NEFA were measured during fasting and 2 hours post oral glucose tolerance test, performed in Cardiovascular Health Study participants not receiving hypoglycemic medication. Participants with prevalent HF or lacking relevant data were excluded. Outcomes were incident HF (primary), and HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (secondary).
RESULTS: Among 2238 participants (age 78±4) with median follow-up of 9.9 years, there were 737 HF events. After adjustment for demographic and lifestyle factors, both fasting (HR=1.11 per SD [95% CI=1.01-1.23], p=0.040) and post-load (HR=1.14 per SD [1.05-1.24], p=0.002) glucose were significantly associated with incident HF. No association was seen for fasting or post-load NEFA. Upon mutual adjustment, only post-load glucose (HR=1.11 [1.003-1.22], p=0.044), but not fasting glucose (HR=1.06 [0.94-1.20], p=0.340), remained associated with HF. Further adjustment for cardiovascular disease and other risk factors in the causal pathway did not affect the association for post-load glucose, but eliminated that for fasting glucose. Associations for fasting and post-load glucose appeared stronger with higher adiposity, and were observed specifically for HFrEF, but not HFpEF.
CONCLUSIONS: Fasting and post-load glucose, but not NEFA, were associated with incident HF. The association was especially robust for post-load glucose, suggesting that pathways involved in post-prandial dysglycemia could offer new targets for HF prevention late in life.
1 aOesterle, Adam1 aBůzková, Petra1 aPellegrini, Cara1 aHirsch, Calvin1 aTracy, Russell, P1 aSiscovick, David, S1 aDjoussé, Luc1 aMukamal, Ken, J1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/925702314nas a2200181 4500008004100000022001400041245016400055210006900219260001600288520166700304100001901971700002401990700002002014700001702034700002402051700002102075856003602096 2022 eng d a1590-372900aFishing for health: Neighborhood variation in fish intake, fish quality and association with stroke risk among older adults in the Cardiovascular Health Study.0 aFishing for health Neighborhood variation in fish intake fish qu c2022 Mar 123 aBACKGROUND AND AIMS: Fish consumption has been associated with better health outcomes. Dietary patterns may vary substantially by neighborhood of residence. However, it is unclear if the benefits of a healthy diet are equivalent in different communities. This study examines associations of fish consumption with stroke incidence and stroke risk factors, and whether these differ by neighborhood socioeconomic status (NSES).
METHODS AND RESULTS: We studied 4007 participants in the Cardiovascular Health Study who were 65 years or older and recruited between 1989 and 1990 from 4 US communities. Outcomes included fish consumption type (bakes/broiled vs. fried) and frequency, stroke incidence, and stroke risk factors. Multilevel regressions models were used to estimate fish consumption associations with clinical outcomes. Lower NSES was associated with higher consumption of fried fish (aOR = 1.47, 95% CI: 1.10-1.98) and lower consumption of non-fried fish (0.64, 0.47-0.86). Frequent fried fish (11.9 vs. 9.2 person-years for at least once weekly vs. less than once a month, respectively) and less frequent non-fried fish (17.7 vs. 9.6 person-years for less than once a month vs. at least once weekly, respectively) were independently associated with an increased risk of stroke (p-values < 0.05). However, among those with similar levels of healthy fish consumption, residents with low NSES had less benefit on stroke risk reduction, compared with high NSES.
CONCLUSION: Fish consumption type and frequency both impact stroke risk. Benefits of healthy fish consumption differ by neighborhood socioeconomic status.
1 aLiang, Li-Jung1 aCasillas, Alejandra1 aLongstreth, W T1 aPhanVo, Lynn1 aVassar, Stefanie, D1 aBrown, Arleen, F uhttps://chs-nhlbi.org/node/902404304nas a2201045 4500008004100000022001400041245011400055210006900169260001300238300001400251490000700265520128500272653002201557653001101579653003401590653001101624653001401635653002801649100001401677700001401691700001701705700002201722700003201744700002401776700001801800700001501818700001401833700001401847700001601861700002101877700001801898700002401916700001901940700002501959700001901984700002102003700002202024700002302046700001902069700002402088700001902112700002502131700002202156700002202178700002802200700002302228700002302251700002502274700001702299700002102316700002402337700001902361700002102380700002002401700002102421700002202442700002002464700002302484700002002507700002502527700002202552700002402574700001702598700002602615700002602641700002402667700002002691700002302711700001902734700002502753700003402778700002102812700002102833700002302854700002002877700002202897700002702919700002102946700002102967700001902988700001403007700002203021700002303043700002303066700002003089700001603109710006503125710003203190856003603222 2022 eng d a1548-710500aA framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.0 aframework for detecting noncoding rarevariant associations of la c2022 Dec a1599-16110 v193 aLarge-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.
10aGenetic Variation10aGenome10aGenome-Wide Association Study10aHumans10aPhenotype10aWhole Genome Sequencing1 aLi, Zilin1 aLi, Xihao1 aZhou, Hufeng1 aGaynor, Sheila, M1 aSelvaraj, Margaret, Sunitha1 aArapoglou, Theodore1 aQuick, Corbin1 aLiu, Yaowu1 aChen, Han1 aSun, Ryan1 aDey, Rounak1 aArnett, Donna, K1 aAuer, Paul, L1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlackwell, Thomas, W1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aConomos, Matthew, P1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 ade Vries, Paul, S1 aDuggirala, Ravindranath1 aFranceschini, Nora1 aFreedman, Barry, I1 aGöring, Harald, H H1 aGuo, Xiuqing1 aKalyani, Rita, R1 aKooperberg, Charles1 aKral, Brian, G1 aLange, Leslie, A1 aLin, Bridget, M1 aManichaikul, Ani1 aManning, Alisa, K1 aMartin, Lisa, W1 aMathias, Rasika, A1 aMeigs, James, B1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRedline, Susan1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aRice, Kenneth, M1 aRich, Stephen, S1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aTaub, Margaret, A1 aVasan, Ramachandran, S1 aWeeks, Daniel, E1 aWilson, James, G1 aYanek, Lisa, R1 aZhao, Wei1 aRotter, Jerome, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aLin, Xihong1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/925301574nas a2200481 4500008004100000245010200041210006900143260000700212300001400219490000800233520029600241100001500537700001600552700001700568700002000585700001100605700001600616700001600632700001900648700001100667700001800678700001800696700001600714700001900730700002100749700001900770700001500789700001700804700001800821700001800839700001700857700001800874700001500892700001700907700001700924700002100941700001700962700001900979700001900998700002001017700001901037856003601056 2022 eng d00a{Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy0 aGene Set Enrichment Analsyes Identify Pathways Involved in Genet c01 a111–1230 v2333 a{To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses.\ .05.\ .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment1 aSobrin, L.1 aSusarla, G.1 aStanwyck, L.1 aRouhana, J., M.1 aLi, A.1 aPollack, S.1 aIgo, R., P.1 aJensen, R., A.1 aLi, X.1 aNg, M., C. Y.1 aSmith, A., V.1 aKuo, J., Z.1 aTaylor, K., D.1 aFreedman, B., I.1 aBowden, D., W.1 aPenman, A.1 aChen, C., J.1 aCraig, J., E.1 aAdler, S., G.1 aChew, E., Y.1 aCotch, M., F.1 aYaspan, B.1 aMitchell, P.1 aWang, J., J.1 aKlein, B., E. K.1 aWong, T., Y.1 aRotter, J., I.1 aBurdon, K., P.1 aIyengar, S., K.1 aSegrè, A., V. uhttps://chs-nhlbi.org/node/897904841nas a2200925 4500008004100000245010600041210006900147260000800216300001600224490000800240520243500248100001502683700001602698700001802714700001502732700002302747700001902770700001102789700001802800700001302818700001302831700001402844700001702858700001902875700003402894700001602928700001602944700002102960700002202981700002203003700002103025700001503046700001403061700001103075700001903086700001803105700002103123700001903144700001603163700001903179700001603198700001803214700002003232700001503252700001203267700001903279700001603298700002403314700002003338700001603358700001903374700001603393700001403409700001603423700001303439700001503452700002603467700001903493700001803512700001903530700001603549700002003565700001803585700001603603700002203619700001803641700001503659700002203674700001603696700002003712700001803732700001603750700001703766700001703783700002103800700002303821700001903844700001603863856003603879 2022 eng d00a{Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate0 aGenemapping study of extremes of cerebral small vessel disease r cJun a1992–20070 v1453 aCerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.1 aMishra, A.1 aDuplaà, C.1 aVojinovic, D.1 aSuzuki, H.1 aSargurupremraj, M.1 aZilhao, N., R.1 aLi, S.1 aBartz, T., M.1 aJian, X.1 aZhao, W.1 aHofer, E.1 aWittfeld, K.1 aHarris, S., E.1 avan der Auwera-Palitschka, S.1 aLuciano, M.1 aBis, J., C.1 aAdams, H., H. H.1 aSatizabal, C., L.1 aGottesman, R., F.1 aGampawar, P., G.1 aBülow, R.1 aWeiss, S.1 aYu, M.1 aBastin, M., E.1 aLopez, O., L.1 aVernooij, M., W.1 aBeiser, A., S.1 aVölker, U.1 aKacprowski, T.1 aSoumare, A.1 aSmith, J., A.1 aKnopman, D., S.1 aMorris, Z.1 aZhu, Y.1 aRotter, J., I.1 aDufouil, C.1 aHernández, Valdés1 aManiega, Muñoz1 aLathrop, M.1 aBoerwinkle, E.1 aSchmidt, R.1 aIhara, M.1 aMazoyer, B.1 aYang, Q.1 aJoutel, A.1 aTournier-Lasserve, E.1 aLauner, L., J.1 aDeary, I., J.1 aMosley, T., H.1 aAmouyel, P.1 aDeCarli, C., S.1 aPsaty, B., M.1 aTzourio, C.1 aKardia, S., L. R.1 aGrabe, H., J.1 aTeumer, A.1 avan Duijn, C., M.1 aSchmidt, H.1 aWardlaw, J., M.1 aIkram, M., A.1 aFornage, M.1 aGudnason, V.1 aSeshadri, S.1 aMatthews, P., M.1 aLongstreth, W., T.1 aCouffinhal, T.1 aDebette, S. uhttps://chs-nhlbi.org/node/910606249nas a2202113 4500008004100000245011900041210006900160260000700229300000900236490000700245520091100252100001801163700001801181700001501199700001401214700001301228700001401241700001801255700001501273700001601288700002201304700001701326700002501343700001601368700001901384700002501403700001401428700002301442700001801465700001701483700001801500700001801518700001401536700002001550700001201570700001201582700001601594700002501610700001701635700001301652700001701665700001601682700001701698700002401715700001901739700002501758700001901783700001201802700001301814700002001827700001601847700001501863700001801878700001601896700001901912700001701931700001501948700001401963700001901977700001501996700001802011700001602029700001302045700001702058700002002075700001802095700001602113700002002129700001602149700001402165700001402179700001202193700001502205700002102220700001802241700002002259700002402279700001802303700002002321700001702341700001602358700001702374700001702391700002102408700001602429700001302445700001802458700001202476700002302488700001602511700001802527700001902545700001902564700002102583700001602604700002202620700002102642700001402663700001602677700001602693700001402709700001302723700001902736700002002755700001602775700002102791700002402812700001902836700002202855700001902877700002302896700001702919700001402936700002102950700001702971700001802988700001303006700002203019700001603041700001903057700002003076700001403096700001603110700001603126700001903142700001503161700001603176700002103192700001603213700001603229700002103245700001703266700002003283700001903303700001803322700001403340700001503354700001403369700001403383700001903397700001603416700001503432700001603447700001703463700002103480700001903501700001503520700001803535700002003553700001903573700001903592700002303611700001203634700002003646700001903666700002603685700001903711700002203730700001903752700001403771700002003785700001603805700001503821700001803836700001903854700001703873700002203890700002203912700001603934700001903950700001903969700001603988700002104004700002004025700001504045700002004060700001904080856003604099 2022 eng d00a{Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways0 aGenetic analyses of the electrocardiographic QT interval and its c09 a51440 v133 a250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.1 aYoung, W., J.1 aLahrouchi, N.1 aIsaacs, A.1 aDuong, T.1 aFoco, L.1 aAhmed, F.1 aBrody, J., A.1 aSalman, R.1 aNoordam, R.1 aBenjamins, J., W.1 aHaessler, J.1 aLyytikäinen, L., P.1 aRepetto, L.1 aConcas, M., P.1 avan den Berg, M., E.1 aWeiss, S.1 aBaldassari, A., R.1 aBartz, T., M.1 aCook, J., P.1 aEvans, D., S.1 aFreudling, R.1 aHines, O.1 aIsaksen, J., L.1 aLin, H.1 aMei, H.1 aMoscati, A.1 aMüller-Nurasyid, M.1 aNursyifa, C.1 aQian, Y.1 aRichmond, A.1 aRoselli, C.1 aRyan, K., A.1 aTarazona-Santos, E.1 aThériault, S.1 avan Duijvenboden, S.1 aWarren, H., R.1 aYao, J.1 aRaza, D.1 aAeschbacher, S.1 aAhlberg, G.1 aAlonso, A.1 aAndreasen, L.1 aBis, J., C.1 aBoerwinkle, E.1 aCampbell, A.1 aCatamo, E.1 aCocca, M.1 aCutler, M., J.1 aDarbar, D.1 aDe Grandi, A.1 aDe Luca, A.1 aDing, J.1 aEllervik, C.1 aEllinor, P., T.1 aFelix, S., B.1 aFroguel, P.1 aFuchsberger, C.1 aGögele, M.1 aGraff, C.1 aGraff, M.1 aGuo, X.1 aHansen, T.1 aHeckbert, S., R.1 aHuang, P., L.1 aHuikuri, H., V.1 aHutri-Kähönen, N.1 aIkram, M., A.1 aJackson, R., D.1 aJunttila, J.1 aKavousi, M.1 aKors, J., A.1 aLeal, T., P.1 aLemaitre, R., N.1 aLin, H., J.1 aLind, L.1 aLinneberg, A.1 aLiu, S.1 aMacfarlane, P., W.1 aMangino, M.1 aMeitinger, T.1 aMezzavilla, M.1 aMishra, P., P.1 aMitchell, R., N.1 aMononen, N.1 aMontasser, M., E.1 aMorrison, A., C.1 aNauck, M.1 aNauffal, V.1 aNavarro, P.1 aNikus, K.1 aPare, G.1 aPatton, K., K.1 aPelliccione, G.1 aPittman, A.1 aPorteous, D., J.1 aPramstaller, P., P.1 aPreuss, M., H.1 aRaitakari, O., T.1 aReiner, A., P.1 aRibeiro, A., L. P.1 aRice, K., M.1 aRisch, L.1 aSchlessinger, D.1 aSchotten, U.1 aSchurmann, C.1 aShen, X.1 aShoemaker, M., B.1 aSinagra, G.1 aSinner, M., F.1 aSoliman, E., Z.1 aStoll, M.1 aStrauch, K.1 aTarasov, K.1 aTaylor, K., D.1 aTinker, A.1 aTrompet, S.1 aUitterlinden, A.1 aVölker, U.1 aVölzke, H.1 aWaldenberger, M.1 aWeng, L., C.1 aWhitsel, E., A.1 aWilson, J., G.1 aAvery, C., L.1 aConen, D.1 aCorrea, A.1 aCucca, F.1 aDörr, M.1 aGharib, S., A.1 aGirotto, G.1 aGrarup, N.1 aHayward, C.1 aJamshidi, Y.1 aJarvelin, M., R.1 aJukema, J., W.1 aKääb, S.1 aKähönen, M.1 aKanters, J., K.1 aKooperberg, C.1 aLehtimäki, T.1 aLima-Costa, M., F.1 aLiu, Y.1 aLoos, R., J. F.1 aLubitz, S., A.1 aMook-Kanamori, D., O.1 aMorris, A., P.1 aO'Connell, J., R.1 aOlesen, M., S.1 aOrini, M.1 aPadmanabhan, S.1 aPattaro, C.1 aPeters, A.1 aPsaty, B., M.1 aRotter, J., I.1 aStricker, B.1 avan der Harst, P.1 avan Duijn, C., M.1 aVerweij, N.1 aWilson, J., F.1 aArking, D., E.1 aRamirez, J.1 aLambiase, P., D.1 aSotoodehnia, N.1 aMifsud, B.1 aNewton-Cheh, C.1 aMunroe, P., B. uhttps://chs-nhlbi.org/node/918602045nas a2200661 4500008004100000245015300041210006900194260000800263300001600271490000700287520025400294100002700548700001500575700001800590700001800608700001600626700001400642700001900656700001800675700001700693700001900710700001900729700001300748700001100761700001200772700001900784700001600803700001900819700001200838700002100850700001600871700001700887700001500904700002400919700002500943700002100968700001700989700001801006700001801024700001601042700002501058700002001083700002201103700001701125700002101142700001201163700001901175700001801194700001901212700001301231700001501244700001601259700001601275700001801291700002201309700001601331856003601347 2022 eng d00a{Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study0 aGenetic and clinical determinants of abdominal aortic diameter g cOct a3566–35790 v313 a0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.1 aPortilla-Fernandez, E.1 aKlarin, D.1 aHwang, S., J.1 aBiggs, M., L.1 aBis, J., C.1 aWeiss, S.1 aRospleszcz, S.1 aNatarajan, P.1 aHoffmann, U.1 aRogers, I., S.1 aTruong, Q., A.1 alker, U.1 arr, M.1 alow, R.1 aCriqui, M., H.1 aAllison, M.1 aGanesh, S., K.1 aYao, J.1 aWaldenberger, M.1 aBamberg, F.1 aRice, K., M.1 aEssers, J.1 aKapteijn, D., M. C.1 avan der Laan, S., W.1 ade Knegt, R., J.1 aGhanbari, M.1 aFelix, J., F.1 aIkram, M., A.1 aKavousi, M.1 aUitterlinden, A., G.1 aRoks, A., J. M.1 aDanser, A., H. J.1 aTsao, P., S.1 aDamrauer, S., M.1 aGuo, X.1 aRotter, J., I.1 aPsaty, B., M.1 aKathiresan, S.1 alzke, H.1 aPeters, A.1 aJohnson, C.1 aStrauch, K.1 aMeitinger, T.1 aO'Donnell, C., J.1 aDehghan, A. uhttps://chs-nhlbi.org/node/931208267nas a2202233 4500008004100000022001400041245015400055210006900209260001600278520193900294100002002233700002102253700002202274700002302296700002102319700002702340700002302367700002002390700002002410700001902430700002202449700002102471700001302492700001802505700002802523700001902551700002602570700002502596700002002621700001802641700001902659700001902678700002102697700002102718700002402739700002102763700001802784700002302802700001802825700001902843700001802862700002002880700002002900700001902920700001902939700002402958700001902982700001803001700001803019700002403037700002303061700002103084700002203105700002203127700002103149700001803170700002503188700002703213700002103240700002303261700002103284700001903305700002603324700002203350700002803372700001803400700001703418700001903435700001403454700001703468700002103485700001603506700002103522700001703543700002603560700002003586700002003606700002003626700002703646700001803673700002003691700002303711700002203734700002103756700001803777700002503795700002103820700002203841700001903863700002103882700002203903700001203925700001903937700001503956700002503971700002003996700002104016700002804037700002004065700002904085700002304114700002204137700001904159700002104178700002504199700001804224700002204242700002604264700002404290700001804314700002404332700001904356700002004375700001704395700001704412700001904429700001904448700002804467700002304495700002304518700002504541700001804566700002604584700002704610700001904637700002304656700002004679700002304699700002304722700002404745700002104769700002004790700002904810700001904839700002204858700002204880700002204902700002804924700001704952700002004969700002204989700001905011700002005030700003205050700002005082700002605102700002305128700001705151700001605168700002005184700002205204700002805226700002005254700002405274700002605298700001905324700002005343700002005363700002105383700002205404700002205426700001505448700002705463700001805490700001705508700001705525700002605542700002005568700002005588700001505608700002405623700002105647700002305668700001905691700001905710700001605729700003105745700002405776700002305800700002005823700002105843700002305864700002205887700001905909700002405928700001805952710002705970856003605997 2022 eng d a1523-175500aGenetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.0 aGenetic loci and prioritization of genes for kidney function dec c2022 Jun 163 aEstimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
1 aGorski, Mathias1 aRasheed, Humaira1 aTeumer, Alexander1 aThomas, Laurent, F1 aGraham, Sarah, E1 aSveinbjornsson, Gardar1 aWinkler, Thomas, W1 aGünther, Felix1 aStark, Klaus, J1 aChai, Jin-Fang1 aTayo, Bamidele, O1 aWuttke, Matthias1 aLi, Yong1 aTin, Adrienne1 aAhluwalia, Tarunveer, S1 aArnlöv, Johan1 aÅsvold, Bjørn, Olav1 aBakker, Stephan, J L1 aBanas, Bernhard1 aBansal, Nisha1 aBiggs, Mary, L1 aBiino, Ginevra1 aBöhnke, Michael1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBrenner, Hermann1 aBrumpton, Ben1 aCarroll, Robert, J1 aChaker, Layal1 aChalmers, John1 aChee, Miao-Li1 aChee, Miao-Ling1 aCheng, Ching-Yu1 aChu, Audrey, Y1 aCiullo, Marina1 aCocca, Massimiliano1 aCook, James, P1 aCoresh, Josef1 aCusi, Daniele1 ade Borst, Martin, H1 aDegenhardt, Frauke1 aEckardt, Kai-Uwe1 aEndlich, Karlhans1 aEvans, Michele, K1 aFeitosa, Mary, F1 aFranke, Andre1 aFreitag-Wolf, Sandra1 aFuchsberger, Christian1 aGampawar, Piyush1 aGansevoort, Ron, T1 aGhanbari, Mohsen1 aGhasemi, Sahar1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGudbjartsson, Daniel, F1 aHallan, Stein1 aHamet, Pavel1 aHishida, Asahi1 aHo, Kevin1 aHofer, Edith1 aHolleczek, Bernd1 aHolm, Hilma1 aHoppmann, Anselm1 aHorn, Katrin1 aHutri-Kähönen, Nina1 aHveem, Kristian1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKarabegović, Irma1 aKhor, Chiea-Chuen1 aKoenig, Wolfgang1 aKramer, Holly1 aKrämer, Bernhard, K1 aKuhnel, Brigitte1 aKuusisto, Johanna1 aLaakso, Markku1 aLange, Leslie, A1 aLehtimäki, Terho1 aLi, Man1 aLieb, Wolfgang1 aLind, Lars1 aLindgren, Cecilia, M1 aLoos, Ruth, J F1 aLukas, Mary, Ann1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aMatias-Garcia, Pamela, R1 aMeisinger, Christa1 aMeitinger, Thomas1 aMelander, Olle1 aMilaneschi, Yuri1 aMishra, Pashupati, P1 aMononen, Nina1 aMorris, Andrew, P1 aMychaleckyj, Josyf, C1 aNadkarni, Girish, N1 aNaito, Mariko1 aNakatochi, Masahiro1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNutile, Teresa1 aO'Donoghue, Michelle, L1 aO'Connell, Jeffrey1 aOlafsson, Isleifur1 aOrho-Melander, Marju1 aParsa, Afshin1 aPendergrass, Sarah, A1 aPenninx, Brenda, W J H1 aPirastu, Mario1 aPreuss, Michael, H1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRizzi, Federica1 aRosenkranz, Alexander, R1 aRossing, Peter1 aRotter, Jerome, I1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSabanayagam, Charumathi1 aSalvi, Erika1 aSchmidt, Helena1 aSchmidt, Reinhold1 aScholz, Markus1 aSchöttker, Ben1 aSchulz, Christina-Alexandra1 aSedaghat, Sanaz1 aShaffer, Christian, M1 aSieber, Karsten, B1 aSim, Xueling1 aSims, Mario1 aSnieder, Harold1 aStanzick, Kira, J1 aThorsteinsdottir, Unnur1 aStocker, Hannah1 aStrauch, Konstantin1 aStringham, Heather, M1 aSulem, Patrick1 aSzymczak, Silke1 aTaylor, Kent, D1 aThio, Chris, H L1 aTremblay, Johanne1 aVaccargiu, Simona1 aHarst, Pim1 avan der Most, Peter, J1 aVerweij, Niek1 aVölker, Uwe1 aWakai, Kenji1 aWaldenberger, Melanie1 aWallentin, Lars1 aWallner, Stefan1 aWang, Judy1 aWaterworth, Dawn, M1 aWhite, Harvey, D1 aWiller, Cristen, J1 aWong, Tien-Yin1 aWoodward, Mark1 aYang, Qiong1 aYerges-Armstrong, Laura, M1 aZimmermann, Martina1 aZonderman, Alan, B1 aBergler, Tobias1 aStefansson, Kari1 aBöger, Carsten, A1 aPattaro, Cristian1 aKöttgen, Anna1 aKronenberg, Florian1 aHeid, Iris, M1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/909301045nas a2200325 4500008004100000022001400041245014300055210006900198260001600267300001200283490000800295653002100303653002100324653001400345653003400359653004100393653001400434653001800448100002400466700002500490700001600515700002300531700002000554700002100574700002000595700002400615700002200639700002200661856003600683 2022 eng d a1524-457100aGenome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus.0 aGenome Wide Association Studies of VariantbyThiazide Interaction c2022 Jul 22 a277-2790 v13110aCholesterol, HDL10aCholesterol, LDL10aDiuretics10aGenome-Wide Association Study10aSodium Chloride Symporter Inhibitors10aThiazides10aTriglycerides1 aDownie, Carolina, G1 aHighland, Heather, M1 aLee, Moa, P1 aRaffield, Laura, M1 aPreuss, Michael1 aWhitsel, Eric, A1 aPsaty, Bruce, M1 aSitlani, Colleen, M1 aGraff, Mariaelisa1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/945202146nas a2200373 4500008004100000022001400041245010500055210006900160260001600229300001100245490000700256520103500263100002701298700001901325700001901344700002201363700002601385700002401411700002301435700002001458700001801478700002301496700001801519700002401537700001901561700001801580700002101598700002601619700002301645700002201668700002901690700001701719856003601736 2022 eng d a2589-004200aGenome-wide analyses identify as a susceptibility locus for premature atrial contraction frequency.0 aGenomewide analyses identify as a susceptibility locus for prema c2022 Oct 21 a1052100 v253 aPremature atrial contractions (PACs) are frequently observed on electrocardiograms and are associated with increased risks of atrial fibrillation (AF), stroke, and mortality. In this study, we aimed to identify genetic susceptibility loci for PAC frequency. We performed a genome-wide association study meta-analysis with PAC frequency obtained from ambulatory cardiac monitoring in 4,831 individuals of European ancestry. We identified a genome-wide significant locus at the gene. The lead variant, rs7373862, located in an intron of , was associated with an increase of 0.12 [95% CI 0.08-0.16] standard deviations of the normalized PAC frequency per risk allele. Among genetic variants previously associated with AF, there was a significant enrichment in concordance of effect for PAC frequency (n = 73/106, p = 5.1 × 10). However, several AF risk loci, including , were not associated with PAC frequency. These findings suggest the existence of both shared and distinct genetic mechanisms for PAC frequency and AF.
1 aThériault, Sébastien1 aImboden, Medea1 aBiggs, Mary, L1 aAustin, Thomas, R1 aAeschbacher, Stefanie1 aSchaffner, Emmanuel1 aBrody, Jennifer, A1 aBartz, Traci, M1 aRisch, Martin1 aGrossmann, Kirsten1 aLin, Henry, J1 aSoliman, Elsayed, Z1 aPost, Wendy, S1 aRisch, Lorenz1 aKrieger, Jose, E1 aPereira, Alexandre, C1 aHeckbert, Susan, R1 aSotoodehnia, Nona1 aProbst-Hensch, Nicole, M1 aConen, David uhttps://chs-nhlbi.org/node/931302028nas a2200745 4500008004100000245016200041210006900203260000800272300001400280490000800294520000700302100002300309700001700332700002300349700001200372700001300384700001800397700001800415700001800433700001200451700001600463700001900479700001800498700001900516700001300535700002100548700001100569700001600580700001200596700001600608700002000624700002300644700001800667700002100685700001300706700002000719700001700739700002500756700001400781700002500795700002200820700002100842700001400863700001700877700002100894700002100915700002000936700001900956700002000975700001800995700002101013700002001034700002001054700001501074700001101089700001701100700001801117700001801135700001901153700001901172700001901191700001701210700001901227856003601246 2022 eng d00a{Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation0 aGenomewide analysis of mitochondrial DNA copy number reveals loc cJan a127–1460 v1413 a).1 aLongchamps, R., J.1 aYang, S., Y.1 aCastellani, C., A.1 aShi, W.1 aLane, J.1 aGrove, M., L.1 aBartz, T., M.1 aSarnowski, C.1 aLiu, C.1 aBurrows, K.1 aGuyatt, A., L.1 aGaunt, T., R.1 aKacprowski, T.1 aYang, J.1 aDe Jager, P., L.1 aYu, L.1 aBergman, A.1 aXia, R.1 aFornage, M.1 aFeitosa, M., F.1 aWojczynski, M., K.1 aKraja, A., T.1 aProvince, M., A.1 aAmin, N.1 aRivadeneira, F.1 aTiemeier, H.1 aUitterlinden, A., G.1 aBroer, L.1 avan Meurs, J., B. J.1 avan Duijn, C., M.1 aRaffield, L., M.1 aLange, L.1 aRich, S., S.1 aLemaitre, R., N.1 aGoodarzi, M., O.1 aSitlani, C., M.1 aMak, A., C. Y.1 aBennett, D., A.1 aRodriguez, S.1 aMurabito, J., M.1 aLunetta, K., L.1 aSotoodehnia, N.1 aAtzmon, G.1 aYe, K.1 aBarzilai, N.1 aBrody, J., A.1 aPsaty, B., M.1 aTaylor, K., D.1 aRotter, J., I.1 aBoerwinkle, E.1 aPankratz, N.1 aArking, D., E. uhttps://chs-nhlbi.org/node/899905288nas a2201585 4500008004100000022001400041245009100055210006900146260001600215520091300231100001601144700002101160700001601181700002001197700001901217700001601236700002501252700001801277700001901295700001901314700002101333700001801354700002101372700002001393700001601413700001801429700001801447700001701465700002401482700001901506700002101525700002801546700002201574700001401596700002001610700002101630700001901651700002401670700002401694700002301718700002701741700002001768700001901788700001901807700002101826700002101847700001901868700002201887700001801909700001801927700001301945700001601958700001301974700001701987700001702004700002502021700002102046700001902067700002002086700001902106700001802125700002402143700002702167700001902194700001902213700002302232700002502255700002102280700002402301700001902325700002602344700002402370700002602394700002102420700002202441700002102463700002302484700002002507700001702527700002202544700002602566700002002592700002302612700002502635700002102660700001702681700002202698700002402720700002002744700001302764700002002777700001202797700001602809700001402825700001602839700001602855700002202871700001902893700002302912700002202935700002202957700002002979700001902999700002403018700001603042700002103058700002303079700001903102700002003121700002103141700002003162700002903182700002603211700002203237700002003259700002403279700002003303700001903323700002003342700002003362700002003382700001903402700002103421700002403442700002603466700002303492700002303515700002203538700002203560700002303582700001803605700002003623700002303643856003603666 2022 eng d a1476-557800aGenome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.0 aGenomewide metaanalyses reveal novel loci for verbal shortterm m c2022 Aug 163 aUnderstanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
1 aLahti, Jari1 aTuominen, Samuli1 aYang, Qiong1 aPergola, Giulio1 aAhmad, Shahzad1 aAmin, Najaf1 aArmstrong, Nicola, J1 aBeiser, Alexa1 aBey, Katharina1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBressler, Jan1 aCampbell, Archie1 aCampbell, Harry1 aChen, Qiang1 aCorley, Janie1 aCox, Simon, R1 aDavies, Gail1 aDe Jager, Philip, L1 aDerks, Eske, M1 aFaul, Jessica, D1 aFitzpatrick, Annette, L1 aFohner, Alison, E1 aFord, Ian1 aFornage, Myriam1 aGerring, Zachary1 aGrabe, Hans, J1 aGrodstein, Francine1 aGudnason, Vilmundur1 aSimonsick, Eleanor1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKajantie, Eero1 aKaprio, Jaakko1 aKarell, Pauliina1 aKleineidam, Luca1 aKnol, Maria, J1 aKochan, Nicole, A1 aKwok, John, B1 aLeber, Markus1 aLam, Max1 aLee, Teresa1 aLi, Shuo1 aLoukola, Anu1 aLuck, Tobias1 aMarioni, Riccardo, E1 aMather, Karen, A1 aMedland, Sarah1 aMirza, Saira, S1 aNalls, Mike, A1 aNho, Kwangsik1 aO'Donnell, Adrienne1 aOldmeadow, Christopher1 aPainter, Jodie1 aPattie, Alison1 aReppermund, Simone1 aRisacher, Shannon, L1 aRose, Richard, J1 aSadashivaiah, Vijay1 aScholz, Markus1 aSatizabal, Claudia, L1 aSchofield, Peter, W1 aSchraut, Katharina, E1 aScott, Rodney, J1 aSimino, Jeannette1 aSmith, Albert, V1 aSmith, Jennifer, A1 aStott, David, J1 aSurakka, Ida1 aTeumer, Alexander1 aThalamuthu, Anbupalam1 aTrompet, Stella1 aTurner, Stephen, T1 avan der Lee, Sven, J1 aVillringer, Arno1 aVölker, Uwe1 aWilson, Robert, S1 aWittfeld, Katharina1 aVuoksimaa, Eero1 aXia, Rui1 aYaffe, Kristine1 aYu, Lei1 aZare, Habil1 aZhao, Wei1 aAmes, David1 aAttia, John1 aBennett, David, A1 aBrodaty, Henry1 aChasman, Daniel, I1 aGoldman, Aaron, L1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, L R1 aLencz, Todd1 aLoeffler, Markus1 aMattay, Venkata, S1 aPalotie, Aarno1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aRidker, Paul, M1 aRiedel-Heller, Steffi, G1 aSachdev, Perminder, S1 aSaykin, Andrew, J1 aScherer, Martin1 aSchofield, Peter, R1 aSidney, Stephen1 aStarr, John, M1 aTrollor, Julian1 aUlrich, William1 aWagner, Michael1 aWeir, David, R1 aWilson, James, F1 aWright, Margaret, J1 aWeinberger, Daniel, R1 aDebette, Stephanie1 aEriksson, Johan, G1 aMosley, Thomas, H1 aLauner, Lenore, J1 aDuijn, Cornelia, M1 aDeary, Ian, J1 aSeshadri, Sudha1 aRäikkönen, Katri uhttps://chs-nhlbi.org/node/916903138nas a2200625 4500008004100000245012100041210006900162260000700231490000600238520150100244100001101745700001401756700001801770700001601788700001801804700001701822700002201839700001601861700001801877700001901895700001301914700001701927700001601944700001501960700002101975700001801996700001902014700001802033700001802051700001602069700002402085700002002109700001902129700001502148700001702163700001502180700001302195700001502208700001402223700002002237700001502257700001902272700001802291700001502309700001902324700001302343700001902356700002402375700001102399700001602410700001602426700001702442700001702459856003602476 2022 eng d00a{Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases0 aGenomewide studies reveal factors associated with circulating ur c050 v73 aUromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.1 aLi, Y.1 aCheng, Y.1 aConsolato, F.1 aSchiano, G.1 aChong, M., R.1 aPietzner, M.1 aNguyen, N., Q. H.1 aScherer, N.1 aBiggs, M., L.1 aKleber, M., E.1 aHaug, S.1 aGöçmen, B.1 aPigeyre, M.1 aSekula, P.1 aSteinbrenner, I.1 aSchlosser, P.1 aJoseph, C., B.1 aBrody, J., A.1 aGrams, M., E.1 aHayward, C.1 aSchultheiss, U., T.1 aKrämer, B., K.1 aKronenberg, F.1 aPeters, A.1 aSeissler, J.1 aSteubl, D.1 aThen, C.1 aWuttke, M.1 aMärz, W.1 aEckardt, K., U.1 aGieger, C.1 aBoerwinkle, E.1 aPsaty, B., M.1 aCoresh, J.1 aOefner, P., J.1 aPare, G.1 aLangenberg, C.1 aScherberich, J., E.1 aYu, B.1 aAkilesh, S.1 aDevuyst, O.1 aRampoldi, L.1 aKöttgen, A. uhttps://chs-nhlbi.org/node/910302773nas a2200349 4500008004100000022001400041245011200055210006900167260001600236300000800252490000700260520176200267653000902029653002802038653001102066653001202077653001102089653002302100653000902123653003402132653003102166100002102197700001902218700002002237700002002257700001702277700002402294700002402318700002102342700002402363856003602387 2022 eng d a1475-284000aGlucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study.0 aGlucose dysregulation and subclinical cardiac dysfunction in old c2022 Jun 20 a1120 v213 aOBJECTIVE: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population.
METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics.
RESULTS: Mean age for the 2433 included participants was 72.0 years, 33.6% were male, and 3.7% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95% confidence interval = 0.03-0.33).
CONCLUSION: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.
10aAged10aCross-Sectional Studies10aFemale10aGlucose10aHumans10aInsulin Resistance10aMale10aVentricular Dysfunction, Left10aVentricular Function, Left1 aGarg, Parveen, K1 aBiggs, Mary, L1 aKizer, Jorge, R1 aShah, Sanjiv, J1 aPsaty, Bruce1 aCarnethon, Mercedes1 aGottdiener, John, S1 aSiscovick, David1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/909200763nas a2200217 4500008004100000022001400041245014700055210006900202260001600271100002000287700002400307700002300331700002600354700001900380700002300399700002000422700002200442700002000464700002500484856003600509 2022 eng d a1556-387100aImmune cell subpopulations as risk factors for atrial fibrillation: The Cardiovascular Health Study and Multi-Ethnic Study of Atherosclerosis.0 aImmune cell subpopulations as risk factors for atrial fibrillati c2022 Oct 181 aFloyd, James, S1 aSitlani, Colleen, M1 aDoyle, Margaret, F1 aFeinstein, Matthew, J1 aOlson, Nels, C1 aHeckbert, Susan, R1 aHuber, Sally, A1 aTracy, Russell, P1 aPsaty, Bruce, M1 aDelaney, Joseph, A C uhttps://chs-nhlbi.org/node/924703702nas a2200253 4500008004100000022001400041245014100055210006900196260001600265300001100281490000600292520292600298100001803224700002103242700001903263700001903282700001603301700001803317700001603335700002103351700001703372700002303389856003603412 2022 eng d a2561-101100aThe Impact of Time Horizon on Classification Accuracy: Application of Machine Learning to Prediction of Incident Coronary Heart Disease.0 aImpact of Time Horizon on Classification Accuracy Application of c2022 Nov 02 ae380400 v63 aBACKGROUND: Many machine learning approaches are limited to classification of outcomes rather than longitudinal prediction. One strategy to use machine learning in clinical risk prediction is to classify outcomes over a given time horizon. However, it is not well-known how to identify the optimal time horizon for risk prediction.
OBJECTIVE: In this study, we aim to identify an optimal time horizon for classification of incident myocardial infarction (MI) using machine learning approaches looped over outcomes with increasing time horizons. Additionally, we sought to compare the performance of these models with the traditional Framingham Heart Study (FHS) coronary heart disease gender-specific Cox proportional hazards regression model.
METHODS: We analyzed data from a single clinic visit of 5201 participants of a cardiovascular health study. We examined 61 variables collected from this baseline exam, including demographic and biologic data, medical history, medications, serum biomarkers, electrocardiographic, and echocardiographic data. We compared several machine learning methods (eg, random forest, L1 regression, gradient boosted decision tree, support vector machine, and k-nearest neighbor) trained to predict incident MI that occurred within time horizons ranging from 500-10,000 days of follow-up. Models were compared on a 20% held-out testing set using area under the receiver operating characteristic curve (AUROC). Variable importance was performed for random forest and L1 regression models across time points. We compared results with the FHS coronary heart disease gender-specific Cox proportional hazards regression functions.
RESULTS: There were 4190 participants included in the analysis, with 2522 (60.2%) female participants and an average age of 72.6 years. Over 10,000 days of follow-up, there were 813 incident MI events. The machine learning models were most predictive over moderate follow-up time horizons (ie, 1500-2500 days). Overall, the L1 (Lasso) logistic regression demonstrated the strongest classification accuracy across all time horizons. This model was most predictive at 1500 days follow-up, with an AUROC of 0.71. The most influential variables differed by follow-up time and model, with gender being the most important feature for the L1 regression and weight for the random forest model across all time frames. Compared with the Framingham Cox function, the L1 and random forest models performed better across all time frames beyond 1500 days.
CONCLUSIONS: In a population free of coronary heart disease, machine learning techniques can be used to predict incident MI at varying time horizons with reasonable accuracy, with the strongest prediction accuracy in moderate follow-up periods. Validation across additional populations is needed to confirm the validity of this approach in risk prediction.
1 aSimon, Steven1 aMandair, Divneet1 aAlbakri, Abdel1 aFohner, Alison1 aSimon, Noah1 aLange, Leslie1 aBiggs, Mary1 aMukamal, Kenneth1 aPsaty, Bruce1 aRosenberg, Michael uhttps://chs-nhlbi.org/node/926017529nas a2206589 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2022 eng d00a{Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis0 aImplicating genes pleiotropy and sexual dimorphism at blood lipi cDec a2680 v233 aGenetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.\ 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.\ Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.1 aKanoni, S.1 aGraham, S., E.1 aWang, Y.1 aSurakka, I.1 aRamdas, S.1 aZhu, X.1 aClarke, S., L.1 aBhatti, K., F.1 aVedantam, S.1 aWinkler, T., W.1 aLocke, A., E.1 aMarouli, E.1 aZajac, G., J. M.1 aWu, K., H.1 aNtalla, I.1 aHui, Q.1 aKlarin, D.1 aHilliard, A., T.1 aWang, Z.1 aXue, C.1 aThorleifsson, G.1 aHelgadottir, A.1 aGudbjartsson, D., F.1 aHolm, H.1 aOlafsson, I.1 aHwang, M., Y.1 aHan, S.1 aAkiyama, M.1 aSakaue, S.1 aTerao, C.1 aKanai, M.1 aZhou, W.1 aBrumpton, B., M.1 aRasheed, H.1 aHavulinna, A., S.1 aVeturi, Y.1 aPacheco, J., A.1 aRosenthal, E., A.1 aLingren, T.1 aFeng, Q.1 aKullo, I., J.1 aNarita, A.1 aTakayama, J.1 aMartin, H., C.1 aHunt, K., A.1 aTrivedi, B.1 aHaessler, J.1 aGiulianini, F.1 aBradford, Y.1 aMiller, J., E.1 aCampbell, A.1 aLin, K.1 aMillwood, I., Y.1 aRasheed, A.1 aHindy, G.1 aFaul, J., D.1 aZhao, W.1 aWeir, D., R.1 aTurman, C.1 aHuang, H.1 aGraff, M.1 aChoudhury, A.1 aSengupta, D.1 aMahajan, A.1 aBrown, M., R.1 aZhang, W.1 aYu, K.1 aSchmidt, E., M.1 aPandit, A.1 aGustafsson, S.1 aYin, X.1 aLuan, J.1 aZhao, J., H.1 aMatsuda, F.1 aJang, H., M.1 aYoon, K.1 aMedina-Gomez, C.1 aPitsillides, A.1 aHottenga, J., J.1 aWood, A., R.1 aJi, Y.1 aGao, Z.1 aHaworth, S.1 aYousri, N., A.1 aMitchell, R., E.1 aChai, J., F.1 aAadahl, M.1 aBjerregaard, A., A.1 aYao, J.1 aManichaikul, A.1 aHwu, C., M.1 aHung, Y., J.1 aWarren, H., R.1 aRamirez, J.1 aBork-Jensen, J.1 arhus, L., L.1 aGoel, A.1 aSabater-Lleal, M.1 aNoordam, R.1 aMauro, P.1 aMatteo, F.1 aMcDaid, A., F.1 aMarques-Vidal, P.1 aWielscher, M.1 aTrompet, S.1 aSattar, N.1 allehave, L., T.1 aMunz, M.1 aZeng, L.1 aHuang, J.1 aYang, B.1 aPoveda, A.1 aKurbasic, A.1 aLamina, C.1 aForer, L.1 aScholz, M.1 aGalesloot, T., E.1 aBradfield, J., P.1 aRuotsalainen, S., E.1 aDaw, E.1 aZmuda, J., M.1 aMitchell, J., S.1 aFuchsberger, C.1 aChristensen, H.1 aBrody, J., A.1 aVazquez-Moreno, M.1 aFeitosa, M., F.1 aWojczynski, M., K.1 aWang, Z.1 aPreuss, M., H.1 aMangino, M.1 aChristofidou, P.1 aVerweij, N.1 aBenjamins, J., W.1 aEngmann, J.1 aTsao, N., L.1 aVerma, A.1 aSlieker, R., C.1 aLo, K., S.1 aZilhao, N., R.1 aLe, P.1 aKleber, M., E.1 aDelgado, G., E.1 aHuo, S.1 aIkeda, D., D.1 aIha, H.1 aYang, J.1 aLiu, J.1 aDemirkan, A.1 aLeonard, H., L.1 aMarten, J.1 aFrank, M.1 aSchmidt, B.1 aSmyth, L., J.1 aadas-Garre, M.1 aWang, C.1 aNakatochi, M.1 aWong, A.1 anen, N.1 aSim, X.1 aXia, R.1 aHuerta-Chagoya, A.1 aFernandez-Lopez, J., C.1 aLyssenko, V.1 aNongmaithem, S., S.1 aBayyana, S.1 aStringham, H., M.1 aIrvin, M., R.1 aOldmeadow, C.1 aKim, H., N.1 aRyu, S.1 aTimmers, P., R. H. J.1 aArbeeva, L.1 aDorajoo, R.1 aLange, L., A.1 aPrasad, G.1 as-Motta, L.1 aPauper, M.1 aLong, J.1 aLi, X.1 aTheusch, E.1 aTakeuchi, F.1 aSpracklen, C., N.1 aLoukola, A.1 aBollepalli, S.1 aWarner, S., C.1 aWang, Y., X.1 aWei, W., B.1 aNutile, T.1 aRuggiero, D.1 aSung, Y., J.1 aChen, S.1 aLiu, F.1 aYang, J.1 aKentistou, K., A.1 aBanas, B.1 aNardone, G., G.1 aMeidtner, K.1 aBielak, L., F.1 aSmith, J., A.1 aHebbar, P.1 aFarmaki, A., E.1 aHofer, E.1 aLin, M.1 aConcas, M., P.1 aVaccargiu, S.1 avan der Most, P., J.1 anen, N.1 aCade, B., E.1 avan der Laan, S., W.1 aChitrala, K., N.1 aWeiss, S.1 aBentley, A., R.1 aDoumatey, A., P.1 aAdeyemo, A., A.1 aLee, J., Y.1 aPetersen, E., R. B.1 aNielsen, A., A.1 aChoi, H., S.1 aNethander, M.1 aFreitag-Wolf, S.1 aSoutham, L.1 aRayner, N., W.1 aWang, C., A.1 aLin, S., Y.1 aWang, J., S.1 aCouture, C.1 ainen, L., P.1 aNikus, K.1 aCuellar-Partida, G.1 aVestergaard, H.1 aHidalgo, B.1 aGiannakopoulou, O.1 aCai, Q.1 aObura, M., O.1 avan Setten, J.1 aLi, X.1 aLiang, J.1 aTang, H.1 aTerzikhan, N.1 aShin, J., H.1 aJackson, R., D.1 aReiner, A., P.1 aMartin, L., W.1 aChen, Z.1 aLi, L.1 aKawaguchi, T.1 aThiery, J.1 aBis, J., C.1 aLauner, L., J.1 aLi, H.1 aNalls, M., A.1 aRaitakari, O., T.1 aIchihara, S.1 aWild, S., H.1 aNelson, C., P.1 aCampbell, H.1 ager, S.1 aNabika, T.1 aAl-Mulla, F.1 aNiinikoski, H.1 aBraund, P., S.1 aKolcic, I.1 aKovacs, P.1 aGiardoglou, T.1 aKatsuya, T.1 ade Kleijn, D.1 ade Borst, G., J.1 aKim, E., K.1 aAdams, H., H. H.1 aIkram, M., A.1 aZhu, X.1 aAsselbergs, F., W.1 aKraaijeveld, A., O.1 aBeulens, J., W. J.1 aShu, X., O.1 aRallidis, L., S.1 aPedersen, O.1 aHansen, T.1 aMitchell, P.1 aHewitt, A., W.1 anen, M.1 arusse, L.1 aBouchard, C.1 anjes, A.1 aChen, Y., I.1 aPennell, C., E.1 aMori, T., A.1 aLieb, W.1 aFranke, A.1 aOhlsson, C.1 am, D.1 aCho, Y., S.1 aLee, H.1 aYuan, J., M.1 aKoh, W., P.1 aRhee, S., Y.1 aWoo, J., T.1 aHeid, I., M.1 aStark, K., J.1 aZimmermann, M., E.1 alzke, H.1 aHomuth, G.1 aEvans, M., K.1 aZonderman, A., B.1 aPolasek, O.1 aPasterkamp, G.1 aHoefer, I., E.1 aRedline, S.1 aPahkala, K.1 aOldehinkel, A., J.1 aSnieder, H.1 aBiino, G.1 aSchmidt, R.1 aSchmidt, H.1 aBandinelli, S.1 aDedoussis, G.1 aThanaraj, T., A.1 aKardia, S., L. R.1 aPeyser, P., A.1 aKato, N.1 aSchulze, M., B.1 aGirotto, G.1 ager, C., A.1 aJung, B.1 aJoshi, P., K.1 aBennett, D., A.1 aDe Jager, P., L.1 aLu, X.1 aMamakou, V.1 aBrown, M.1 aCaulfield, M., J.1 aMunroe, P., B.1 aGuo, X.1 aCiullo, M.1 aJonas, J., B.1 aSamani, N., J.1 aKaprio, J.1 aPajukanta, P.1 aLuna, T., -1 aAguilar-Salinas, C., A.1 aAdair, L., S.1 aBechayda, S., A.1 ade Silva, H., J.1 aWickremasinghe, A., R.1 aKrauss, R., M.1 aWu, J., Y.1 aZheng, W.1 aHollander, A., I.1 aBharadwaj, D.1 aCorrea, A.1 aWilson, J., G.1 aLind, L.1 aHeng, C., K.1 aNelson, A., E.1 aGolightly, Y., M.1 aWilson, J., F.1 aPenninx, B.1 aKim, H., L.1 aAttia, J.1 aScott, R., J.1 aRao, D., C.1 aArnett, D., K.1 aHunt, S., C.1 aWalker, M.1 aKoistinen, H., A.1 aChandak, G., R.1 aMercader, J., M.1 aCostanzo, M., C.1 aJang, D.1 aBurtt, N., P.1 aVillalpando, C., G.1 aOrozco, L.1 aFornage, M.1 aTai, E.1 avan Dam, R., M.1 aki, T.1 aChaturvedi, N.1 aYokota, M.1 aLiu, J.1 aReilly, D., F.1 aMcKnight, A., J.1 aKee, F.1 ackel, K., H.1 aMcCarthy, M., I.1 aPalmer, C., N. A.1 aVitart, V.1 aHayward, C.1 aSimonsick, E.1 avan Duijn, C., M.1 aJin, Z., B.1 aQu, J.1 aHishigaki, H.1 aLin, X.1 arz, W.1 aGudnason, V.1 aTardif, J., C.1 aLettre, G.1 aHart, L., M. '1 aElders, P., J. M.1 aDamrauer, S., M.1 aKumari, M.1 aKivimaki, M.1 avan der Harst, P.1 aSpector, T., D.1 aLoos, R., J. F.1 aProvince, M., A.1 aParra, E., J.1 aCruz, M.1 aPsaty, B., M.1 aBrandslund, I.1 aPramstaller, P., P.1 aRotimi, C., N.1 aChristensen, K.1 aRipatti, S.1 an, E.1 aHakonarson, H.1 aGrant, S., F. A.1 aKiemeney, L., A. L. M.1 ade Graaf, J.1 aLoeffler, M.1 aKronenberg, F.1 aGu, D.1 aErdmann, J.1 aSchunkert, H.1 aFranks, P., W.1 aLinneberg, A.1 aJukema, J., W.1 aKhera, A., V.1 aö, M.1 aJarvelin, M., R.1 aKutalik, Z.1 aFrancesco, C.1 aMook-Kanamori, D., O.1 avan Dijk, K., W.1 aWatkins, H.1 aStrachan, D., P.1 aGrarup, N.1 aSever, P.1 aPoulter, N.1 aChuang, L., M.1 aRotter, J., I.1 aDantoft, T., M.1 aKarpe, F.1 aNeville, M., J.1 aTimpson, N., J.1 aCheng, C., Y.1 aWong, T., Y.1 aKhor, C., C.1 aLi, H.1 aSabanayagam, C.1 aPeters, A.1 aGieger, C.1 aHattersley, A., T.1 aPedersen, N., L.1 aMagnusson, P., K. E.1 aBoomsma, D., I.1 aWillemsen, A., H. M.1 aCupples, L.1 avan Meurs, J., B. J.1 aGhanbari, M.1 aGordon-Larsen, P.1 aHuang, W.1 aKim, Y., J.1 aTabara, Y.1 aWareham, N., J.1 aLangenberg, C.1 aZeggini, E.1 aKuusisto, J.1 aLaakso, M.1 aIngelsson, E.1 aAbecasis, G.1 aChambers, J., C.1 aKooner, J., S.1 ade Vries, P., S.1 aMorrison, A., C.1 aHazelhurst, S.1 aRamsay, M.1 aNorth, K., E.1 aDaviglus, M.1 aKraft, P.1 aMartin, N., G.1 aWhitfield, J., B.1 aAbbas, S.1 aSaleheen, D.1 aWalters, R., G.1 aHolmes, M., V.1 aBlack, C.1 aSmith, B., H.1 aBaras, A.1 aJustice, A., E.1 aBuring, J., E.1 aRidker, P., M.1 aChasman, D., I.1 aKooperberg, C.1 aTamiya, G.1 aYamamoto, M.1 avan Heel, D., A.1 aTrembath, R., C.1 aWei, W., Q.1 aJarvik, G., P.1 aNamjou, B.1 aHayes, M., G.1 aRitchie, M., D.1 aJousilahti, P.1 aSalomaa, V.1 aHveem, K.1 asvold, B., O.1 aKubo, M.1 aKamatani, Y.1 aOkada, Y.1 aMurakami, Y.1 aKim, B., J.1 aThorsteinsdottir, U.1 aStefansson, K.1 aZhang, J.1 aChen, Y.1 aHo, Y., L.1 aLynch, J., A.1 aRader, D., J.1 aTsao, P., S.1 aChang, K., M.1 aCho, K.1 aO'Donnell, C., J.1 aGaziano, J., M.1 aWilson, P., W. F.1 aFrayling, T., M.1 aHirschhorn, J., N.1 aKathiresan, S.1 aMohlke, K., L.1 aSun, Y., V.1 aMorris, A., P.1 aBoehnke, M.1 aBrown, C., D.1 aNatarajan, P.1 aDeloukas, P.1 aWiller, C., J.1 aAssimes, T., L.1 aPeloso, G., M. uhttps://chs-nhlbi.org/node/925005976nas a2201393 4500008004100000022001400041245013400055210006900189260001600258300003400274520189200308100002102200700001402221700001702235700002202252700003002274700002502304700002502329700001502354700002302369700002302392700001702415700002002432700002202452700001302474700001902487700002402506700001902530700001802549700002302567700001902590700002602609700001602635700002302651700002402674700002102698700002902719700002202748700001602770700001902786700001802805700002102823700001802844700002602862700002202888700002102910700001802931700001602949700002002965700001902985700001803004700002403022700002503046700002203071700002103093700002203114700001703136700001703153700002003170700002103190700003303211700002403244700001703268700002203285700003403307700002503341700002203366700002103388700002103409700001903430700002203449700002003471700001903491700001403510700002503524700002103549700002503570700001703595700001403612700002303626700001803649700001703667700002203684700002103706700002203727700002403749700002103773700001903794700002203813700002103835700001903856700002603875700002103901700002003922700001903942700001903961700002503980700002004005700002304025700002404048700002204072700002304094700001404117700002004131700002004151700002004171700001904191700002104210700002204231700002404253700002104277700002504298700001804323700001704341700002104358700002404379710014304403856003604546 2022 eng d a1524-456300aInsights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.0 aInsights From a LargeScale WholeGenome Sequencing Study of Systo c2022 Jun 02 a101161HYPERTENSIONAHA122193243 aBACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.
METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.
RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively).
DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.
1 aKelly, Tanika, N1 aSun, Xiao1 aHe, Karen, Y1 aBrown, Michael, R1 aTaliun, Sarah, A Gagliano1 aHellwege, Jacklyn, N1 aIrvin, Marguerite, R1 aMi, Xuenan1 aBrody, Jennifer, A1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 ade Vries, Paul, S1 aGao, Yan1 aMoscati, Arden1 aNadkarni, Girish, N1 aYanek, Lisa, R1 aElfassy, Tali1 aSmith, Jennifer, A1 aChung, Ren-Hua1 aBeitelshees, Amber, L1 aPatki, Amit1 aAslibekyan, Stella1 aBlobner, Brandon, M1 aPeralta, Juan, M1 aAssimes, Themistocles, L1 aPalmas, Walter, R1 aLiu, Chunyu1 aBress, Adam, P1 aHuang, Zhijie1 aBecker, Lewis, C1 aHwa, Chii-Min1 aO'Connell, Jeffrey, R1 aCarlson, Jenna, C1 aWarren, Helen, R1 aDas, Sayantan1 aGiri, Ayush1 aMartin, Lisa, W1 aJohnson, Craig1 aFox, Ervin, R1 aBottinger, Erwin, P1 aRazavi, Alexander, C1 aVaidya, Dhananjay1 aChuang, Lee-Ming1 aChang, Yen-Pei, C1 aNaseri, Take1 aJain, Deepti1 aKang, Hyun, Min1 aHung, Adriana, M1 aSrinivasasainagendra, Vinodh1 aSnively, Beverly, M1 aGu, Dongfeng1 aMontasser, May, E1 aReupena, Muagututi'a, Sefuiva1 aHeavner, Benjamin, D1 aLeFaive, Jonathon1 aHixson, James, E1 aRice, Kenneth, M1 aWang, Fei, Fei1 aNielsen, Jonas, B1 aHuang, Jianfeng1 aKhan, Alyna, T1 aZhou, Wei1 aNierenberg, Jovia, L1 aLaurie, Cathy, C1 aArmstrong, Nicole, D1 aShi, Mengyao1 aPan, Yang1 aStilp, Adrienne, M1 aEmery, Leslie1 aWong, Quenna1 aHawley, Nicola, L1 aMinster, Ryan, L1 aCurran, Joanne, E1 aMunroe, Patricia, B1 aWeeks, Daniel, E1 aNorth, Kari, E1 aTracy, Russell, P1 aKenny, Eimear, E1 aShimbo, Daichi1 aChakravarti, Aravinda1 aRich, Stephen, S1 aReiner, Alex, P1 aBlangero, John1 aRedline, Susan1 aMitchell, Braxton, D1 aRao, Dabeeru, C1 aChen, Yii-Der, Ida1 aKardia, Sharon, L R1 aKaplan, Robert, C1 aMathias, Rasika, A1 aHe, Jiang1 aPsaty, Bruce, M1 aFornage, Myriam1 aLoos, Ruth, J F1 aCorrea, Adolfo1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aKooperberg, Charles1 aEdwards, Todd, L1 aAbecasis, Goncalo, R1 aZhu, Xiaofeng1 aLevy, Daniel1 aArnett, Donna, K1 aMorrison, Alanna, C1 aNHLBI Trans-Omics for Precision Medicine TOPMed) Consortium, The Samoan Obesity, Lifestyle, and Genetic Adaptations Study (OLaGA) Group† uhttps://chs-nhlbi.org/node/909904351nas a2200373 4500008004100000022001400041245010200055210006900157260001600226300001200242490000600254520332100260653001003581653000903591653002803600653001903628653001803647653001103665653001103676653001703687653001603704653001703720100002103737700001903758700001803777700002203795700002003817700001703837700002003854700002203874700002103896700002403917856003603941 2022 eng d a2574-380500aIntake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults.0 aIntake and Sources of Dietary Fiber Inflammation and Cardiovascu c2022 Mar 01 ae2250120 v53 aImportance: Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date.
Objectives: To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD).
Design, Setting, and Participants: At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed.
Exposures: Total fiber intake and sources of fiber (cereal, vegetable, and fruit).
Main Outcomes and Measures: Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis.
Results: Of 4125 individuals, 0.1% (n = 3) were Asian or Pacific Islander, 4.4% (n = 183) were Black, 0.3% (n = 12) were Native American, 95.0% (n = 3918) were White, and 0.2% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4%]; and 3942 individuals of other races and ethnicitites [95.6%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5% for interleukin 18 to 14.2% for C-reactive protein, and 16.1% for their primary principal component.
Conclusions and Relevance: Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.
10aAdult10aAged10aCardiovascular Diseases10aCohort Studies10aDietary Fiber10aFemale10aHumans10aInflammation10aMiddle Aged10aRisk Factors1 aShivakoti, Rupak1 aBiggs, Mary, L1 aDjoussé, Luc1 aDurda, Peter, Jon1 aKizer, Jorge, R1 aPsaty, Bruce1 aReiner, Alex, P1 aTracy, Russell, P1 aSiscovick, David1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/902503954nas a2200805 4500008004100000022001400041245007700055210006900132260001300201300001100214490000700225520175800232653001501990653002802005653002002033653002402053653001602077653001102093653000902104653001402113100001902127700001802146700002002164700002802184700001602212700002302228700002102251700001502272700002402287700002802311700002002339700001702359700002602376700002002402700001602422700001402438700001602452700002002468700001902488700002002507700001802527700002602545700002202571700002302593700002102616700002302637700002002660700001902680700002002699700002202719700002402741700001702765700002202782700002002804700002602824700001802850700002002868700001402888700002202902700002702924700001602951700002502967700002002992700002103012700002303033700001803056700002103074700001703095856003603112 2022 eng d a1474-972600aIntegrative analysis of clinical and epigenetic biomarkers of mortality.0 aIntegrative analysis of clinical and epigenetic biomarkers of mo c2022 Jun ae136080 v213 aDNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P = 4.1 × 10 ) and negatively associated with longevity (Beta = -1.9, P = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.
10aBiomarkers10aCardiovascular Diseases10aDNA Methylation10aEpigenesis, Genetic10aEpigenomics10aHumans10aMale10aNeoplasms1 aHuan, Tianxiao1 aNguyen, Steve1 aColicino, Elena1 aOchoa-Rosales, Carolina1 aHill, David1 aBrody, Jennifer, A1 aSoerensen, Mette1 aZhang, Yan1 aBaldassari, Antoine1 aElhadad, Mohamed, Ahmed1 aToshiko, Tanaka1 aZheng, Yinan1 aDomingo-Relloso, Arce1 aLee, Dong, Heon1 aMa, Jiantao1 aYao, Chen1 aLiu, Chunyu1 aHwang, Shih-Jen1 aJoehanes, Roby1 aFornage, Myriam1 aBressler, Jan1 avan Meurs, Joyce, B J1 aDebrabant, Birgit1 aMengel-From, Jonas1 aHjelmborg, Jacob1 aChristensen, Kaare1 aVokonas, Pantel1 aSchwartz, Joel1 aGahrib, Sina, A1 aSotoodehnia, Nona1 aSitlani, Colleen, M1 aKunze, Sonja1 aGieger, Christian1 aPeters, Annette1 aWaldenberger, Melanie1 aDeary, Ian, J1 aFerrucci, Luigi1 aQu, Yishu1 aGreenland, Philip1 aLloyd-Jones, Donald, M1 aHou, Lifang1 aBandinelli, Stefania1 aVoortman, Trudy1 aHermann, Brenner1 aBaccarelli, Andrea1 aWhitsel, Eric1 aPankow, James, S1 aLevy, Daniel uhttps://chs-nhlbi.org/node/909405087nas a2201237 4500008004100000022001400041245010900055210006900164260001200233300001400245490000700259520156200266653002801828653003801856653003401894653001101928653003601939653001701975100002701992700001502019700002402034700002002058700002302078700001602101700002002117700001802137700001402155700001802169700001802187700002402205700002002229700002102249700002302270700001802293700002202311700002802333700002502361700002302386700002202409700002202431700002302453700002002476700001502496700001802511700001602529700001902545700002402564700002202588700002002610700001202630700002002642700002502662700001902687700002202706700002202728700002702750700002302777700002202800700001902822700002102841700001702862700002102879700001602900700002002916700002302936700002102959700002002980700002003000700002003020700001903040700002403059700001503083700002403098700002303122700002203145700002403167700002203191700001603213700001903229700002203248700002503270700002203295700002103317700002103338700002103359700001503380700002103395700002303416700002503439700002403464700002103488700002003509700002003529700002303549700002303572700001403595700001603609700002003625700003003645700002903675710003003704710003303734710001803767710002803785856003603813 2022 eng d a1546-170X00aLarge-scale genome-wide association study of coronary artery disease in genetically diverse populations.0 aLargescale genomewide association study of coronary artery disea c2022 08 a1679-16920 v283 aWe report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
10aCoronary Artery Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aTcheandjieu, Catherine1 aZhu, Xiang1 aHilliard, Austin, T1 aClarke, Shoa, L1 aNapolioni, Valerio1 aMa, Shining1 aLee, Kyung, Min1 aFang, Huaying1 aChen, Fei1 aLu, Yingchang1 aTsao, Noah, L1 aRaghavan, Sridharan1 aKoyama, Satoshi1 aGorman, Bryan, R1 aVujkovic, Marijana1 aKlarin, Derek1 aLevin, Michael, G1 aSinnott-Armstrong, Nasa1 aWojcik, Genevieve, L1 aPlomondon, Mary, E1 aMaddox, Thomas, M1 aWaldo, Stephen, W1 aBick, Alexander, G1 aPyarajan, Saiju1 aHuang, Jie1 aSong, Rebecca1 aHo, Yuk-Lam1 aBuyske, Steven1 aKooperberg, Charles1 aHaessler, Jeffrey1 aLoos, Ruth, J F1 aDo, Ron1 aVerbanck, Marie1 aChaudhary, Kumardeep1 aNorth, Kari, E1 aAvery, Christy, L1 aGraff, Mariaelisa1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aWilkens, Lynne, R1 aBis, Joshua, C1 aLeonard, Hampton1 aShen, Botong1 aLange, Leslie, A1 aGiri, Ayush1 aDikilitas, Ozan1 aKullo, Iftikhar, J1 aStanaway, Ian, B1 aJarvik, Gail, P1 aGordon, Adam, S1 aHebbring, Scott1 aNamjou, Bahram1 aKaufman, Kenneth, M1 aIto, Kaoru1 aIshigaki, Kazuyoshi1 aKamatani, Yoichiro1 aVerma, Shefali, S1 aRitchie, Marylyn, D1 aKember, Rachel, L1 aBaras, Aris1 aLotta, Luca, A1 aKathiresan, Sekar1 aHauser, Elizabeth, R1 aMiller, Donald, R1 aLee, Jennifer, S1 aSaleheen, Danish1 aReaven, Peter, D1 aCho, Kelly1 aGaziano, Michael1 aNatarajan, Pradeep1 aHuffman, Jennifer, E1 aVoight, Benjamin, F1 aRader, Daniel, J1 aChang, Kyong-Mi1 aLynch, Julie, A1 aDamrauer, Scott, M1 aWilson, Peter, W F1 aTang, Hua1 aSun, Yan, V1 aTsao, Philip, S1 aO'Donnell, Christopher, J1 aAssimes, Themistocles, L1 aRegeneron Genetics Center1 aCARDIoGRAMplusC4D Consortium1 aBiobank Japan1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/917603449nas a2200517 4500008004100000022001400041245015400055210006900209260001200278300001000290490000800300520194800308653002002256653003102276653003102307653001402338653001102352653002202363653001102385653001402396653001702410653001802427653002002445653002602465653000902491653001402500653001102514653002502525100002602550700002102576700001902597700002302616700002402639700002202663700002002685700001702705700001702722700002102739700001702760700002502777700002702802700002202829700002002851700002402871856003602895 2022 eng d a1879-148400aMonocyte subsets, T cell activation profiles, and stroke in men and women: The Multi-Ethnic Study of Atherosclerosis and Cardiovascular Health Study.0 aMonocyte subsets T cell activation profiles and stroke in men an c2022 06 a18-250 v3513 aBACKGROUND AND AIMS: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes - key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke.
METHODS: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models.
RESULTS: We observed associations of intermediate monocytes, early-activated CD4 T cells, and both CD4 and CD8 T cells producing interleukin-4 after cytokine stimulation (T and T, respectively) with higher risk for incident stroke; effect sizes ranged from 35% to 62% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women.
CONCLUSIONS: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention.
10aAtherosclerosis10aCD4-Positive T-Lymphocytes10aCD8-Positive T-Lymphocytes10aCytokines10aFemale10aFollow-Up Studies10aHumans10aIncidence10aInflammation10aInterleukin-410aIschemic Stroke10aLymphocyte Activation10aMale10aMonocytes10aStroke10aT-Lymphocyte Subsets1 aFeinstein, Matthew, J1 aBůzková, Petra1 aOlson, Nels, C1 aDoyle, Margaret, F1 aSitlani, Colleen, M1 aFohner, Alison, E1 aHuber, Sally, A1 aFloyd, James1 aSinha, Arjun1 aThorp, Edward, B1 aLanday, Alan1 aFreiberg, Matthew, S1 aLongstreth, William, T1 aTracy, Russell, P1 aPsaty, Bruce, M1 aDelaney, Joseph, Ac uhttps://chs-nhlbi.org/node/909003474nas a2200565 4500008004100000022001400041245008100055210006900136260001600205520182300221100002002044700002402064700002102088700002202109700002002131700001802151700002502169700002602194700002902220700002502249700002002274700001902294700001902313700002402332700002102356700001602377700001902393700002502412700002302437700002402460700001802484700002002502700002102522700001902543700002502562700002502587700002402612700002002636700001902656700001902675700001902694700002102713700002202734700002402756700002202780700002402802700002402826700002202850856003602872 2022 eng d a1524-453900aMonogenic and Polygenic Contributions to QTc Prolongation in the Population.0 aMonogenic and Polygenic Contributions to QTc Prolongation in the c2022 Apr 073 a Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95% CI 1.3 -1.5; p-value=1.1×10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.
1 aNauffal, Victor1 aMorrill, Valerie, N1 aJurgens, Sean, J1 aChoi, Seung, Hoan1 aHall, Amelia, W1 aWeng, Lu-Chen1 aHalford, Jennifer, L1 aAustin-Tse, Christina1 aHaggerty, Christopher, M1 aHarris, Stephanie, L1 aWong, Eugene, K1 aAlonso, Alvaro1 aArking, Dan, E1 aBenjamin, Emelia, J1 aBoerwinkle, Eric1 aMin, Yuan-I1 aCorrea, Adolfo1 aFornwalt, Brandon, K1 aHeckbert, Susan, R1 aKooperberg, Charles1 aLin, Henry, J1 aLoos, Ruth, J F1 aRice, Kenneth, M1 aGupta, Namrata1 aBlackwell, Thomas, W1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPsaty, Bruce, M1 aPost, Wendy, S1 aRedline, Susan1 aRehm, Heidi, L1 aRich, Stephen, S1 aRotter, Jerome, I1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aLunetta, Kathryn, L1 aEllinor, Patrick, T1 aLubitz, Steven, A uhttps://chs-nhlbi.org/node/903813363nas a2204429 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2022 eng d a1546-171800aMulti-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.0 aMultiancestry genetic study of type 2 diabetes highlights the po c2022 May a560-5720 v543 aWe assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
10aDiabetes Mellitus, Type 210aEthnicity10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aZhang, Weihua1 aC Y Ng, Maggie1 aPetty, Lauren, E1 aKitajima, Hidetoshi1 aYu, Grace, Z1 aRüeger, Sina1 aSpeidel, Leo1 aKim, Young, Jin1 aHorikoshi, Momoko1 aMercader, Josep, M1 aTaliun, Daniel1 aMoon, Sanghoon1 aKwak, Soo-Heon1 aRobertson, Neil, R1 aRayner, Nigel, W1 aLoh, Marie1 aKim, Bong-Jo1 aChiou, Joshua1 aMiguel-Escalada, Irene1 aParolo, Pietro, Della Brio1 aLin, Kuang1 aBragg, Fiona1 aPreuss, Michael, H1 aTakeuchi, Fumihiko1 aNano, Jana1 aGuo, Xiuqing1 aLamri, Amel1 aNakatochi, Masahiro1 aScott, Robert, A1 aLee, Jung-Jin1 aHuerta-Chagoya, Alicia1 aGraff, Mariaelisa1 aChai, Jin-Fang1 aParra, Esteban, J1 aYao, Jie1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aSteinthorsdottir, Valgerdur1 aCook, James, P1 aKals, Mart1 aGrarup, Niels1 aSchmidt, Ellen, M1 aPan, Ian1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aAhmad, Meraj1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aLecoeur, Cécile1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aJensen, Richard, A1 aTajuddin, Salman1 aKabagambe, Edmond, K1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aFlanagan, Jack1 aAbaitua, Fernando1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAkiyama, Masato1 aAnand, Sonia, S1 aBertoni, Alain1 aBian, Zheng1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBrummett, Chad, M1 aBuchanan, Thomas, A1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFornage, Myriam1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aFuchsberger, Christian1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGoodarzi, Mark, O1 aGordon-Larsen, Penny1 aGorkin, David1 aGross, Myron1 aGuo, Yu1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKamatani, Yoichiro1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKohara, Katsuhiko1 aKriebel, Jennifer1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLigthart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLyssenko, Valeriya1 aMamakou, Vasiliki1 aMani, Radha, K1 aMeitinger, Thomas1 aMetspalu, Andres1 aMorris, Andrew, D1 aNadkarni, Girish, N1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNongmaithem, Suraj, S1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPorneala, Bianca1 aPrasad, Gauri1 aPreissl, Sebastian1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Kathryn1 aSabanayagam, Charumathi1 aSander, Maike1 aSandow, Kevin1 aSattar, Naveed1 aSchönherr, Sebastian1 aSchurmann, Claudia1 aShahriar, Mohammad1 aShi, Jinxiu1 aShin, Dong, Mun1 aShriner, Daniel1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aSuzuki, Ken1 aTakahashi, Atsushi1 aTaylor, Kent, D1 aThorand, Barbara1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTorres, Jason, M1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aVujkovic, Marijana1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWhitsel, Eric, A1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamauchi, Toshimasa1 aYengo, Loic1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZhang, Liang1 aZheng, Wei1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aHanis, Craig, L1 aPeyser, Patricia, A1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aZeggini, Eleftheria1 aYokota, Mitsuhiro1 aRich, Stephen, S1 aKooperberg, Charles1 aPankow, James, S1 aEngert, James, C1 aChen, Yii-Der Ida1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aKardia, Sharon, L R1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aGroop, Leif1 aMook-Kanamori, Dennis, O1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aBottinger, Erwin, P1 aDehghan, Abbas1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aPalmer, Colin, N A1 aLiu, Simin1 aAbecasis, Goncalo1 aKooner, Jaspal, S1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aFlorez, Jose, C1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aMägi, Reedik1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aMaeda, Shiro1 aKadowaki, Takashi1 aLee, Juyoung1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aMyers, Simon, R1 aFerrer, Jorge1 aGaulton, Kyle, J1 aMeigs, James, B1 aMohlke, Karen, L1 aGloyn, Anna, L1 aBowden, Donald, W1 aBelow, Jennifer, E1 aChambers, John, C1 aSim, Xueling1 aBoehnke, Michael1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aMorris, Andrew, P1 aFinnGen1 aeMERGE Consortium uhttps://chs-nhlbi.org/node/910403010nas a2200697 4500008004100000022001400041245012100055210006900176260001600245300000900261490000700270520097500277653001001252653003001262653003801292653003401330653001101364653001701375653003101392653001501423653001701438100002501455700002401480700002101504700001801525700002201543700001901565700001701584700001901601700002001620700001801640700002201658700001301680700001901693700002301712700001301735700002401748700002201772700001401794700002001808700001501828700003201843700002101875700002701896700002101923700002001944700001901964700001901983700002402002700002002026700002202046700002002068700002202088700002102110700002402131700002302155700001702178700001702195710006402212856003602276 2022 eng d a2041-172300aA multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood.0 amultiethnic polygenic risk score is associated with hypertension c2022 Jun 21 a35490 v133 aIn a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.
10aAdult10aDiabetes Mellitus, Type 210aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aMultifactorial Inheritance10aPrevalence10aRisk Factors1 aKurniansyah, Nuzulul1 aGoodman, Matthew, O1 aKelly, Tanika, N1 aElfassy, Tali1 aWiggins, Kerri, L1 aBis, Joshua, C1 aGuo, Xiuqing1 aPalmas, Walter1 aTaylor, Kent, D1 aLin, Henry, J1 aHaessler, Jeffrey1 aGao, Yan1 aShimbo, Daichi1 aSmith, Jennifer, A1 aYu, Bing1 aFeofanova, Elena, V1 aSmit, Roelof, A J1 aWang, Zhe1 aHwang, Shih-Jen1 aLiu, Simin1 aWassertheil-Smoller, Sylvia1 aManson, JoAnn, E1 aLloyd-Jones, Donald, M1 aRich, Stephen, S1 aLoos, Ruth, J F1 aRedline, Susan1 aCorrea, Adolfo1 aKooperberg, Charles1 aFornage, Myriam1 aKaplan, Robert, C1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aArnett, Donna, K1 aMorrison, Alanna, C1 aFranceschini, Nora1 aLevy, Daniel1 aSofer, Tamar1 aNHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/910003357nas a2200613 4500008004100000022001400041245014200055210006900197260001600266300001400282490000700296520143400303653001901737653001901756653001801775653001501793653001901808653002201827653002701849653002401876653002201900653001101922653002801933653002001961653002401981100001602005700001502021700001802036700002102054700002302075700001802098700001902116700002102135700002102156700002402177700002302201700001702224700002502241700002402266700002102290700001902311700002302330700002302353700001902376700002702395700002202422700001702444700001402461700002302475700001502498710009702513710009702610856003602707 2022 eng d a1939-327X00aMulti-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease.0 aMultiScalar Data Integration Links Glomerular AngiopoietinTie Si c2022 Dec 01 a2664-26760 v713 aDiabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.
10aAngiopoietin-110aAngiopoietin-210aAngiopoietins10aBiomarkers10aCohort Studies10aDiabetes Mellitus10aDiabetic Nephropathies10aDisease Progression10aEndothelial Cells10aHumans10aKidney Failure, Chronic10aReceptor, TIE-210aSignal Transduction1 aLiu, Jiahao1 aNair, Viji1 aZhao, Yi-Yang1 aChang, Dong-Yuan1 aLimonte, Christine1 aBansal, Nisha1 aFermin, Damian1 aEichinger, Felix1 aTanner, Emily, C1 aBellovich, Keith, A1 aSteigerwalt, Susan1 aBhat, Zeenat1 aHawkins, Jennifer, J1 aSubramanian, Lalita1 aRosas, Sylvia, E1 aSedor, John, R1 aVasquez, Miguel, A1 aWaikar, Sushrut, S1 aBitzer, Markus1 aPennathur, Subramaniam1 aBrosius, Frank, C1 ade Boer, Ian1 aChen, Min1 aKretzler, Matthias1 aJu, Wenjun1 aKidney Precision Medicine Project and Michigan Translational Core C-PROBE Investigator Group1 aKidney Precision Medicine Project and Michigan Translational Core C-PROBE Investigator Group uhttps://chs-nhlbi.org/node/925415436nas a2205137 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2022 eng d a1546-171800aNew insights into the genetic etiology of Alzheimer's disease and related dementias.0 aNew insights into the genetic etiology of Alzheimers disease and c2022 Apr a412-4360 v543 aCharacterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
10aAlzheimer Disease10aCognitive Dysfunction10aGenome-Wide Association Study10aHumans10atau Proteins1 aBellenguez, Céline1 aKüçükali, Fahri1 aJansen, Iris, E1 aKleineidam, Luca1 aMoreno-Grau, Sonia1 aAmin, Najaf1 aNaj, Adam, C1 aCampos-Martin, Rafael1 aGrenier-Boley, Benjamin1 aAndrade, Victor1 aHolmans, Peter, A1 aBoland, Anne1 aDamotte, Vincent1 avan der Lee, Sven, J1 aCosta, Marcos, R1 aKuulasmaa, Teemu1 aYang, Qiong1 ade Rojas, Itziar1 aBis, Joshua, C1 aYaqub, Amber1 aProkic, Ivana1 aChapuis, Julien1 aAhmad, Shahzad1 aGiedraitis, Vilmantas1 aAarsland, Dag1 aGarcia-Gonzalez, Pablo1 aAbdelnour, Carla1 aAlarcón-Martín, Emilio1 aAlcolea, Daniel1 aAlegret, Montserrat1 aAlvarez, Ignacio1 aAlvarez, Victoria1 aArmstrong, Nicola, J1 aTsolaki, Anthoula1 aAntunez, Carmen1 aAppollonio, Ildebrando1 aArcaro, Marina1 aArchetti, Silvana1 aPastor, Alfonso, Arias1 aArosio, Beatrice1 aAthanasiu, Lavinia1 aBailly, Henri1 aBanaj, Nerisa1 aBaquero, Miquel1 aBarral, Sandra1 aBeiser, Alexa1 aPastor, Ana, Belén1 aBelow, Jennifer, E1 aBenchek, Penelope1 aBenussi, Luisa1 aBerr, Claudine1 aBesse, Céline1 aBessi, Valentina1 aBinetti, Giuliano1 aBizarro, Alessandra1 aBlesa, Rafael1 aBoada, Merce1 aBoerwinkle, Eric1 aBorroni, Barbara1 aBoschi, Silvia1 aBossù, Paola1 aBråthen, Geir1 aBressler, Jan1 aBresner, Catherine1 aBrodaty, Henry1 aBrookes, Keeley, J1 aBrusco, Luis, Ignacio1 aBuiza-Rueda, Dolores1 aBûrger, Katharina1 aBurholt, Vanessa1 aBush, William, S1 aCalero, Miguel1 aCantwell, Laura, B1 aChene, Geneviève1 aChung, Jaeyoon1 aCuccaro, Michael, L1 aCarracedo, Angel1 aCecchetti, Roberta1 aCervera-Carles, Laura1 aCharbonnier, Camille1 aChen, Hung-Hsin1 aChillotti, Caterina1 aCiccone, Simona1 aClaassen, Jurgen, A H R1 aClark, Christopher1 aConti, Elisa1 aCorma-Gómez, Anaïs1 aCostantini, Emanuele1 aCustodero, Carlo1 aDaian, Delphine1 aDalmasso, Maria, Carolina1 aDaniele, Antonio1 aDardiotis, Efthimios1 aDartigues, Jean-François1 ade Deyn, Peter, Paul1 aLopes, Katia, de Paiva1 ade Witte, Lot, D1 aDebette, Stephanie1 aDeckert, Jürgen1 aDel Ser, Teodoro1 aDenning, Nicola1 aDeStefano, Anita1 aDichgans, Martin1 aDiehl-Schmid, Janine1 aDiez-Fairen, Monica1 aRossi, Paolo, Dionigi1 aDjurovic, Srdjan1 aDuron, Emmanuelle1 aDüzel, Emrah1 aDufouil, Carole1 aEiriksdottir, Gudny1 aEngelborghs, Sebastiaan1 aEscott-Price, Valentina1 aEspinosa, Ana1 aEwers, Michael1 aFaber, Kelley, M1 aFabrizio, Tagliavini1 aNielsen, Sune, Fallgaard1 aFardo, David, W1 aFarotti, Lucia1 aFenoglio, Chiara1 aFernández-Fuertes, Marta1 aFerrari, Raffaele1 aFerreira, Catarina, B1 aFerri, Evelyn1 aFin, Bertrand1 aFischer, Peter1 aFladby, Tormod1 aFließbach, Klaus1 aFongang, Bernard1 aFornage, Myriam1 aFortea, Juan1 aForoud, Tatiana, M1 aFostinelli, Silvia1 aFox, Nick, C1 aFranco-Macías, Emlio1 aBullido, María, J1 aFrank-García, Ana1 aFroelich, Lutz1 aFulton-Howard, Brian1 aGalimberti, Daniela1 aGarcía-Alberca, Jose, Maria1 aGarcia-Gonzalez, Pablo1 aGarcia-Madrona, Sebastian1 aGarcia-Ribas, Guillermo1 aGhidoni, Roberta1 aGiegling, Ina1 aGiorgio, Giaccone1 aGoate, Alison, M1 aGoldhardt, Oliver1 aGomez-Fonseca, Duber1 aGonzález-Perez, Antonio1 aGraff, Caroline1 aGrande, Giulia1 aGreen, Emma1 aGrimmer, Timo1 aGrünblatt, Edna1 aGrunin, Michelle1 aGudnason, Vilmundur1 aGuetta-Baranes, Tamar1 aHaapasalo, Annakaisa1 aHadjigeorgiou, Georgios1 aHaines, Jonathan, L1 aHamilton-Nelson, Kara, L1 aHampel, Harald1 aHanon, Olivier1 aHardy, John1 aHartmann, Annette, M1 aHausner, Lucrezia1 aHarwood, Janet1 aHeilmann-Heimbach, Stefanie1 aHelisalmi, Seppo1 aHeneka, Michael, T1 aHernandez, Isabel1 aHerrmann, Martin, J1 aHoffmann, Per1 aHolmes, Clive1 aHolstege, Henne1 aVilas, Raquel, Huerto1 aHulsman, Marc1 aHumphrey, Jack1 aBiessels, Geert, Jan1 aJian, Xueqiu1 aJohansson, Charlotte1 aJun, Gyungah, R1 aKastumata, Yuriko1 aKauwe, John1 aKehoe, Patrick, G1 aKilander, Lena1 aStåhlbom, Anne, Kinhult1 aKivipelto, Miia1 aKoivisto, Anne1 aKornhuber, Johannes1 aKosmidis, Mary, H1 aKukull, Walter, A1 aKuksa, Pavel, P1 aKunkle, Brian, W1 aKuzma, Amanda, B1 aLage, Carmen1 aLaukka, Erika, J1 aLauner, Lenore1 aLauria, Alessandra1 aLee, Chien-Yueh1 aLehtisalo, Jenni1 aLerch, Ondrej1 aLleo, Alberto1 aLongstreth, William1 aLopez, Oscar1 ade Munain, Adolfo, Lopez1 aLove, Seth1 aLöwemark, Malin1 aLuckcuck, Lauren1 aLunetta, Kathryn, L1 aMa, Yiyi1 aMacías, Juan1 aMacLeod, Catherine, A1 aMaier, Wolfgang1 aMangialasche, Francesca1 aSpallazzi, Marco1 aMarquié, Marta1 aMarshall, Rachel1 aMartin, Eden, R1 aMontes, Angel, Martín1 aRodríguez, Carmen, Martínez1 aMasullo, Carlo1 aMayeux, Richard1 aMead, Simon1 aMecocci, Patrizia1 aMedina, Miguel1 aMeggy, Alun1 aMehrabian, Shima1 aMendoza, Silvia1 aMenéndez-González, Manuel1 aMir, Pablo1 aMoebus, Susanne1 aMol, Merel1 aMolina-Porcel, Laura1 aMontrreal, Laura1 aMorelli, Laura1 aMoreno, Fermin1 aMorgan, Kevin1 aMosley, Thomas1 aNöthen, Markus, M1 aMuchnik, Carolina1 aMukherjee, Shubhabrata1 aNacmias, Benedetta1 aNgandu, Tiia1 aNicolas, Gaël1 aNordestgaard, Børge, G1 aOlaso, Robert1 aOrellana, Adelina1 aOrsini, Michela1 aOrtega, Gemma1 aPadovani, Alessandro1 aPaolo, Caffarra1 aPapenberg, Goran1 aParnetti, Lucilla1 aPasquier, Florence1 aPastor, Pau1 aPeloso, Gina1 aPérez-Cordón, Alba1 aPérez-Tur, Jordi1 aPericard, Pierre1 aPeters, Oliver1 aPijnenburg, Yolande, A L1 aPineda, Juan, A1 aPiñol-Ripoll, Gerard1 aPisanu, Claudia1 aPolak, Thomas1 aPopp, Julius1 aPosthuma, Danielle1 aPriller, Josef1 aPuerta, Raquel1 aQuenez, Olivier1 aQuintela, Inés1 aThomassen, Jesper, Qvist1 aRábano, Alberto1 aRainero, Innocenzo1 aRajabli, Farid1 aRamakers, Inez1 aReal, Luis, M1 aReinders, Marcel, J T1 aReitz, Christiane1 aReyes-Dumeyer, Dolly1 aRidge, Perry1 aRiedel-Heller, Steffi1 aRiederer, Peter1 aRoberto, Natalia1 aRodriguez-Rodriguez, Eloy1 aRongve, Arvid1 aAllende, Irene, Rosas1 aRosende-Roca, Maitée1 aRoyo, Jose, Luis1 aRubino, Elisa1 aRujescu, Dan1 aSáez, María, Eugenia1 aSakka, Paraskevi1 aSaltvedt, Ingvild1 aSanabria, Ángela1 aSánchez-Arjona, María, Bernal1 aSanchez-Garcia, Florentino1 aJuan, Pascual, Sánchez1 aSánchez-Valle, Raquel1 aSando, Sigrid, B1 aSarnowski, Chloe1 aSatizabal, Claudia, L1 aScamosci, Michela1 aScarmeas, Nikolaos1 aScarpini, Elio1 aScheltens, Philip1 aScherbaum, Norbert1 aScherer, Martin1 aSchmid, Matthias1 aSchneider, Anja1 aSchott, Jonathan, M1 aSelbæk, Geir1 aSeripa, Davide1 aSerrano, Manuel1 aSha, Jin1 aShadrin, Alexey, A1 aSkrobot, Olivia1 aSlifer, Susan1 aSnijders, Gijsje, J L1 aSoininen, Hilkka1 aSolfrizzi, Vincenzo1 aSolomon, Alina1 aSong, Yeunjoo1 aSorbi, Sandro1 aSotolongo-Grau, Oscar1 aSpalletta, Gianfranco1 aSpottke, Annika1 aSquassina, Alessio1 aStordal, Eystein1 aTartan, Juan, Pablo1 aTarraga, Lluis1 aTesí, Niccolo1 aThalamuthu, Anbupalam1 aThomas, Tegos1 aTosto, Giuseppe1 aTraykov, Latchezar1 aTremolizzo, Lucio1 aTybjærg-Hansen, Anne1 aUitterlinden, Andre1 aUllgren, Abbe1 aUlstein, Ingun1 aValero, Sergi1 aValladares, Otto1 aVan Broeckhoven, Christine1 aVance, Jeffery1 aVardarajan, Badri, N1 avan der Lugt, Aad1 aVan Dongen, Jasper1 avan Rooij, Jeroen1 avan Swieten, John1 aVandenberghe, Rik1 aVerhey, Frans1 aVidal, Jean-Sébastien1 aVogelgsang, Jonathan1 aVyhnalek, Martin1 aWagner, Michael1 aWallon, David1 aSan Wang, Li-1 aWang, Ruiqi1 aWeinhold, Leonie1 aWiltfang, Jens1 aWindle, Gill1 aWoods, Bob1 aYannakoulia, Mary1 aZare, Habil1 aZhao, Yi1 aZhang, Xiaoling1 aZhu, Congcong1 aZulaica, Miren1 aFarrer, Lindsay, A1 aPsaty, Bruce, M1 aGhanbari, Mohsen1 aRaj, Towfique1 aSachdev, Perminder1 aMather, Karen1 aJessen, Frank1 aIkram, Arfan, M1 ade Mendonça, Alexandre1 aHort, Jakub1 aTsolaki, Magda1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aWilliams, Julie1 aFrikke-Schmidt, Ruth1 aClarimon, Jordi1 aDeleuze, Jean-Francois1 aRossi, Giacomina1 aSeshadri, Sudha1 aAndreassen, Ole, A1 aIngelsson, Martin1 aHiltunen, Mikko1 aSleegers, Kristel1 aSchellenberg, Gerard, D1 aDuijn, Cornelia, M1 aSims, Rebecca1 avan der Flier, Wiesje, M1 aRuiz, Agustin1 aRamirez, Alfredo1 aLambert, Jean-Charles1 aEADB1 aGR@ACE1 aDEGESCO1 aEADI1 aGERAD1 aDemgene1 aFinnGen1 aADGC1 aCHARGE uhttps://chs-nhlbi.org/node/903502763nas a2200481 4500008004100000022001400041245012500055210006900180260001500249300000800264490000600272520128200278653003801560653003401598653001101632653002101643653003101664653003601695100002001731700002101751700002801772700002501800700002301825700001701848700001801865700002001883700001301903700001401916700001901930700002701949700002101976700002001997700002002017700002202037700002102059700002402080700002002104700001702124700001902141700001702160710006802177856003602245 2022 eng d a2399-364200aNon-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations.0 aNonlinear machine learning models incorporating SNPs and PRS imp c2022 08 22 a8560 v53 aPolygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22% for height, 27% for HDL cholesterol, 43% for body mass index, 50% for sleep duration, 58% for systolic blood pressure, 64% for total cholesterol, 66% for triglycerides, 77% for LDL cholesterol, and 100% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.
10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMachine Learning10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide1 aElgart, Michael1 aLyons, Genevieve1 aRomero-Brufau, Santiago1 aKurniansyah, Nuzulul1 aBrody, Jennifer, A1 aGuo, Xiuqing1 aLin, Henry, J1 aRaffield, Laura1 aGao, Yan1 aChen, Han1 ade Vries, Paul1 aLloyd-Jones, Donald, M1 aLange, Leslie, A1 aPeloso, Gina, M1 aFornage, Myriam1 aRotter, Jerome, I1 aRich, Stephen, S1 aMorrison, Alanna, C1 aPsaty, Bruce, M1 aLevy, Daniel1 aRedline, Susan1 aSofer, Tamar1 aNHLBI’s Trans-Omics in Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/916103499nas a2200745 4500008004100000245008400041210006900125260000800194300001400202490000700216520159100223100001101814700001701825700001601842700001501858700002101873700001801894700002301912700002001935700001401955700001201969700002001981700002102001700001802022700002002040700002302060700001102083700001702094700001702111700001602128700002102144700001802165700001402183700002102197700001502218700001102233700002002244700001502264700001702279700001902296700001202315700001202327700001802339700001502357700002102372700002002393700001802413700002202431700001902453700002002472700002102492700001702513700001302530700001902543700001602562700001702578700002002595700001902615700001802634700001902652700001502671700001602686700001502702856003602717 2022 eng d00a{Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol0 aObesity Partially Mediates the Diabetogenic Effect of Lowering L cJan a232–2400 v453 aLDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.\ We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.\ A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).\ These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.1 aWu, P.1 aMoon, J., Y.1 aDaghlas, I.1 aFranco, G.1 aPorneala, B., C.1 aAhmadizar, F.1 aRichardson, T., G.1 aIsaksen, J., L.1 aHindy, G.1 aYao, J.1 aSitlani, C., M.1 aRaffield, L., M.1 aYanek, L., R.1 aFeitosa, M., F.1 aCuadrat, R., R. C.1 aQi, Q.1 aIkram, Arfan1 aEllervik, C.1 aEricson, U.1 aGoodarzi, M., O.1 aBrody, J., A.1 aLange, L.1 aMercader, J., M.1 aVaidya, D.1 aAn, P.1 aSchulze, M., B.1 aMasana, L.1 aGhanbari, M.1 aOlesen, M., S.1 aCai, J.1 aGuo, X.1 aFloyd, J., S.1 aJäger, S.1 aProvince, M., A.1 aKalyani, R., R.1 aPsaty, B., M.1 aOrho-Melander, M.1 aRidker, P., M.1 aKanters, J., K.1 aUitterlinden, A.1 aSmith, Davey1 aGill, D.1 aKaplan, R., C.1 aKavousi, M.1 aRaghavan, S.1 aChasman, D., I.1 aRotter, J., I.1 aMeigs, J., B.1 aFlorez, J., C.1 aDupuis, J.1 aLiu, C., T.1 aMerino, J. uhttps://chs-nhlbi.org/node/898202982nas a2200397 4500008004100000022001400041245011500055210006900170260001300239300001100252490000700263520181400270653001202084653002202096653002802118653003002146653001602176653001102192653002002203653002402223100002402247700002002271700002102291700002202312700002002334700002302354700002402377700002202401700002002423700001902443700002402462700002002486700002202506700002002528856003602548 2022 eng d a2352-396400aPlasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study.0 aPlasma epoxyeicosatrienoic acids and diabetesrelated cardiovascu c2022 Sep a1041890 v833 aBACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free + esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).
METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.
FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.
INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.
FUNDING: US National Institutes of Health.
10aAnimals10aArachidonic Acids10aCardiovascular Diseases10aDiabetes Mellitus, Type 210aEicosanoids10aHumans10aIschemic Stroke10aProspective Studies1 aLemaitre, Rozenn, N1 aJensen, Paul, N1 aZeigler, Maxwell1 aFretts, Amanda, M1 aUmans, Jason, G1 aHoward, Barbara, V1 aSitlani, Colleen, M1 aMcKnight, Barbara1 aGharib, Sina, A1 aKing, Irena, B1 aSiscovick, David, S1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aTotah, Rheem, A uhttps://chs-nhlbi.org/node/917103102nas a2200361 4500008004100000022001400041245012400055210006900179260001500248300001200263490000700275520200300282653002002285653002802305653001902333653003702352653001102389653001602400653001702416100003402433700002102467700002502488700002402513700001802537700001902555700002402574700002202598700002502620700002002645700001902665700002002684856003602704 2022 eng d a2047-998000aPlasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts.0 aPlasma Levels of Advanced Glycation Endproducts and Risk of Card c2022 08 02 ae0240120 v113 aBackground Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α-dicarbonyl-derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new-onset CVD in 2 population-based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case-cohort sample (n=1631) from the Multi-Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi-Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow-up of 11 years, 439 participants in the Multi-Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl-lysine, 3-deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi-Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α-dicarbonyl-derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle-aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α-dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high-risk older populations.
10aAtherosclerosis10aCardiovascular Diseases10aCohort Studies10aGlycation End Products, Advanced10aHumans10aMiddle Aged10aRisk Factors1 aLamprea-Montealegre, Julio, A1 aArnold, Alice, M1 aMcClelland, Robyn, L1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aBiggs, Mary, L1 aSiscovick, David, S1 aTracy, Russell, P1 aBeisswenger, Paul, J1 aPsaty, Bruce, M1 aIx, Joachim, H1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/917002778nas a2200385 4500008004100000022001400041245007500055210006900130260001300199300001100212490000700223520174600230653001001976653001101986653000901997653001802006653001102024653002302035653000902058653001502067653001802082100001802100700001902118700002302137700002702160700002002187700002202207700002002229700002202249700001602271700002202287700002402309700002302333856003602356 2022 eng d a1474-972600aPlasma proteomic signature of decline in gait speed and grip strength.0 aPlasma proteomic signature of decline in gait speed and grip str c2022 Dec ae137360 v213 aThe biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 × 10 ), pleiotrophin (1.23 × 10 ), and TIMP-1 (5.97 × 10 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10 ), CDON (2.38 × 10 ), and SMOC1 (7.47 × 10 ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline.
10aAdult10aFemale10aGait10aHand Strength10aHumans10aIndependent Living10aMale10aProteomics10aWalking Speed1 aLiu, Xiaojuan1 aPan, Stephanie1 aXanthakis, Vanessa1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aAustin, Thomas, R1 aNewman, Anne, B1 aSanders, Jason, L1 aWu, Chenkai1 aTracy, Russell, P1 aGerszten, Robert, E1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/925503962nas a2200733 4500008004100000022001400041245014300055210006900198260001600267520182100283100001602104700001602120700001502136700001802151700002202169700002102191700002002212700001802232700001602250700001302266700001902279700002302298700001702321700002002338700002602358700002002384700002302404700003102427700001902458700001902477700002502496700002502521700002002546700001702566700002202583700002102605700002002626700002002646700002402666700002702690700001902717700002102736700002402757700002102781700002202802700001702824700001902841700002002860700002002880700001902900700001902919700002502938700002302963700002602986700002403012700001703036700002503053700002403078700002003102700001903122700002103141710003003162856003603192 2022 eng d a1537-660500aPolygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.0 aPolygenic transcriptome risk scores for COPD and lung function i c2022 Mar 313 aWhile polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.
1 aHu, Xiaowei1 aQiao, Dandi1 aKim, Wonji1 aMoll, Matthew1 aBalte, Pallavi, P1 aLange, Leslie, A1 aBartz, Traci, M1 aKumar, Rajesh1 aLi, Xingnan1 aYu, Bing1 aCade, Brian, E1 aLaurie, Cecelia, A1 aSofer, Tamar1 aRuczinski, Ingo1 aNickerson, Deborah, A1 aMuzny, Donna, M1 aMetcalf, Ginger, A1 aDoddapaneni, Harshavardhan1 aGabriel, Stacy1 aGupta, Namrata1 aDugan-Perez, Shannon1 aCupples, Adrienne, L1 aLoehr, Laura, R1 aJain, Deepti1 aRotter, Jerome, I1 aWilson, James, G1 aPsaty, Bruce, M1 aFornage, Myriam1 aMorrison, Alanna, C1 aVasan, Ramachandran, S1 aWashko, George1 aRich, Stephen, S1 aO'Connor, George, T1 aBleecker, Eugene1 aKaplan, Robert, C1 aKalhan, Ravi1 aRedline, Susan1 aGharib, Sina, A1 aMeyers, Deborah1 aOrtega, Victor1 aDupuis, Josée1 aLondon, Stephanie, J1 aLappalainen, Tuuli1 aOelsner, Elizabeth, C1 aSilverman, Edwin, K1 aBarr, Graham1 aThornton, Timothy, A1 aWheeler, Heather, E1 aCho, Michael, H1 aIm, Hae, Kyung1 aManichaikul, Ani1 aTOPMed Lung Working Group uhttps://chs-nhlbi.org/node/903702953nas a2200505 4500008004100000245009000041210006900131260000800200300001600208490000600224520161100230100002101841700001601862700001701878700001201895700001601907700001101923700001901934700001401953700001901967700001901986700001802005700001702023700002102040700001602061700002002077700001802097700002302115700001902138700001702157700001902174700001802193700001402211700001502225700001802240700002202258700002002280700001902300700001902319700001602338700001802354700001702372700002202389856003602411 2022 eng d00a{A population-based meta-analysis of circulating GFAP for cognition and dementia risk0 apopulationbased metaanalysis of circulating GFAP for cognition a cOct a1574–15850 v93 aExpression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings.\ Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models.\ 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52-4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42-4.53]) over up to 15-years of follow-up.\ Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.1 aGonzales, M., M.1 aWiedner, C.1 aWang, C., P.1 aLiu, Q.1 aBis, J., C.1 aLi, Z.1 aHimali, J., J.1 aGhosh, S.1 aThomas, E., A.1 aParent, D., M.1 aKautz, T., F.1 aPase, M., P.1 aAparicio, H., J.1 aDjousse, L.1 aMukamal, K., J.1 aPsaty, B., M.1 aLongstreth, W., T.1 aMosley, T., H.1 aGudnason, V.1 aMbangdadji, D.1 aLopez, O., L.1 aYaffe, K.1 aSidney, S.1 aBryan, R., N.1 aNasrallah, I., M.1 aDeCarli, C., S.1 aBeiser, A., S.1 aLauner, L., J.1 aFornage, M.1 aTracy, R., P.1 aSeshadri, S.1 aSatizabal, C., L. uhttps://chs-nhlbi.org/node/916603392nas a2200565 4500008004100000022001400041245014400055210006900199260001600268520170200284100002201986700002302008700002302031700001902054700002402073700002002097700001902117700001802136700002102154700002002175700003002195700002602225700002002251700002002271700002202291700002402313700002302337700002002360700002002380700002402400700002002424700002202444700001302466700002402479700002002503700001502523700002302538700002702561700001702588700001602605700002402621700002002645700002402665700002202689700002202711700002202733700001502755700002002770856003602790 2022 eng d a1573-728400aProteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing.0 aProteomics and Population Biology in the Cardiovascular Health S c2022 Jul 053 aBACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.
METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.
CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.
1 aAustin, Thomas, R1 aMcHugh, Caitlin, P1 aBrody, Jennifer, A1 aBis, Joshua, C1 aSitlani, Colleen, M1 aBartz, Traci, M1 aBiggs, Mary, L1 aBansal, Nisha1 aBůzková, Petra1 aCarr, Steven, A1 adeFilippi, Christopher, R1 aElkind, Mitchell, S V1 aFink, Howard, A1 aFloyd, James, S1 aFohner, Alison, E1 aGerszten, Robert, E1 aHeckbert, Susan, R1 aKatz, Daniel, H1 aKizer, Jorge, R1 aLemaitre, Rozenn, N1 aLongstreth, W T1 aMcKnight, Barbara1 aMei, Hao1 aMukamal, Kenneth, J1 aNewman, Anne, B1 aNgo, Debby1 aOdden, Michelle, C1 aVasan, Ramachandran, S1 aShojaie, Ali1 aSimon, Noah1 aSmith, George Davey1 aDavies, Neil, M1 aSiscovick, David, S1 aSotoodehnia, Nona1 aTracy, Russell, P1 aWiggins, Kerri, L1 aZheng, Jie1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/908608881nas a2202605 4500008004100000022001400041245012200055210006900177260001500246300001000261490000800271520141300279653001201692653001801704653002501722653002601747653002301773653003001796653001001826653003801836653002201874653002501896653003401921653001101955653002101966653001101987653001001998653003402008653003102042653002402073653001402097653003602111100001802147700001902165700002102184700002002205700001802225700003202243700001702275700001702292700003102309700003002340700002102370700002102391700002302412700001602435700002802451700002902479700001802508700002102526700002402547700001902571700001902590700002102609700002502630700002102655700002202676700002102698700002302719700001902742700001902761700001902780700002702799700001702826700002002843700002102863700002002884700002002904700001902924700002902943700002402972700001902996700002503015700002203040700001703062700002203079700002303101700002403124700002803148700002203176700002403198700002103222700002003243700002003263700002303283700002103306700003103327700002803358700001803386700002203404700002203426700002103448700002303469700003903492700002203531700002103553700001803574700001903592700001703611700001903628700001503647700002003662700001903682700001403701700002603715700001703741700002103758700002503779700002603804700002003830700002003850700002403870700001803894700002103912700001903933700001703952700001703969700002003986700002504006700002404031700002204055700002004077700001904097700002104116700001504137700001704152700001804169700002104187700002404208700002104232700001704253700002004270700002204290700002304312700002004335700002804355700003604383700002304419700002504442700002004467700002004487700002204507700001904529700002604548700002304574700001504597700002104612700002204633700002004655700002904675700002404704700002004728700002104748700002204769700002604791700002504817700001904842700002304861700002604884700002104910700002104931700001904952700002104971700002404992700001905016700002005035700002005055700001405075700001405089700001905103700002505122700003105147700002105178700001905199700002405218700002305242700001705265700001905282700001705301700001605318700002105334700001805355700002305373700001905396700002205415700002005437700001905457700002005476700002105496700002105517700002205538700002305560700002405583700002105607700002005628700002705648700003005675700001905705700001605724700001805740700002105758700002105779700002105800700001905821700001905840700002205859700002105881700002205902700002105924700002205945700002305967700002305990700002306013700001906036700002006055710006106075710006506136710003806201856003606239 2022 eng d a1537-660500aRare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.0 aRare coding variants in 35 genes associate with circulating lipi c2022 01 06 a81-960 v1093 aLarge-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
10aAlleles10aBlood Glucose10aCase-Control Studies10aComputational Biology10aDatabases, Genetic10aDiabetes Mellitus, Type 210aExome10aGenetic Predisposition to Disease10aGenetic Variation10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aLipids10aLiver10aMolecular Sequence Annotation10aMultifactorial Inheritance10aOpen Reading Frames10aPhenotype10aPolymorphism, Single Nucleotide1 aHindy, George1 aDornbos, Peter1 aChaffin, Mark, D1 aLiu, Dajiang, J1 aWang, Minxian1 aSelvaraj, Margaret, Sunitha1 aZhang, David1 aPark, Joseph1 aAguilar-Salinas, Carlos, A1 aAntonacci-Fulton, Lucinda1 aArdissino, Diego1 aArnett, Donna, K1 aAslibekyan, Stella1 aAtzmon, Gil1 aBallantyne, Christie, M1 aBarajas-Olmos, Francisco1 aBarzilai, Nir1 aBecker, Lewis, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBottinger, Erwin1 aBowden, Donald, W1 aBown, Matthew, J1 aBrody, Jennifer, A1 aBroome, Jai, G1 aBurtt, Noel, P1 aCade, Brian, E1 aCenteno-Cruz, Federico1 aChan, Edmund1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aCheng, Ching-Yu1 aChoi, Won, Jung1 aChowdhury, Raj1 aContreras-Cubas, Cecilia1 aCórdova, Emilio, J1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDanesh, John1 ade Vries, Paul, S1 aDeFronzo, Ralph, A1 aDoddapaneni, Harsha1 aDuggirala, Ravindranath1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aFlorez, Jose, C1 aFornage, Myriam1 aFreedman, Barry, I1 aFuster, Valentin1 aGaray-Sevilla, Ma, Eugenia1 aGarcía-Ortiz, Humberto1 aGermer, Soren1 aGibbs, Richard, A1 aGieger, Christian1 aGlaser, Benjamin1 aGonzalez, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGraff, Mariaelisa1 aGraham, Sarah, E1 aGrarup, Niels1 aGroop, Leif, C1 aGuo, Xiuqing1 aGupta, Namrata1 aHan, Sohee1 aHanis, Craig, L1 aHansen, Torben1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aIrvin, Marguerite, R1 aIslas-Andrade, Sergio1 aJarvik, Gail, P1 aKang, Hyun, Min1 aKardia, Sharon, L R1 aKelly, Tanika1 aKenny, Eimear, E1 aKhan, Alyna, T1 aKim, Bong-Jo1 aKim, Ryan, W1 aKim, Young, Jin1 aKoistinen, Heikki, A1 aKooperberg, Charles1 aKuusisto, Johanna1 aKwak, Soo, Heon1 aLaakso, Markku1 aLange, Leslie, A1 aLee, Jiwon1 aLee, Juyoung1 aLee, Seonwook1 aLehman, Donna, M1 aLemaitre, Rozenn, N1 aLinneberg, Allan1 aLiu, Jianjun1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aLyssenko, Valeriya1 aMa, Ronald, C W1 aMartin, Lisa, Warsinger1 aMartínez-Hernández, Angélica1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMcPherson, Ruth1 aMeigs, James, B1 aMeitinger, Thomas1 aMelander, Olle1 aMendoza-Caamal, Elvia1 aMetcalf, Ginger, A1 aMi, Xuenan1 aMohlke, Karen, L1 aMontasser, May, E1 aMoon, Jee-Young1 aMoreno-Macias, Hortensia1 aMorrison, Alanna, C1 aMuzny, Donna, M1 aNelson, Sarah, C1 aNilsson, Peter, M1 aO'Connell, Jeffrey, R1 aOrho-Melander, Marju1 aOrozco, Lorena1 aPalmer, Colin, N A1 aPalmer, Nicholette, D1 aPark, Cheol, Joo1 aPark, Kyong, Soo1 aPedersen, Oluf1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPost, Wendy, S1 aPreuss, Michael1 aPsaty, Bruce, M1 aQi, Qibin1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRevilla-Monsalve, Cristina1 aRich, Stephen, S1 aSamani, Nilesh1 aSchunkert, Heribert1 aSchurmann, Claudia1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSim, Xueling1 aSladek, Rob1 aSmall, Kerrin, S1 aSo, Wing, Yee1 aStilp, Adrienne, M1 aTai, Shyong, E1 aTam, Claudia, H T1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aThameem, Farook1 aTomlinson, Brian1 aTsai, Michael, Y1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 avan Dam, Rob, M1 aVasan, Ramachandran, S1 aMartinez, Karine, A Viaud1 aWang, Fei, Fei1 aWang, Xuzhi1 aWatkins, Hugh1 aWeeks, Daniel, E1 aWilson, James, G1 aWitte, Daniel, R1 aWong, Tien-Yin1 aYanek, Lisa, R1 aKathiresan, Sekar1 aRader, Daniel, J1 aRotter, Jerome, I1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aFlannick, Jason, A1 aKhera, Amit, V1 aPeloso, Gina, M1 aAMP-T2D-GENES, Myocardial Infarction Genetics Consortium1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aNHLBI TOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/897504507nas a2201189 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2022 eng d a2397-337400aRare genetic variants explain missing heritability in smoking.0 aRare genetic variants explain missing heritability in smoking c2022 Aug 043 aCommon genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
1 aJang, Seon-Kyeong1 aEvans, Luke1 aFialkowski, Allison1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBecker, Diane, M1 aBis, Joshua, C1 aBlangero, John1 aBleecker, Eugene, R1 aBoorgula, Meher, Preethi1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aJenkins, Brenda, W Campbell1 aCarson, April, P1 aChavan, Sameer1 aCupples, Adrienne, L1 aCuster, Brian1 aDamrauer, Scott, M1 aDavid, Sean, P1 ade Andrade, Mariza1 aDinardo, Carla, L1 aFingerlin, Tasha, E1 aFornage, Myriam1 aFreedman, Barry, I1 aGarrett, Melanie, E1 aGharib, Sina, A1 aGlahn, David, C1 aHaessler, Jeffrey1 aHeckbert, Susan, R1 aHokanson, John, E1 aHou, Lifang1 aHwang, Shih-Jen1 aHyman, Matthew, C1 aJudy, Renae1 aJustice, Anne, E1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKelly, Shannon1 aKim, Wonji1 aKooperberg, Charles1 aLevy, Daniel1 aLloyd-Jones, Donald, M1 aLoos, Ruth, J F1 aManichaikul, Ani, W1 aGladwin, Mark, T1 aMartin, Lisa, Warsinger1 aNouraie, Mehdi1 aMelander, Olle1 aMeyers, Deborah, A1 aMontgomery, Courtney, G1 aNorth, Kari, E1 aOelsner, Elizabeth, C1 aPalmer, Nicholette, D1 aPayton, Marinelle1 aPeljto, Anna, L1 aPeyser, Patricia, A1 aPreuss, Michael1 aPsaty, Bruce, M1 aQiao, Dandi1 aRader, Daniel, J1 aRafaels, Nicholas1 aRedline, Susan1 aReed, Robert, M1 aReiner, Alexander, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aSchwartz, David, A1 aShadyab, Aladdin, H1 aSilverman, Edwin, K1 aSmith, Nicholas, L1 aSmith, Gustav1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTang, Weihong1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aVasan, Ramachandran, S1 aGordeuk, Victor, R1 aWang, Zhe1 aWiggins, Kerri, L1 aYanek, Lisa, R1 aYang, Ivana, V1 aYoung, Kendra, A1 aYoung, Kristin, L1 aZhang, Yingze1 aLiu, Dajiang, J1 aKeller, Matthew, C1 aVrieze, Scott uhttps://chs-nhlbi.org/node/916802689nas a2200217 4500008004100000022001400041245012200055210007100177260001600248520198600264100002402250700002102274700001902295700002702314700001702341700001802358700002002376700001702396700002202413856003602435 2022 eng d a1879-191300aRelation of Cigarette Smoking and Heart Failure in Adults ≥65 Years of Age (From the Cardiovascular Health Study).0 aRelation of Cigarette Smoking and Heart Failure in Adults ≥65 Ye c2022 Jan 163 aCigarette smoking is associated with adverse cardiac outcomes, including incident heart failure (HF). However, key components of potential pathways from smoking to HF have not been evaluated in older adults. In a community-based study, we studied cross-sectional associations of smoking with blood and imaging biomarkers reflecting mechanisms of cardiac disease. Serial nested, multivariable Cox models were used to determine associations of smoking with HF, and to assess the influence of biochemical and functional (cardiac strain) phenotypes on these associations. Compared with never smokers, smokers had higher levels of inflammation (C-reactive protein and interleukin-6), cardiomyocyte injury (cardiac troponin T [hscTnT]), myocardial "stress"/fibrosis (soluble suppression of tumorigenicity 2 [sST2], galectin 3), and worse left ventricle systolic and diastolic function. In models adjusting for age, gender, and race (DEMO) and for clinical factors potentially in the causal pathway (CLIN), smoking exposures were associated with C-reactive protein and interleukin-6, sST2, hscTnT, and with N-terminal pro-brain natriuretic protein (in Whites). In DEMO adjusted models, the cumulative burden of smoking was associated with worse left ventricle systolic strain. Current smoking and former smoking were associated with HF in DEMO models (hazard ratio 1.41, 95% confidence interval 1.22 to 1.64 and hazard ratio 1.14, 95% confidence interval 1.03 to 1.25, respectively), and with current smoking after CLIN adjustment. Adjustment for time-varying myocardial infarction, inflammation, cardiac strain, hscTnT, sST2, and galectin 3 did not materially alter the associations. Smoking was associated with HF with preserved and decreased ejection fraction. In conclusion, in older adults, smoking is associated with multiple blood and imaging biomarker measures of pathophysiology previously linked to HF, and to incident HF even after adjustment for clinical intermediates.
1 aGottdiener, John, S1 aBůzková, Petra1 aKahn, Peter, A1 aDeFilippi, Christopher1 aShah, Sanjiv1 aBarasch, Eddy1 aKizer, Jorge, R1 aPsaty, Bruce1 aGardin, Julius, M uhttps://chs-nhlbi.org/node/897419775nas a2207657 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2022 eng d00a{A saturated map of common genetic variants associated with human height0 asaturated map of common genetic variants associated with human h cOct a704–7120 v6103 a) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.1 aYengo, L.1 aVedantam, S.1 aMarouli, E.1 aSidorenko, J.1 aBartell, E.1 aSakaue, S.1 aGraff, M.1 aEliasen, A., U.1 aJiang, Y.1 aRaghavan, S.1 aMiao, J.1 aArias, J., D.1 aGraham, S., E.1 aMukamel, R., E.1 aSpracklen, C., N.1 aYin, X.1 aChen, S., H.1 aFerreira, T.1 aHighland, H., H.1 aJi, Y.1 aKaraderi, T.1 aLin, K.1 all, K.1 aMalden, D., E.1 aMedina-Gomez, C.1 aMachado, M.1 aMoore, A.1 aeger, S.1 aSim, X.1 aVrieze, S.1 aAhluwalia, T., S.1 aAkiyama, M.1 aAllison, M., A.1 aAlvarez, M.1 aAndersen, M., K.1 aAni, A.1 aAppadurai, V.1 aArbeeva, L.1 aBhaskar, S.1 aBielak, L., F.1 aBollepalli, S.1 aBonnycastle, L., L.1 aBork-Jensen, J.1 aBradfield, J., P.1 aBradford, Y.1 aBraund, P., S.1 aBrody, J., A.1 aBurgdorf, K., S.1 aCade, B., E.1 aCai, H.1 aCai, Q.1 aCampbell, A.1 aadas-Garre, M.1 aCatamo, E.1 aChai, J., F.1 aChai, X.1 aChang, L., C.1 aChang, Y., C.1 aChen, C., H.1 aChesi, A.1 aChoi, S., H.1 aChung, R., H.1 aCocca, M.1 aConcas, M., P.1 aCouture, C.1 aCuellar-Partida, G.1 aDanning, R.1 aDaw, E., W.1 aDegenhard, F.1 aDelgado, G., E.1 aDelitala, A.1 aDemirkan, A.1 aDeng, X.1 aDevineni, P.1 aDietl, A.1 aDimitriou, M.1 aDimitrov, L.1 aDorajoo, R.1 aEkici, A., B.1 aEngmann, J., E.1 aFairhurst-Hunter, Z.1 aFarmaki, A., E.1 aFaul, J., D.1 aFernandez-Lopez, J., C.1 aForer, L.1 aFrancescatto, M.1 aFreitag-Wolf, S.1 aFuchsberger, C.1 aGalesloot, T., E.1 aGao, Y.1 aGao, Z.1 aGeller, F.1 aGiannakopoulou, O.1 aGiulianini, F.1 aGjesing, A., P.1 aGoel, A.1 aGordon, S., D.1 aGorski, M.1 aGrove, J.1 aGuo, X.1 aGustafsson, S.1 aHaessler, J.1 aHansen, T., F.1 aHavulinna, A., S.1 aHaworth, S., J.1 aHe, J.1 aHeard-Costa, N.1 aHebbar, P.1 aHindy, G.1 aHo, Y., A.1 aHofer, E.1 aHolliday, E.1 aHorn, K.1 aHornsby, W., E.1 aHottenga, J., J.1 aHuang, H.1 aHuang, J.1 aHuerta-Chagoya, A.1 aHuffman, J., E.1 aHung, Y., J.1 aHuo, S.1 aHwang, M., Y.1 aIha, H.1 aIkeda, D., D.1 aIsono, M.1 aJackson, A., U.1 ager, S.1 aJansen, I., E.1 aJohansson, I.1 aJonas, J., B.1 aJonsson, A.1 argensen, T.1 aKalafati, I., P.1 aKanai, M.1 aKanoni, S.1 arhus, L., L.1 aKasturiratne, A.1 aKatsuya, T.1 aKawaguchi, T.1 aKember, R., L.1 aKentistou, K., A.1 aKim, H., N.1 aKim, Y., J.1 aKleber, M., E.1 aKnol, M., J.1 aKurbasic, A.1 aLauzon, M.1 aLe, P.1 aLea, R.1 aLee, J., Y.1 aLeonard, H., L.1 aLi, S., A.1 aLi, X.1 aLi, X.1 aLiang, J.1 aLin, H.1 aLin, S., Y.1 aLiu, J.1 aLiu, X.1 aLo, K., S.1 aLong, J.1 aLorés-Motta, L.1 aLuan, J.1 aLyssenko, V.1 ainen, L., P.1 aMahajan, A.1 aMamakou, V.1 aMangino, M.1 aManichaikul, A.1 aMarten, J.1 aMattheisen, M.1 aMavarani, L.1 aMcDaid, A., F.1 aMeidtner, K.1 aMelendez, T., L.1 aMercader, J., M.1 aMilaneschi, Y.1 aMiller, J., E.1 aMillwood, I., Y.1 aMishra, P., P.1 aMitchell, R., E.1 allehave, L., T.1 aMorgan, A.1 aMucha, S.1 aMunz, M.1 aNakatochi, M.1 aNelson, C., P.1 aNethander, M.1 aNho, C., W.1 aNielsen, A., A.1 aNolte, I., M.1 aNongmaithem, S., S.1 aNoordam, R.1 aNtalla, I.1 aNutile, T.1 aPandit, A.1 aChristofidou, P.1 arna, K.1 aPauper, M.1 aPetersen, E., R. B.1 aPetersen, L., V.1 anen, N.1 aek, O.1 aPoveda, A.1 aPreuss, M., H.1 aPyarajan, S.1 aRaffield, L., M.1 aRakugi, H.1 aRamirez, J.1 aRasheed, A.1 aRaven, D.1 aRayner, N., W.1 aRiveros, C.1 aRohde, R.1 aRuggiero, D.1 aRuotsalainen, S., E.1 aRyan, K., A.1 aSabater-Lleal, M.1 aSaxena, R.1 aScholz, M.1 aSendamarai, A.1 aShen, B.1 aShi, J.1 aShin, J., H.1 aSidore, C.1 aSitlani, C., M.1 aSlieker, R., C.1 aSmit, R., A. J.1 aSmith, A., V.1 aSmith, J., A.1 aSmyth, L., J.1 aSoutham, L.1 aSteinthorsdottir, V.1 aSun, L.1 aTakeuchi, F.1 aTallapragada, D., S. P.1 aTaylor, K., D.1 aTayo, B., O.1 aTcheandjieu, C.1 aTerzikhan, N.1 aTesolin, P.1 aTeumer, A.1 aTheusch, E.1 aThompson, D., J.1 aThorleifsson, G.1 aTimmers, P., R. H. J.1 aTrompet, S.1 aTurman, C.1 aVaccargiu, S.1 avan der Laan, S., W.1 avan der Most, P., J.1 avan Klinken, J., B.1 avan Setten, J.1 aVerma, S., S.1 aVerweij, N.1 aVeturi, Y.1 aWang, C., A.1 aWang, C.1 aWang, L.1 aWang, Z.1 aWarren, H., R.1 aBin Wei, W.1 aWickremasinghe, A., R.1 aWielscher, M.1 aWiggins, K., L.1 aWinsvold, B., S.1 aWong, A.1 aWu, Y.1 aWuttke, M.1 aXia, R.1 aXie, T.1 aYamamoto, K.1 aYang, J.1 aYao, J.1 aYoung, H.1 aYousri, N., A.1 aYu, L.1 aZeng, L.1 aZhang, W.1 aZhang, X.1 aZhao, J., H.1 aZhao, W.1 aZhou, W.1 aZimmermann, M., E.1 aZoledziewska, M.1 aAdair, L., S.1 aAdams, H., H. H.1 aAguilar-Salinas, C., A.1 aAl-Mulla, F.1 aArnett, D., K.1 aAsselbergs, F., W.1 asvold, B., O.1 aAttia, J.1 aBanas, B.1 aBandinelli, S.1 aBennett, D., A.1 aBergler, T.1 aBharadwaj, D.1 aBiino, G.1 aBisgaard, H.1 aBoerwinkle, E.1 ager, C., A.1 annelykke, K.1 aBoomsma, D., I.1 arglum, A., D.1 aBorja, J., B.1 aBouchard, C.1 aBowden, D., W.1 aBrandslund, I.1 aBrumpton, B.1 aBuring, J., E.1 aCaulfield, M., J.1 aChambers, J., C.1 aChandak, G., R.1 aChanock, S., J.1 aChaturvedi, N.1 aChen, Y., I.1 aChen, Z.1 aCheng, C., Y.1 aChristophersen, I., E.1 aCiullo, M.1 aCole, J., W.1 aCollins, F., S.1 aCooper, R., S.1 aCruz, M.1 aCucca, F.1 aCupples, L., A.1 aCutler, M., J.1 aDamrauer, S., M.1 aDantoft, T., M.1 ade Borst, G., J.1 ade Groot, L., C. P. G. M1 aDe Jager, P., L.1 ade Kleijn, D., P. V.1 ade Silva, Janaka1 aDedoussis, G., V.1 aHollander, A., I. den1 aDu, S.1 aEaston, D., F.1 aElders, P., J. M.1 aEliassen, A., H.1 aEllinor, P., T.1 ahl, S.1 aErdmann, J.1 aEvans, M., K.1 aFatkin, D.1 aFeenstra, B.1 aFeitosa, M., F.1 aFerrucci, L.1 aFord, I.1 aFornage, M.1 aFranke, A.1 aFranks, P., W.1 aFreedman, B., I.1 aGasparini, P.1 aGieger, C.1 aGirotto, G.1 aGoddard, M., E.1 aGolightly, Y., M.1 aGonzalez-Villalpando, C.1 aGordon-Larsen, P.1 aGrallert, H.1 aGrant, S., F. A.1 aGrarup, N.1 aGriffiths, L.1 aGudnason, V.1 aHaiman, C.1 aHakonarson, H.1 aHansen, T.1 aHartman, C., A.1 aHattersley, A., T.1 aHayward, C.1 aHeckbert, S., R.1 aHeng, C., K.1 aHengstenberg, C.1 aHewitt, A., W.1 aHishigaki, H.1 aHoyng, C., B.1 aHuang, P., L.1 aHuang, W.1 aHunt, S., C.1 aHveem, K.1 anen, E.1 aIacono, W., G.1 aIchihara, S.1 aIkram, M., A.1 aIsasi, C., R.1 aJackson, R., D.1 aJarvelin, M., R.1 aJin, Z., B.1 ackel, K., H.1 aJoshi, P., K.1 aJousilahti, P.1 aJukema, J., W.1 anen, M.1 aKamatani, Y.1 aKang, K., D.1 aKaprio, J.1 aKardia, S., L. R.1 aKarpe, F.1 aKato, N.1 aKee, F.1 aKessler, T.1 aKhera, A., V.1 aKhor, C., C.1 aKiemeney, L., A. L. M.1 aKim, B., J.1 aKim, E., K.1 aKim, H., L.1 aKirchhof, P.1 aKivimaki, M.1 aKoh, W., P.1 aKoistinen, H., A.1 aKolovou, G., D.1 aKooner, J., S.1 aKooperberg, C.1 attgen, A.1 aKovacs, P.1 aKraaijeveld, A.1 aKraft, P.1 aKrauss, R., M.1 aKumari, M.1 aKutalik, Z.1 aLaakso, M.1 aLange, L., A.1 aLangenberg, C.1 aLauner, L., J.1 aLe Marchand, L.1 aLee, H.1 aLee, N., R.1 aki, T.1 aLi, H.1 aLi, L.1 aLieb, W.1 aLin, X.1 aLind, L.1 aLinneberg, A.1 aLiu, C., T.1 aLiu, J.1 aLoeffler, M.1 aLondon, B.1 aLubitz, S., A.1 aLye, S., J.1 aMackey, D., A.1 agi, R.1 aMagnusson, P., K. E.1 aMarcus, G., M.1 aVidal, P., M.1 aMartin, N., G.1 arz, W.1 aMatsuda, F.1 aMcGarrah, R., W.1 aMcGue, M.1 aMcKnight, A., J.1 aMedland, S., E.1 am, D.1 aMetspalu, A.1 aMitchell, B., D.1 aMitchell, P.1 aMook-Kanamori, D., O.1 aMorris, A., D.1 aMucci, L., A.1 aMunroe, P., B.1 aNalls, M., A.1 aNazarian, S.1 aNelson, A., E.1 aNeville, M., J.1 aNewton-Cheh, C.1 aNielsen, C., S.1 athen, M., M.1 aOhlsson, C.1 aOldehinkel, A., J.1 aOrozco, L.1 aPahkala, K.1 aPajukanta, P.1 aPalmer, C., N. A.1 aParra, E., J.1 aPattaro, C.1 aPedersen, O.1 aPennell, C., E.1 aPenninx, B., W. J. H.1 aPérusse, L.1 aPeters, A.1 aPeyser, P., A.1 aPorteous, D., J.1 aPosthuma, D.1 aPower, C.1 aPramstaller, P., P.1 aProvince, M., A.1 aQi, Q.1 aQu, J.1 aRader, D., J.1 aRaitakari, O., T.1 aRalhan, S.1 aRallidis, L., S.1 aRao, D., C.1 aRedline, S.1 aReilly, D., F.1 aReiner, A., P.1 aRhee, S., Y.1 aRidker, P., M.1 aRienstra, M.1 aRipatti, S.1 aRitchie, M., D.1 aRoden, D., M.1 aRosendaal, F., R.1 aRotter, J., I.1 aRudan, I.1 aRutters, F.1 aSabanayagam, C.1 aSaleheen, D.1 aSalomaa, V.1 aSamani, N., J.1 aSanghera, D., K.1 aSattar, N.1 aSchmidt, B.1 aSchmidt, H.1 aSchmidt, R.1 aSchulze, M., B.1 aSchunkert, H.1 aScott, L., J.1 aScott, R., J.1 aSever, P.1 aShiroma, E., J.1 aShoemaker, M., B.1 aShu, X., O.1 aSimonsick, E., M.1 aSims, M.1 aSingh, J., R.1 aSingleton, A., B.1 aSinner, M., F.1 aSmith, J., G.1 aSnieder, H.1 aSpector, T., D.1 aStampfer, M., J.1 aStark, K., J.1 aStrachan, D., P.1 aHart, L., M. 't1 aTabara, Y.1 aTang, H.1 aTardif, J., C.1 aThanaraj, T., A.1 aTimpson, N., J.1 anjes, A.1 aTremblay, A.1 aTuomi, T.1 aTuomilehto, J.1 aLuna, M., T. -1 aUitterlinden, A., G.1 avan Dam, R., M.1 avan der Harst, P.1 aVan der Velde, N.1 avan Duijn, C., M.1 avan Schoor, N., M.1 aVitart, V.1 alker, U.1 aVollenweider, P.1 alzke, H.1 aWacher-Rodarte, N., H.1 aWalker, M.1 aWang, Y., X.1 aWareham, N., J.1 aWatanabe, R., M.1 aWatkins, H.1 aWeir, D., R.1 aWerge, T., M.1 aWidén, E.1 aWilkens, L., R.1 aWillemsen, G.1 aWillett, W., C.1 aWilson, J., F.1 aWong, T., Y.1 aWoo, J., T.1 aWright, A., F.1 aWu, J., Y.1 aXu, H.1 aYajnik, C., S.1 aYokota, M.1 aYuan, J., M.1 aZeggini, E.1 aZemel, B., S.1 aZheng, W.1 aZhu, X.1 aZmuda, J., M.1 aZonderman, A., B.1 aZwart, J., A.1 aChasman, D., I.1 aCho, Y., S.1 aHeid, I., M.1 aMcCarthy, M., I.1 aNg, M., C. Y.1 aO'Donnell, C., J.1 aRivadeneira, F.1 aThorsteinsdottir, U.1 aSun, Y., V.1 aTai, E., S.1 aBoehnke, M.1 aDeloukas, P.1 aJustice, A., E.1 aLindgren, C., M.1 aLoos, R., J. F.1 aMohlke, K., L.1 aNorth, K., E.1 aStefansson, K.1 aWalters, R., G.1 aWinkler, T., W.1 aYoung, K., L.1 aLoh, P., R.1 aYang, J.1 aEsko, T.1 aAssimes, T., L.1 aAuton, A.1 aAbecasis, G., R.1 aWiller, C., J.1 aLocke, A., E.1 aBerndt, S., I.1 aLettre, G.1 aFrayling, T., M.1 aOkada, Y.1 aWood, A., R.1 aVisscher, P., M.1 aHirschhorn, J., N.1 aPartida, G., C.1 aSun, Y.1 aCroteau-Chonka, D.1 aVonk, J., M.1 aChanock, S.1 aLe Marchand, L. uhttps://chs-nhlbi.org/node/926302430nas a2200241 4500008004100000022001400041245012600055210006900181260001600250520166100266100001401927700001801941700002401959700002201983700002002005700002002025700001902045700002302064700002202087700002302109700002002132856003602152 2022 eng d a1532-541500aSex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults.0 aSex and racespecific associations of bone mineral density with i c2022 Nov 053 aBACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent.
METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC.
RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm decrement [95% CI = 1.23-1.62]), and showed the same to be true for White men (HR = 1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men.
CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.
1 aGao, Hans1 aPatel, Sheena1 aFohtung, Raymond, B1 aCawthon, Peggy, M1 aNewman, Anne, B1 aCauley, Jane, A1 aCarbone, Laura1 aChaves, Paulo, H M1 aStein, Phyllis, K1 aCivitelli, Roberto1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/924802453nas a2200253 4500008004100000022001400041245012100055210006900176260001300245300001100258490000700269520168400276100001901960700002501979700001902004700001902023700001802042700002302060700001702083700002202100700001902122700002202141856003602163 2022 eng d a1877-783X00aSleep problems and risk of cancer incidence and mortality in an older cohort: The Cardiovascular Health Study (CHS).0 aSleep problems and risk of cancer incidence and mortality in an c2022 Feb a1020570 v763 aBACKGROUND: Sleep problems (SP) can indicate underlying sleep disorders, such as obstructive sleep apnea, which may adversely impact cancer risk and mortality.
METHODS: We assessed the association of baseline and longitudinal sleep apnea and insomnia symptoms with incident cancer (N = 3930) and cancer mortality (N = 4580) in the Cardiovascular Health Study. We used Cox proportional hazards regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the associations.
RESULTS: Overall, 885 incident cancers and 804 cancer deaths were identified over a median follow-up of 12 and 14 years, respectively. Compared to participants who reported no sleep apnea symptoms, the risk of incident cancer was inversely associated [(HR (95%CI)] with snoring [0.84 (0.71, 0.99)]. We noted an elevated prostate cancer incidence for apnea [2.34 (1.32, 4.15)] and snoring [1.69 (1.11, 2.57)]. We also noted an elevated HR for lymphatic or hematopoietic cancers [daytime sleepiness: 1.81 (1.06, 3.08)]. We found an inverse relationship for cancer mortality with respect to snoring [0.73 (0.62, 0.8)] and apnea [(0.69 (0.51, 0.94))]. We noted a significant inverse relationship between difficulty falling asleep and colorectal cancer death [0.32 (0.15, 0.69)] and snoring with lung cancer death [0.56 (0.35, 0.89)].
CONCLUSIONS: The relationship between SP and cancer risk and mortality was heterogeneous. Larger prospective studies addressing more cancer sites, molecular type-specific associations, and better longitudinal SP assessments are needed for improved delineation of SP-cancer risk dyad.
1 aSillah, Arthur1 aWatson, Nathaniel, F1 aPeters, Ulrike1 aBiggs, Mary, L1 aNieto, Javier1 aLi, Christopher, I1 aGozal, David1 aThornton, Timothy1 aBarrie, Sonnah1 aPhipps, Amanda, I uhttps://chs-nhlbi.org/node/900309141nas a2202533 4500008004100000022001400041245008200055210006900137260001600206520188300222100001902105700001802124700002202142700002202164700002002186700002202206700002502228700001802253700002202271700001802293700001402311700002502325700001602350700001802366700001902384700002002403700001502423700003202438700003302470700001802503700001802521700002002539700002202559700001802581700002002599700002802619700001702647700001702664700002902681700001602710700002702726700002202753700002402775700001802799700002802817700001902845700001902864700001902883700001702902700002202919700002502941700002002966700002002986700002203006700001903028700002203047700001903069700001603088700002003104700001503124700002003139700002103159700001803180700002203198700001903220700002103239700002403260700002503284700002203309700002403331700001403355700001303369700002103382700001603403700002203419700002303441700002603464700002003490700001903510700002303529700002003552700002303572700002003595700002303615700002303638700002103661700001603682700001703698700002203715700001803737700001703755700001403772700001503786700002103801700002003822700002503842700002203867700002503889700002603914700002303940700002203963700001903985700002804004700002504032700002004057700003104077700002104108700002004129700002004149700002104169700002104190700002204211700002004233700002104253700002904274700002004303700003304323700001904356700002604375700002404401700002104425700002304446700002104469700001804490700001604508700001604524700001904540700002304559700002804582700002204610700003204632700002004664700002404684700002604708700002104734700001604755700002204771700002204793700002104815700001604836700002304852700001604875700001604891700002004907700002204927700002204949700002404971700001904995700001905014700002105033700002005054700002005074700001905094700002205113700002405135700002505159700001705184700003205201700002305233700002305256700002005279700002505299700002105324700001605345700002605361700001805387700002405405700001605429700002205445700002505467700002505492700001805517700002605535700002105561700003005582700002005612700001905632700002105651700002105672700002305693700002305716700002205739700002905761700002205790700002305812700002005835700001805855700002005873700003005893700002205923700002305945700002305968700002505991700001706016700002306033700002106056700002306077710002306100710002206123710007406145710002106219710002406240710002306264710004106287710002606328710002106354710004706375710003106422710005206453710001806505710002206523710002606545856003606571 2022 eng d a1476-468700aStroke genetics informs drug discovery and risk prediction across ancestries.0 aStroke genetics informs drug discovery and risk prediction acros c2022 Sep 303 aPrevious genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
1 aMishra, Aniket1 aMalik, Rainer1 aHachiya, Tsuyoshi1 aJürgenson, Tuuli1 aNamba, Shinichi1 aPosner, Daniel, C1 aKamanu, Frederick, K1 aKoido, Masaru1 aLe Grand, Quentin1 aShi, Mingyang1 aHe, Yunye1 aGeorgakis, Marios, K1 aCaro, Ilana1 aKrebs, Kristi1 aLiaw, Yi-Ching1 aVaura, Felix, C1 aLin, Kuang1 aWinsvold, Bendik, Slagsvold1 aSrinivasasainagendra, Vinodh1 aParodi, Livia1 aBae, Hee-Joon1 aChauhan, Ganesh1 aChong, Michael, R1 aTomppo, Liisa1 aAkinyemi, Rufus1 aRoshchupkin, Gennady, V1 aHabib, Naomi1 aJee, Yon, Ho1 aThomassen, Jesper, Qvist1 aAbedi, Vida1 aCárcel-Márquez, Jara1 aNygaard, Marianne1 aLeonard, Hampton, L1 aYang, Chaojie1 aYonova-Doing, Ekaterina1 aKnol, Maria, J1 aLewis, Adam, J1 aJudy, Renae, L1 aAgo, Tetsuro1 aAmouyel, Philippe1 aArmstrong, Nicole, D1 aBakker, Mark, K1 aBartz, Traci, M1 aBennett, David, A1 aBis, Joshua, C1 aBordes, Constance1 aBørte, Sigrid1 aCain, Anael1 aRidker, Paul, M1 aCho, Kelly1 aChen, Zhengming1 aCruchaga, Carlos1 aCole, John, W1 aDe Jager, Phil, L1 ade Cid, Rafael1 aEndres, Matthias1 aFerreira, Leslie, E1 aGeerlings, Mirjam, I1 aGasca, Natalie, C1 aGudnason, Vilmundur1 aHata, Jun1 aHe, Jing1 aHeath, Alicia, K1 aHo, Yuk-Lam1 aHavulinna, Aki, S1 aHopewell, Jemma, C1 aHyacinth, Hyacinth, I1 aInouye, Michael1 aJacob, Mina, A1 aJeon, Christina, E1 aJern, Christina1 aKamouchi, Masahiro1 aKeene, Keith, L1 aKitazono, Takanari1 aKittner, Steven, J1 aKonuma, Takahiro1 aKumar, Amit1 aLacaze, Paul1 aLauner, Lenore, J1 aLee, Keon-Joo1 aLepik, Kaido1 aLi, Jiang1 aLi, Liming1 aManichaikul, Ani1 aMarkus, Hugh, S1 aMarston, Nicholas, A1 aMeitinger, Thomas1 aMitchell, Braxton, D1 aMontellano, Felipe, A1 aMorisaki, Takayuki1 aMosley, Thomas, H1 aNalls, Mike, A1 aNordestgaard, Børge, G1 aO'Donnell, Martin, J1 aOkada, Yukinori1 aOnland-Moret, Charlotte, N1 aOvbiagele, Bruce1 aPeters, Annette1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRosand, Jonathan1 aSabatine, Marc, S1 aSacco, Ralph, L1 aSaleheen, Danish1 aSandset, Else, Charlotte1 aSalomaa, Veikko1 aSargurupremraj, Muralidharan1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSchmidt, Carsten, O1 aShimizu, Atsushi1 aSmith, Nicholas, L1 aSloane, Kelly, L1 aSutoh, Yoichi1 aSun, Yan, V1 aTanno, Kozo1 aTiedt, Steffen1 aTatlisumak, Turgut1 aTorres-Aguila, Nuria, P1 aTiwari, Hemant, K1 aTrégouët, David-Alexandre1 aTrompet, Stella1 aTuladhar, Anil, Man1 aTybjærg-Hansen, Anne1 avan Vugt, Marion1 aVibo, Riina1 aVerma, Shefali, S1 aWiggins, Kerri, L1 aWennberg, Patrik1 aWoo, Daniel1 aWilson, Peter, W F1 aXu, Huichun1 aYang, Qiong1 aYoon, Kyungheon1 aMillwood, Iona, Y1 aGieger, Christian1 aNinomiya, Toshiharu1 aGrabe, Hans, J1 aJukema, Wouter1 aRissanen, Ina, L1 aStrbian, Daniel1 aKim, Young, Jin1 aChen, Pei-Hsin1 aMayerhofer, Ernst1 aHowson, Joanna, M M1 aIrvin, Marguerite, R1 aAdams, Hieab1 aWassertheil-Smoller, Sylvia1 aChristensen, Kaare1 aIkram, Mohammad, A1 aRundek, Tatjana1 aWorrall, Bradford, B1 aLathrop, Mark, G1 aRiaz, Moeen1 aSimonsick, Eleanor, M1 aKõrv, Janika1 aFrança, Paulo, H C1 aZand, Ramin1 aPrasad, Kameshwar1 aFrikke-Schmidt, Ruth1 ade Leeuw, Frank-Erik1 aLiman, Thomas1 aHaeusler, Karl, Georg1 aRuigrok, Ynte, M1 aHeuschmann, Peter, Ulrich1 aLongstreth, W T1 aJung, Keum, Ji1 aBastarache, Lisa1 aParé, Guillaume1 aDamrauer, Scott, M1 aChasman, Daniel, I1 aRotter, Jerome, I1 aAnderson, Christopher, D1 aZwart, John-Anker1 aNiiranen, Teemu, J1 aFornage, Myriam1 aLiaw, Yung-Po1 aSeshadri, Sudha1 aFernandez-Cadenas, Israel1 aWalters, Robin, G1 aRuff, Christian, T1 aOwolabi, Mayowa, O1 aHuffman, Jennifer, E1 aMilani, Lili1 aKamatani, Yoichiro1 aDichgans, Martin1 aDebette, Stephanie1 aCOMPASS Consortium1 aINVENT Consortium1 aDutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group1 aEstonian Biobank1 aPRECISEQ Consortium1 aFinnGen Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aMEGASTROKE Consortium1 aSIREN Consortium1 aChina Kadoorie Biobank Collaborative Group1 aVA Million Veteran Program1 aInternational Stroke Genetics Consortium (ISGC)1 aBiobank Japan1 aCHARGE Consortium1 aGIGASTROKE Consortium uhttps://chs-nhlbi.org/node/917203348nas a2200541 4500008004100000022001400041245012000055210006900175260001600244520177900260100002002039700001702059700001902076700002502095700001702120700001502137700002002152700002002172700001402192700002402206700002102230700001702251700002002268700001702288700002202305700002202327700002202349700002802371700002002399700001902419700001802438700002102456700002002477700002302497700002102520700001602541700001702557700002002574700002702594700002102621700002102642700002202663700001702685700001902702700001802721710003102739856003602770 2022 eng d a1535-497000aTargeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.0 aTargeted Genome Sequencing Identifies Multiple Rare Variants in c2022 Jul 133 aINTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes.
METHODS: Leveraging high depth genomic sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleve-land Family Study (CFS) followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry.
RESULTS: Linkage analysis in CFS identified a suggestive linkage peak on chromosome 7q31 (LOD=2.31). Gene-based analysis identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (p=7.4×10-8). These non-coding variants together significantly contributed to the linkage evidence (p<10-3). Follow-up anal-ysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (p=0.024) and higher minimum overnight oxygen saturation (p=0.007).
CONCLUSION: Rare variants in CAV1, a membrane scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.
1 aLiang, Jingjing1 aWang, Heming1 aCade, Brian, E1 aKurniansyah, Nuzulul1 aHe, Karen, Y1 aLee, Jiwon1 aSands, Scott, A1 aBrody, Jennifer1 aChen, Han1 aGottlieb, Daniel, J1 aEvans, Daniel, S1 aGuo, Xiuqing1 aGharib, Sina, A1 aHale, Lauren1 aHillman, David, R1 aLutsey, Pamela, L1 aMukherjee, Sutapa1 aOchs-Balcom, Heather, M1 aPalmer, Lyle, J1 aPurcell, Shaun1 aSaxena, Richa1 aPatel, Sanjay, R1 aStone, Katie, L1 aTranah, Gregory, J1 aBoerwinkle, Eric1 aLin, Xihong1 aLiu, Yongmei1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aManichaikul, Ani1 aRich, Stephen, S1 aRotter, Jerome, I1 aSofer, Tamar1 aRedline, Susan1 aZhu, Xiaofeng1 aTOPMed Sleep Working Group uhttps://chs-nhlbi.org/node/910104203nas a2200697 4500008004100000022001400041245011000055210006900165260000900234300001100243490000700254520220700261653001902468653002202487653003402509653001102543653001202554653002802566100001402594700002102608700002002629700002102649700002002670700001902690700001902709700002302728700002002751700001502771700002802786700002402814700002402838700001802862700002702880700002102907700002302928700001902951700002102970700002102991700001903012700001903031700002303050700002303073700001703096700002103113700002103134700002203155700002403177700002203201700001903223700002403242700001903266700002103285700002503306700002303331700002403354700002403378700002503402700002203427700002003449856003603469 2022 eng d a1664-239200aThe Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.0 aValue of Rare Genetic Variation in the Prediction of Common Obes c2022 a8638930 v133 aPolygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.
10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aHumans10aObesity10aWhole Genome Sequencing1 aWang, Zhe1 aChoi, Shing, Wan1 aChami, Nathalie1 aBoerwinkle, Eric1 aFornage, Myriam1 aRedline, Susan1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aKim, Wonji1 aMcDonald, Merry-Lynn, N1 aRegan, Elizabeth, A1 aSilverman, Edwin, K1 aLiu, Ching-Ti1 aVasan, Ramachandran, S1 aKalyani, Rita, R1 aMathias, Rasika, A1 aYanek, Lisa, R1 aArnett, Donna, K1 aJustice, Anne, E1 aNorth, Kari, E1 aKaplan, Robert1 aHeckbert, Susan, R1 ade Andrade, Mariza1 aGuo, Xiuqing1 aLange, Leslie, A1 aRich, Stephen, S1 aRotter, Jerome, I1 aEllinor, Patrick, T1 aLubitz, Steven, A1 aBlangero, John1 aShoemaker, Benjamin1 aDarbar, Dawood1 aGladwin, Mark, T1 aAlbert, Christine, M1 aChasman, Daniel, I1 aJackson, Rebecca, D1 aKooperberg, Charles1 aReiner, Alexander, P1 aO'Reilly, Paul, F1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/910903215nas a2200481 4500008004100000022001400041245015300055210006900208260001600277520174000293100002102033700001402054700002302068700002002091700001902111700002502130700002602155700001802181700002102199700001802220700002202238700002102260700002102281700002202302700002402324700001902348700002102367700002302388700001902411700002202430700002302452700001702475700002002492700001802512700002802530700002302558700001902581700003002600700002002630700002402650700002302674856003602697 2022 eng d a1460-208300aWhole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.0 aWhole exome sequencing of 14 389 individuals from the ESP and CH c2022 May 123 aPlasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.
1 aPankratz, Nathan1 aWei, Peng1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aVries, Paul, S1 aHuffman, Jennifer, E1 aStimson, Mary, Rachel1 aAuer, Paul, L1 aBoerwinkle, Eric1 aCushman, Mary1 aMaat, Moniek, P M1 aFolsom, Aaron, R1 aFranco, Oscar, H1 aGibbs, Richard, A1 aHaagenson, Kelly, K1 aHofman, Albert1 aJohnsen, Jill, M1 aKovar, Christie, L1 aKraaij, Robert1 aMcKnight, Barbara1 aMetcalf, Ginger, A1 aMuzny, Donna1 aPsaty, Bruce, M1 aTang, Weihong1 aUitterlinden, André, G1 aRooij, Jeroen, G J1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aReiner, Alex, P1 aMorrison, Alanna, C1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/910705141nas a2201381 4500008004100000022001400041245014300055210006900198260001500267300000800282490000600290520117000296653003001466653001201496653001201508653001101520653001201531653005301543653002601596653003601622653002301658653002701681653001801708100002001726700002201746700002201768700002601790700002301816700002501839700001501864700002101879700002501900700001801925700002401943700002201967700002301989700002002012700001702032700002002049700002602069700001902095700002202114700001902136700001702155700001702172700003302189700002102222700001902243700001802262700002602280700002002306700002102326700002302347700002602370700002202396700002402418700002302442700002202465700002002487700002202507700002002529700002502549700002102574700002102595700001802616700001802634700002002652700002102672700002102693700001702714700002102731700003102752700002502783700003402808700002202842700002302864700002102887700001602908700001302924700001402937700002002951700001902971700002102990700001903011700002103030700001903051700002503070700002203095700002803117700001403145700002303159700002403182700001703206700002403223700001503247700002303262700002503285700002503310700002403335700002403359700002003383700001903403700002303422700002003445700002703465700003003492700002003522700002103542700001903563700002103582700002203603700001603625700001903641700002003660700002103680700002203701856003603723 2022 eng d a2399-364200aWhole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.0 aWhole genome sequence association analysis of fasting glucose an c2022 07 28 a7560 v53 aThe genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.
10aDiabetes Mellitus, Type 210aFasting10aGlucose10aHumans10aInsulin10aNational Heart, Lung, and Blood Institute (U.S.)10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPrecision Medicine10aReceptors, Immunologic10aUnited States1 aDiCorpo, Daniel1 aGaynor, Sheila, M1 aRussell, Emily, M1 aWesterman, Kenneth, E1 aRaffield, Laura, M1 aMajarian, Timothy, D1 aWu, Peitao1 aSarnowski, Chloe1 aHighland, Heather, M1 aJackson, Anne1 aHasbani, Natalie, R1 ade Vries, Paul, S1 aBrody, Jennifer, A1 aHidalgo, Bertha1 aGuo, Xiuqing1 aPerry, James, A1 aO'Connell, Jeffrey, R1 aLent, Samantha1 aMontasser, May, E1 aCade, Brian, E1 aJain, Deepti1 aWang, Heming1 aAlbanus, Ricardo, D'Oliveira1 aVarshney, Arushi1 aYanek, Lisa, R1 aLange, Leslie1 aPalmer, Nicholette, D1 aAlmeida, Marcio1 aPeralta, Juan, M1 aAslibekyan, Stella1 aBaldridge, Abigail, S1 aBertoni, Alain, G1 aBielak, Lawrence, F1 aChen, Chung-Shiuan1 aChen, Yii-Der Ida1 aChoi, Won, Jung1 aGoodarzi, Mark, O1 aFloyd, James, S1 aIrvin, Marguerite, R1 aKalyani, Rita, R1 aKelly, Tanika, N1 aLee, Seonwook1 aLiu, Ching-Ti1 aLoesch, Douglas1 aManson, JoAnn, E1 aMinster, Ryan, L1 aNaseri, Take1 aPankow, James, S1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aSelvin, Elizabeth1 aSmith, Jennifer, A1 aWeeks, Daniel, E1 aXu, Huichun1 aYao, Jie1 aZhao, Wei1 aParker, Stephen1 aAlonso, Alvaro1 aArnett, Donna, K1 aBlangero, John1 aBoerwinkle, Eric1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDuggirala, Ravindranath1 aHe, Jiang1 aHeckbert, Susan, R1 aKardia, Sharon, L R1 aKim, Ryan, W1 aKooperberg, Charles1 aLiu, Simin1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aShuldiner, Alan, R1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aViaud-Martinez, Karine, A1 aFlorez, Jose, C1 aWilson, James, G1 aSladek, Robert1 aRich, Stephen, S1 aRotter, Jerome, I1 aLin, Xihong1 aDupuis, Josée1 aMeigs, James, B1 aWessel, Jennifer1 aManning, Alisa, K uhttps://chs-nhlbi.org/node/915803611nas a2200889 4500008004100000022001400041245012300055210006900178260001600247300000900263490000700272520111000279653001601389653003401405653001101439653002801450100002301478700002301501700001701524700002701541700001801568700001301586700002401599700002301623700001501646700001901661700002301680700001301703700002401716700002001740700001301760700001901773700002001792700002201812700001801834700002001852700001301872700001701885700001501902700002001917700001901937700001901956700001801975700002101993700001902014700002002033700002202053700002002075700002202095700002102117700002002138700002502158700002402183700002002207700002002227700002102247700002202268700001402290700002202304700002102326700002502347700002502372700002102397700002302418700002302441700002602464700002402490700001202514700002802526700002702554700002102581700002402602700002102626700001802647700002002665856003602685 2022 eng d a2041-172300aWhole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.0 aWhole genome sequencing identifies structural variants contribut c2022 Dec 08 a75920 v133 aGenome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
10aBlood Cells10aGenome-Wide Association Study10aHumans10aWhole Genome Sequencing1 aWheeler, Marsha, M1 aStilp, Adrienne, M1 aRao, Shuquan1 aHalldorsson, Bjarni, V1 aBeyter, Doruk1 aWen, Jia1 aMihkaylova, Anna, V1 aMcHugh, Caitlin, P1 aLane, John1 aJiang, Min-Zhi1 aRaffield, Laura, M1 aJun, Goo1 aSedlazeck, Fritz, J1 aMetcalf, Ginger1 aYao, Yao1 aBis, Joshua, B1 aChami, Nathalie1 ade Vries, Paul, S1 aDesai, Pinkal1 aFloyd, James, S1 aGao, Yan1 aKammers, Kai1 aKim, Wonji1 aMoon, Jee-Young1 aRatan, Aakrosh1 aYanek, Lisa, R1 aAlmasy, Laura1 aBecker, Lewis, C1 aBlangero, John1 aCho, Michael, H1 aCurran, Joanne, E1 aFornage, Myriam1 aKaplan, Robert, C1 aLewis, Joshua, P1 aLoos, Ruth, J F1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPreuss, Michael1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRotter, Jerome, I1 aTang, Hua1 aTracy, Russell, P1 aBoerwinkle, Eric1 aAbecasis, Goncalo, R1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aJohnson, Andrew, D1 aMathias, Rasika, A1 aNickerson, Deborah, A1 aConomos, Matthew, P1 aLi, Yun1 aÞorsteinsdottir, Unnur1 aMagnússon, Magnús, K1 aStefansson, Kari1 aPankratz, Nathan, D1 aBauer, Daniel, E1 aAuer, Paul, L1 aReiner, Alex, P uhttps://chs-nhlbi.org/node/926104169nas a2200757 4500008004100000022001400041245010600055210006900161260001600230520193200246100001402178700001402192700001502206700001802221700001702239700002102256700001702277700002002294700002302314700001802337700001902355700002102374700002302395700002202418700002402440700002602464700001802490700002102508700001702529700002002546700002502566700002302591700001902614700002202633700002202655700002002677700002702697700001602724700002302740700002502763700002402788700002402812700002102836700001902857700002302876700002702899700002102926700001702947700002202964700001902986700002203005700002403027700002503051700002003076700002203096700002203118700002403140700002003164700002103184700001403205700002103219710006503240710004103305710002903346856003603375 2022 eng d a1460-208300aWhole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease.0 aWholeExome Sequencing Study Identifies Four Novel Gene Loci Asso c2022 Nov 293 aDiabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.
1 aPan, Yang1 aSun, Xiao1 aMi, Xuenan1 aHuang, Zhijie1 aHsu, Yenchih1 aHixson, James, E1 aMunzy, Donna1 aMetcalf, Ginger1 aFranceschini, Nora1 aTin, Adrienne1 aKöttgen, Anna1 aFrancis, Michael1 aBrody, Jennifer, A1 aKestenbaum, Bryan1 aSitlani, Colleen, M1 aMychaleckyj, Josyf, C1 aKramer, Holly1 aLange, Leslie, A1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aIrvin, Marguerite, R1 aSmith, Jennifer, A1 aYanek, Lisa, R1 aVaidya, Dhananjay1 aChen, Yii-Der Ida1 aFornage, Myriam1 aLloyd-Jones, Donald, M1 aHou, Lifang1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aPeyser, Patricia, A1 aKardia, Sharon, L R1 aArnett, Donna, K1 aCorrea, Adolfo1 aRaffield, Laura, M1 aVasan, Ramachandran, S1 aCupple, Adrienne1 aLevy, Daniel1 aKaplan, Robert, C1 aNorth, Kari, E1 aRotter, Jerome, I1 aKooperberg, Charles1 aReiner, Alexander, P1 aPsaty, Bruce, M1 aTracy, Russell, P1 aGibbs, Richard, A1 aMorrison, Alanna, C1 aFeldman, Harold1 aBoerwinkle, Eric1 aHe, Jiang1 aKelly, Tanika, N1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Kidney Function Working Group1 aCRIC Study Investigators uhttps://chs-nhlbi.org/node/925803215nas a2200589 4500008004100000245016000041210006900201260000800270300001400278490000700292520160900299100001101908700002101919700001801940700002001958700001601978700001501994700002402009700001802033700002102051700001402072700001502086700002102101700001502122700001102137700001202148700001802160700001302178700001802191700001902209700001502228700001802243700001702261700001702278700001102295700002002306700002302326700001602349700001802365700002302383700002002406700001502426700001202441700001602453700002802469700002102497700001602518700001702534700001902551700001902570856003602589 2022 eng d00a{Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project0 aWholeGenome Sequencing Association Analyses of Stroke and Its Su cMar a875–8850 v533 aStroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).\ Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis.\ .\ We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.1 aHu, Y.1 aHaessler, J., W.1 aManansala, R.1 aWiggins, K., L.1 aMoscati, A.1 aBeiser, A.1 aHeard-Costa, N., L.1 aSarnowski, C.1 aRaffield, L., M.1 aChung, J.1 aMarini, S.1 aAnderson, C., D.1 aRosand, J.1 aXu, H.1 aSun, X.1 aKelly, T., N.1 aWong, Q.1 aLange, L., A.1 aRotter, J., I.1 aCorrea, A.1 aVasan, R., S.1 aSeshadri, S.1 aRich, S., S.1 aDo, R.1 aLoos, R., J. F.1 aLongstreth, W., T.1 aBis, J., C.1 aPsaty, B., M.1 aTirschwell, D., L.1 aAssimes, T., L.1 aSilver, B.1 aLiu, S.1 aJackson, R.1 aWassertheil-Smoller, S.1 aMitchell, B., D.1 aFornage, M.1 aAuer, P., L.1 aReiner, A., P.1 aKooperberg, C. uhttps://chs-nhlbi.org/node/899606073nas a2201597 4500008004100000022001400041245008800055210006900143260001300212300001200225490000800237520158400245653001201829653001201841653002501853653003401878653001801912653002901930653001101959653000901970653001301979653003001992100002502022700002802047700002902075700002202104700001902126700001902145700001702164700001802181700001702199700001302216700002202229700001902251700002602270700002602296700002302322700001902345700002002364700001702384700002202401700003102423700001902454700002302473700002602496700002102522700002102543700002402564700002002588700002102608700002002629700002002649700001602669700002702685700001902712700001902731700002002750700001902770700002302789700002402812700001802836700001602854700002602870700002302896700002202919700002002941700001902961700002702980700001903007700002103026700002403047700002403071700001403095700002203109700001503131700001903146700002303165700002303188700002203211700002103233700002503254700001903279700002303298700001903321700002203340700001903362700002303381700001303404700002303417700002203440700002103462700002203483700002303505700002103528700002303549700001803572700001903590700002203609700002103631700002803652700002203680700001903702700002203721700002003743700001703763700001403780700001603794700002203810700001803832700002303850700001803873700002403891700002403915700001903939700001803958700002203976700002403998700001504022700002104037700001804058700002304076700002304099700002504122700002504147700002104172700001804193700002504211700002304236700002204259700002104281700002504302700002304327700002404350710006504374856003604439 2023 eng d a1476-468700aAberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.0 aAberrant activation of TCL1A promotes stem cell expansion in clo c2023 Apr a755-7630 v6163 aMutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
10aAlleles10aAnimals10aClonal Hematopoiesis10aGenome-Wide Association Study10aHematopoiesis10aHematopoietic Stem Cells10aHumans10aMice10aMutation10aPromoter Regions, Genetic1 aWeinstock, Joshua, S1 aGopakumar, Jayakrishnan1 aBurugula, Bala, Bharathi1 aUddin, Md, Mesbah1 aJahn, Nikolaus1 aBelk, Julia, A1 aBouzid, Hind1 aDaniel, Bence1 aMiao, Zhuang1 aLy, Nghi1 aMack, Taralynn, M1 aLuna, Sofia, E1 aProthro, Katherine, P1 aMitchell, Shaneice, R1 aLaurie, Cecelia, A1 aBroome, Jai, G1 aTaylor, Kent, D1 aGuo, Xiuqing1 aSinner, Moritz, F1 avon Falkenhausen, Aenne, S1 aKääb, Stefan1 aShuldiner, Alan, R1 aO'Connell, Jeffrey, R1 aLewis, Joshua, P1 aBoerwinkle, Eric1 aBarnes, Kathleen, C1 aChami, Nathalie1 aKenny, Eimear, E1 aLoos, Ruth, J F1 aFornage, Myriam1 aHou, Lifang1 aLloyd-Jones, Donald, M1 aRedline, Susan1 aCade, Brian, E1 aPsaty, Bruce, M1 aBis, Joshua, C1 aBrody, Jennifer, A1 aSilverman, Edwin, K1 aYun, Jeong, H1 aQiao, Dandi1 aPalmer, Nicholette, D1 aFreedman, Barry, I1 aBowden, Donald, W1 aCho, Michael, H1 aDeMeo, Dawn, L1 aVasan, Ramachandran, S1 aYanek, Lisa, R1 aBecker, Lewis, C1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aHe, Jiang1 aRienstra, Michiel1 aHarst, Pim1 aKaplan, Robert1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aArnett, Donna, K1 aIrvin, Marguerite, R1 aTiwari, Hemant1 aCutler, Michael, J1 aKnight, Stacey1 aMuhlestein, Brent1 aCorrea, Adolfo1 aRaffield, Laura, M1 aGao, Yan1 ade Andrade, Mariza1 aRotter, Jerome, I1 aRich, Stephen, S1 aTracy, Russell, P1 aKonkle, Barbara, A1 aJohnsen, Jill, M1 aWheeler, Marsha, M1 aSmith, Gustav1 aMelander, Olle1 aNilsson, Peter, M1 aCuster, Brian, S1 aDuggirala, Ravindranath1 aCurran, Joanne, E1 aBlangero, John1 aMcGarvey, Stephen1 aWilliams, Keoki1 aXiao, Shujie1 aYang, Mao1 aGu, Charles1 aChen, Yii-Der Ida1 aLee, Wen-Jane1 aMarcus, Gregory, M1 aKane, John, P1 aPullinger, Clive, R1 aShoemaker, Benjamin1 aDarbar, Dawood1 aRoden, Dan, M1 aAlbert, Christine1 aKooperberg, Charles1 aZhou, Ying1 aManson, JoAnn, E1 aDesai, Pinkal1 aJohnson, Andrew, D1 aMathias, Rasika, A1 aBlackwell, Thomas, W1 aAbecasis, Goncalo, R1 aSmith, Albert, V1 aKang, Hyun, M1 aSatpathy, Ansuman, T1 aNatarajan, Pradeep1 aKitzman, Jacob, O1 aWhitsel, Eric, A1 aReiner, Alexander, P1 aBick, Alexander, G1 aJaiswal, Siddhartha1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/938704341nas a2200385 4500008004100000022001400041245006700055210006600122260001600188520323500204100002603439700001203465700001703477700002603494700001503520700002103535700002303556700002303579700001903602700002603621700002303647700002003670700001903690700002203709700002003731700002003751700002003771700002003791700002103811700002003832700002303852700002103875700002303896856003603919 2023 eng d a2168-615700aAssociation Between Acute Myocardial Infarction and Cognition.0 aAssociation Between Acute Myocardial Infarction and Cognition c2023 May 303 aIMPORTANCE: The magnitude of cognitive change after incident myocardial infarction (MI) is unclear.
OBJECTIVE: To assess whether incident MI is associated with changes in cognitive function after adjusting for pre-MI cognitive trajectories.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study included adults without MI, dementia, or stroke and with complete covariates from the following US population-based cohort studies conducted from 1971 to 2019: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Data were analyzed from July 2021 to January 2022.
EXPOSURES: Incident MI.
MAIN OUTCOMES AND MEASURES: The main outcome was change in global cognition. Secondary outcomes were changes in memory and executive function. Outcomes were standardized as mean (SD) T scores of 50 (10); a 1-point difference represented a 0.1-SD difference in cognition. Linear mixed-effects models estimated changes in cognition at the time of MI (change in the intercept) and the rate of cognitive change over the years after MI (change in the slope), controlling for pre-MI cognitive trajectories and participant factors, with interaction terms for race and sex.
RESULTS: The study included 30 465 adults (mean [SD] age, 64 [10] years; 56% female), of whom 1033 had 1 or more MI event, and 29 432 did not have an MI event. Median follow-up was 6.4 years (IQR, 4.9-19.7 years). Overall, incident MI was not associated with an acute decrease in global cognition (-0.18 points; 95% CI, -0.52 to 0.17 points), executive function (-0.17 points; 95% CI, -0.53 to 0.18 points), or memory (0.62 points; 95% CI, -0.07 to 1.31 points). However, individuals with incident MI vs those without MI demonstrated faster declines in global cognition (-0.15 points per year; 95% CI, -0.21 to -0.10 points per year), memory (-0.13 points per year; 95% CI, -0.22 to -0.04 points per year), and executive function (-0.14 points per year; 95% CI, -0.20 to -0.08 points per year) over the years after MI compared with pre-MI slopes. The interaction analysis suggested that race and sex modified the degree of change in the decline in global cognition after MI (race × post-MI slope interaction term, P = .02; sex × post-MI slope interaction term, P = .04), with a smaller change in the decline over the years after MI in Black individuals than in White individuals (difference in slope change, 0.22 points per year; 95% CI, 0.04-0.40 points per year) and in females than in males (difference in slope change, 0.12 points per year; 95% CI, 0.01-0.23 points per year).
CONCLUSIONS: This cohort study using pooled data from 6 cohort studies found that incident MI was not associated with a decrease in global cognition, memory, or executive function at the time of the event compared with no MI but was associated with faster declines in global cognition, memory, and executive function over time. These findings suggest that prevention of MI may be important for long-term brain health.
1 aJohansen, Michelle, C1 aYe, Wen1 aGross, Alden1 aGottesman, Rebecca, F1 aHan, Dehua1 aWhitney, Rachael1 aBriceño, Emily, M1 aGiordani, Bruno, J1 aShore, Supriya1 aElkind, Mitchell, S V1 aManly, Jennifer, J1 aSacco, Ralph, L1 aFohner, Alison1 aGriswold, Michael1 aPsaty, Bruce, M1 aSidney, Stephen1 aSussman, Jeremy1 aYaffe, Kristine1 aMoran, Andrew, E1 aHeckbert, Susan1 aHughes, Timothy, M1 aGalecki, Andrzej1 aLevine, Deborah, A uhttps://chs-nhlbi.org/node/937703922nas a2200673 4500008004100000022001400041245014500055210006900200260001600269300001200285520190200297100001302199700001802212700001902230700001902249700001402268700002202282700002302304700002402327700001402351700002702365700002202392700001702414700002502431700001302456700001702469700001502486700002402501700002102525700002102546700002002567700002402587700002302611700002002634700002102654700002002675700002402695700002302719700002702742700002802769700002002797700001402817700002102831700002202852700001902874700002202893700002402915700001602939700002002955700002102975700001702996700002203013700001903035700002603054700001903080700001603099710009703115856003603212 2023 eng d a2047-998000aAssociation Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.0 aAssociation Between Whole BloodDerived Mitochondrial DNA Copy Nu c2023 Oct 07 ae0290903 aBackground The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.
1 aLiu, Xue1 aSun, Xianbang1 aZhang, Yuankai1 aJiang, Wenqing1 aLai, Meng1 aWiggins, Kerri, L1 aRaffield, Laura, M1 aBielak, Lawrence, F1 aZhao, Wei1 aPitsillides, Achilleas1 aHaessler, Jeffrey1 aZheng, Yinan1 aBlackwell, Thomas, W1 aYao, Jie1 aGuo, Xiuqing1 aQian, Yong1 aThyagarajan, Bharat1 aPankratz, Nathan1 aRich, Stephen, S1 aTaylor, Kent, D1 aPeyser, Patricia, A1 aHeckbert, Susan, R1 aSeshadri, Sudha1 aBoerwinkle, Eric1 aGrove, Megan, L1 aLarson, Nicholas, B1 aSmith, Jennifer, A1 aVasan, Ramachandran, S1 aFitzpatrick, Annette, L1 aFornage, Myriam1 aDing, Jun1 aCarson, April, P1 aAbecasis, Goncalo1 aDupuis, Josée1 aReiner, Alexander1 aKooperberg, Charles1 aHou, Lifang1 aPsaty, Bruce, M1 aWilson, James, G1 aLevy, Daniel1 aRotter, Jerome, I1 aBis, Joshua, C1 aSatizabal, Claudia, L1 aArking, Dan, E1 aLiu, Chunyu1 aTOPMed mtDNA Working Group in NHLBI Trans‐Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/950202665nas a2200313 4500008004100000022001400041245010000055210006900155260001600224520170900240100002001949700002101969700002501990700002002015700002402035700002202059700001502081700002102096700002402117700003002141700002002171700002202191700001902213700002002232700002302252700002002275700002002295856003602315 2023 eng d a1432-082700aAssociation of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.0 aAssociation of Immune Cell Subsets with Incident Hip Fracture Th c2023 Aug 313 aIn this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.
1 aElam, Rachel, E1 aBůzková, Petra1 aDelaney, Joseph, A C1 aFink, Howard, A1 aBarzilay, Joshua, I1 aCarbone, Laura, D1 aSaha, Rick1 aRobbins, John, A1 aMukamal, Kenneth, J1 aValderrábano, Rodrigo, J1 aPsaty, Bruce, M1 aTracy, Russell, P1 aOlson, Nels, C1 aHuber, Sally, A1 aDoyle, Margaret, F1 aLanday, Alan, L1 aCauley, Jane, A uhttps://chs-nhlbi.org/node/947804492nas a2200649 4500008004100000022001400041245014000055210006900195260001600264520258200280100001902862700001302881700002202894700002502916700001702941700002402958700001402982700001902996700002203015700002703037700002903064700001703093700001903110700002203129700002103151700001903172700002103191700001803212700002203230700001603252700002303268700002203291700001903313700001703332700001903349700002303368700002103391700002203412700002003434700001903454700002403473700002403497700002003521700002103541700002003562700002403582700002303606700002003629700002503649700001903674700002003693700002303713700002803736700001603764700002603780856003603806 2023 eng d a1526-632X00aAssociation of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.0 aAssociation of Mitochondrial DNA Copy Number With Brain MRI Mark c2023 Mar 163 aBACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.
METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.
RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.
DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.
1 aZhang, Yuankai1 aLiu, Xue1 aWiggins, Kerri, L1 aKurniansyah, Nuzulul1 aGuo, Xiuqing1 aRodrigue, Amanda, L1 aZhao, Wei1 aYanek, Lisa, R1 aRatliff, Scott, M1 aPitsillides, Achilleas1 aPatiño, Juan, Sebastian1 aSofer, Tamar1 aArking, Dan, E1 aAustin, Thomas, R1 aBeiser, Alexa, S1 aBlangero, John1 aBoerwinkle, Eric1 aBressler, Jan1 aCurran, Joanne, E1 aHou, Lifang1 aHughes, Timothy, M1 aKardia, Sharon, L1 aLauner, Lenore1 aLevy, Daniel1 aMosley, Tom, H1 aNasrallah, Ilya, M1 aRich, Stephen, S1 aRotter, Jerome, I1 aSeshadri, Sudha1 aTarraf, Wassim1 aGonzález, Kevin, A1 aRamachandran, Vasan1 aYaffe, Kristine1 aNyquist, Paul, A1 aPsaty, Bruce, M1 aDeCarli, Charles, S1 aSmith, Jennifer, A1 aGlahn, David, C1 aGonzález, Hector, M1 aBis, Joshua, C1 aFornage, Myriam1 aHeckbert, Susan, R1 aFitzpatrick, Annette, L1 aLiu, Chunyu1 aSatizabal, Claudia, L uhttps://chs-nhlbi.org/node/932305367nas a2201033 4500008004100000022001400041245012400055210006900179260001600248300001200264490000800276520243900284653002502723653002502748653002902773653001102802653001602813653002402829653003302853653001702886100002102903700002002924700001802944700002002962700001802982700001903000700002203019700001603041700002003057700002703077700002603104700002403130700001703154700002103171700002203192700002403214700002103238700002103259700002503280700001803305700002003323700001803343700002503361700003103386700002303417700002003440700002203460700001903482700002303501700002203524700002303546700002403569700002003593700002003613700002503633700002303658700002103681700002303702700002603725700001703751700002203768700002603790700002303816700002103839700002103860700002003881700001903901700002003920700001803940700001503958700001703973700001203990700002104002700001904023700001704042700001504059700002204074700002104096700002204117700001604139700001804155700001804173700001904191700002004210700002404230700002504254700001804279856003604297 2023 eng d a1756-183300aAssociation of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts.0 aAssociation of omega 3 polyunsaturated fatty acids with incident c2023 Jan 18 ae0729090 v3803 aOBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).
DESIGN: Pooled analysis.
DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.
STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.
DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.
MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate.
RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.
CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.
10aalpha-Linolenic Acid10aFatty Acids, Omega-310aFatty Acids, Unsaturated10aHumans10aMiddle Aged10aProspective Studies10aRenal Insufficiency, Chronic10aRisk Factors1 aOng, Kwok, Leung1 aMarklund, Matti1 aHuang, Liping1 aRye, Kerry-Anne1 aHui, Nicholas1 aPan, Xiong-Fei1 aRebholz, Casey, M1 aKim, Hyunju1 aSteffen, Lyn, M1 avan Westing, Anniek, C1 aGeleijnse, Johanna, M1 aHoogeveen, Ellen, K1 aChen, Yun-Yu1 aChien, Kuo-Liong1 aFretts, Amanda, M1 aLemaitre, Rozenn, N1 aImamura, Fumiaki1 aForouhi, Nita, G1 aWareham, Nicholas, J1 aBirukov, Anna1 aJäger, Susanne1 aKuxhaus, Olga1 aSchulze, Matthias, B1 ade Mello, Vanessa, Derenji1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aLindström, Jaana1 aTintle, Nathan1 aHarris, William, S1 aYamasaki, Keisuke1 aHirakawa, Yoichiro1 aNinomiya, Toshiharu1 aTanaka, Toshiko1 aFerrucci, Luigi1 aBandinelli, Stefania1 aVirtanen, Jyrki, K1 aVoutilainen, Ari1 aJayasena, Tharusha1 aThalamuthu, Anbupalam1 aPoljak, Anne1 aBustamante, Sonia1 aSachdev, Perminder, S1 aSenn, Mackenzie, K1 aRich, Stephen, S1 aTsai, Michael, Y1 aWood, Alexis, C1 aLaakso, Markku1 aLankinen, Maria1 aYang, Xiaowei1 aSun, Liang1 aLi, Huaixing1 aLin, Xu1 aNowak, Christoph1 aArnlöv, Johan1 aRiserus, Ulf1 aLind, Lars1 aLe Goff, Mélanie1 aSamieri, Cecilia1 aHelmer, Catherine1 aQian, Frank1 aMicha, Renata1 aTin, Adrienne1 aKöttgen, Anna1 ade Boer, Ian, H1 aSiscovick, David, S1 aMozaffarian, Dariush1 aWu, Jason, HY uhttps://chs-nhlbi.org/node/945603674nas a2200457 4500008004100000022001400041245015600055210006900211260001600280520226600296100002402562700002302586700001602609700002102625700002402646700001802670700002102688700002402709700002202733700002002755700001602775700002702791700002002818700002202838700001902860700002702879700001702906700002302923700002102946700001702967700002002984700002203004700002203026700002303048700002603071700002103097700002003118700002303138700001903161856003603180 2023 eng d a2380-659100aAssociation of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease.0 aAssociation of Rare ProteinTruncating DNA Variants in APOB or PC c2023 Feb 013 aIMPORTANCE: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.
OBJECTIVE: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.
DESIGN, SETTING, AND PARTICIPANTS: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.
EXPOSURES: PTVs in APOB and PCSK9.
MAIN OUTCOMES AND MEASURES: Estimated untreated LDL cholesterol levels and CHD.
RESULTS: Among 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).
CONCLUSIONS AND RELEVANCE: Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.
1 aDron, Jacqueline, S1 aPatel, Aniruddh, P1 aZhang, Yiyi1 aJurgens, Sean, J1 aMaamari, Dimitri, J1 aWang, Minxian1 aBoerwinkle, Eric1 aMorrison, Alanna, C1 ade Vries, Paul, S1 aFornage, Myriam1 aHou, Lifang1 aLloyd-Jones, Donald, M1 aPsaty, Bruce, M1 aTracy, Russell, P1 aBis, Joshua, C1 aVasan, Ramachandran, S1 aLevy, Daniel1 aHeard-Costa, Nancy1 aRich, Stephen, S1 aGuo, Xiuqing1 aTaylor, Kent, D1 aGibbs, Richard, A1 aRotter, Jerome, I1 aWiller, Cristen, J1 aOelsner, Elizabeth, C1 aMoran, Andrew, E1 aPeloso, Gina, M1 aNatarajan, Pradeep1 aKhera, Amit, V uhttps://chs-nhlbi.org/node/928501675nas a2200565 4500008004100000022001400041245012700055210006900182260001600251300001400267490000800281653002100289653001300310653001100323653002500334653003300359100001600392700002400408700002400432700001900456700001600475700002200491700002600513700002100539700002100560700001500581700002000596700002300616700002200639700002000661700002100681700002800702700002200730700002000752700002700772700001600799700002000815700001900835700002000854700002700874700002600901700002100927700002100948700002100969700001700990700001901007700002601026700002101052856003601073 2023 eng d a1524-453900aAssociation of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease.0 aAssociation of Severe Hypercholesterolemia and Familial Hypercho c2023 May 16 a1556-15590 v14710aCoronary Disease10aGenotype10aHumans10aHypercholesterolemia10aHyperlipoproteinemia Type II1 aZhang, Yiyi1 aDron, Jacqueline, S1 aBellows, Brandon, K1 aKhera, Amit, V1 aLiu, Junxiu1 aBalte, Pallavi, P1 aOelsner, Elizabeth, C1 aAmr, Sami, Samir1 aLebo, Matthew, S1 aNagy, Anna1 aPeloso, Gina, M1 aNatarajan, Pradeep1 aRotter, Jerome, I1 aWiller, Cristen1 aBoerwinkle, Eric1 aBallantyne, Christie, M1 aLutsey, Pamela, L1 aFornage, Myriam1 aLloyd-Jones, Donald, M1 aHou, Lifang1 aPsaty, Bruce, M1 aBis, Joshua, C1 aFloyd, James, S1 aVasan, Ramachandran, S1 aHeard-Costa, Nancy, L1 aCarson, April, P1 aHall, Michael, E1 aRich, Stephen, S1 aGuo, Xiuqing1 aKazi, Dhruv, S1 ade Ferranti, Sarah, D1 aMoran, Andrew, E uhttps://chs-nhlbi.org/node/938802320nas a2200397 4500008004100000245009900041210006900140260000800209300001300217490000600230520121100236100001901447700001301466700002001479700001801499700001401517700002001531700002601551700002101577700002001598700001801618700001801636700001901654700002101673700001901694700002201713700002201735700001401757700002301771700001501794700002101809700001701830700001901847700002001866856003601886 2023 eng d00a{Associations Between Vascular Risk Factor Levels and Cognitive Decline Among Stroke Survivors0 aAssociations Between Vascular Risk Factor Levels and Cognitive D cMay ae23138790 v63 aIncident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain.\ To evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline.\ Individual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023.\ Time-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels.\ The primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.\ .002) but not executive function or memory declines.\ In this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.1 aLevine, D., A.1 aChen, B.1 aGalecki, A., T.1 aGross, A., L.1 ao, E., M.1 aWhitney, R., T.1 aPloutz-Snyder, R., J.1 aGiordani, B., J.1 aSussman, J., B.1 aBurke, J., F.1 aLazar, R., M.1 aHoward, V., J.1 aAparicio, H., J.1 aBeiser, A., S.1 aElkind, M., S. V.1 aGottesman, R., F.1 aKoton, S.1 aPendlebury, S., T.1 aSharma, A.1 aSpringer, M., V.1 aSeshadri, S.1 aRomero, J., R.1 aHayward, R., A. uhttps://chs-nhlbi.org/node/938102760nas a2200265 4500008004100000022001400041245008600055210006900141260001600210520197300226100001702199700002102216700001902237700002002256700002002276700002402296700001702320700002002337700001902357700002002376700002402396700001802420700002002438856003602458 2023 eng d a2641-765000aCardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study.0 aCardiac Mechanics and Kidney Function Decline in the Cardiovascu c2023 Mar 083 aBACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown.
METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e'). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30% decline in eGFR over 7 years.
RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e' were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30% decline in eGFR.
CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.
1 aMehta, Rupal1 aBůzková, Petra1 aPatel, Harnish1 aCheng, Jeanette1 aKizer, Jorge, R1 aGottdiener, John, S1 aPsaty, Bruce1 aKhan, Sadiya, S1 aIx, Joachim, H1 aIsakova, Tamara1 aShlipak, Michael, G1 aBansal, Nisha1 aShah, Sanjiv, J uhttps://chs-nhlbi.org/node/932004742nas a2200769 4500008004100000245009400041210006900135260001600204520254400220100002502764700001802789700002402807700002102831700002402852700001802876700001602894700002502910700001602935700002202951700001202973700002102985700002003006700002003026700002403046700001903070700002003089700002003109700002103129700002003150700002003170700001603190700001903206700001903225700002303244700002003267700002703287700002603314700002303340700002203363700001903385700001903404700002103423700002403444700002403468700001803492700002103510700002103531700002303552700002103575700001903596700002103615700002003636700001703656700002403673700002203697700001903719700002003738700002503758700001203783700002903795700002403824700002303848700002203871700002203893700002103915856003603936 2023 eng d00aCarriers of rare damaging genetic variants are at lower risk of atherosclerotic disease.0 aCarriers of rare damaging genetic variants are at lower risk of c2023 Aug 163 aBACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.
METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.
RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95%CI: 0.39-0.96; OR : 0.64 95%CI: 0.34-1.19; OR : 0.64 95%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.
CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.
1 aGeorgakis, Marios, K1 aMalik, Rainer1 aHasbani, Natalie, R1 aShakt, Gabrielle1 aMorrison, Alanna, C1 aTsao, Noah, L1 aJudy, Renae1 aMitchell, Braxton, D1 aXu, Huichun1 aMontasser, May, E1 aDo, Ron1 aKenny, Eimear, E1 aLoos, Ruth, J F1 aTerry, James, G1 aCarr, John, Jeffrey1 aBis, Joshua, C1 aPsaty, Bruce, M1 aLongstreth, W T1 aYoung, Kendra, A1 aLutz, Sharon, M1 aCho, Michael, H1 aBroome, Jai1 aKhan, Alyna, T1 aWang, Fei, Fei1 aHeard-Costa, Nancy1 aSeshadri, Sudha1 aVasan, Ramachandran, S1 aPalmer, Nicholette, D1 aFreedman, Barry, I1 aBowden, Donald, W1 aYanek, Lisa, R1 aKral, Brian, G1 aBecker, Lewis, C1 aPeyser, Patricia, A1 aBielak, Lawrence, F1 aAmmous, Farah1 aCarson, April, P1 aHall, Michael, E1 aRaffield, Laura, M1 aRich, Stephen, S1 aPost, Wendy, S1 aTracy, Russel, P1 aTaylor, Kent, D1 aGuo, Xiuqing1 aMahaney, Michael, C1 aCurran, Joanne, E1 aBlangero, John1 aClarke, Shoa, L1 aHaessler, Jeffrey, W1 aHu, Yao1 aAssimes, Themistocles, L1 aKooperberg, Charles1 aDamrauer, Scott, M1 aRotter, Jerome, I1 ade Vries, Paul, S1 aDichgans, Martin uhttps://chs-nhlbi.org/node/947902516nas a2200325 4500008004100000022001400041245014100055210006900196260001300265300000900278490000600287520149900293653001801792653003101810653002401841653002201865653002801887653002301915100001901938700002301957700002101980700002002001700002002021700002402041700002202065700002002087700002402107700002302131856003602154 2023 eng d a2398-923800aCirculating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.0 aCirculating differentiated and senescent lymphocyte subsets and c2023 Jan ae3840 v63 aINTRODUCTION: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain.
METHODS: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA ), memory (CD45RO ), senescent (CD28 ), and T effector memory RA (TEMRA) (CD28 CD57 CD45RA ) CD4 and CD8 T cells, and memory B cells (CD19 CD27 ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4 and CD8 subsets with incident DM risk.
RESULTS: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4 , CD8 or CD19 cell phenotypes with incident DM.
CONCLUSIONS: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults.
10aCD28 Antigens10aCD8-Positive T-Lymphocytes10aCellular Senescence10aDiabetes Mellitus10aLeukocytes, Mononuclear10aLymphocyte Subsets1 aOlson, Nels, C1 aDoyle, Margaret, F1 aBůzková, Petra1 aHuber, Sally, A1 ade Boer, Ian, H1 aSitlani, Colleen, M1 aTracy, Russell, P1 aPsaty, Bruce, M1 aMukamal, Kenneth, J1 aDelaney, Joseph, A uhttps://chs-nhlbi.org/node/924002575nas a2200253 4500008004100000022001400041245014800055210006900203260001600272520175400288100002002042700001802062700001602080700002002096700002202116700001602138700002202154700002302176700002002199700002002219700002202239700002402261856003602285 2023 eng d a1758-535X00aCirculating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders.0 aCirculating Growth Differentiation Factors 11 and 8 Their Antago c2023 Aug 253 aBACKGROUND: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8.
METHODS: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and follistatin-like (FSTL)-3 by immunoassay, in two longitudinal cohorts of older adults.
RESULTS: In 2,599 participants (age 75.2±4.3) followed for 10.8±5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks and lower kidney function.
CONCLUSIONS: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-βsuperfamily pathways as potential therapeutic targets.
1 aKizer, Jorge, R1 aPatel, Sheena1 aGanz, Peter1 aNewman, Anne, B1 aBhasin, Shalender1 aLee, Se-Jin1 aCawthon, Peggy, M1 aLeBrasseur, Nathan1 aShah, Sanjiv, J1 aPsaty, Bruce, M1 aTracy, Russell, P1 aCummings, Steven, R uhttps://chs-nhlbi.org/node/948102761nas a2200241 4500008004100000022001400041245009800055210006900153260001600222520200500238100002902243700001802272700002102290700002502311700002402336700001902360700001902379700001902398700001702417700002402434700002502458856003602483 2023 eng d a1875-890800aCirculating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults.0 aCirculating Omega3 and Omega6 Fatty Acids Cognitive Decline and c2023 Aug 233 aBACKGROUND: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown.
OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study.
METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes.
RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA.
CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.
1 aOtto, Marcia, C de Olive1 aH Y Wu, Jason1 aThacker, Evan, L1 aLai, Heidi, Tsz Mung1 aLemaitre, Rozenn, N1 aPadhye, Nikhil1 aSong, Xiaoling1 aKing, Irena, B1 aLopez, Oscar1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/947702645nas a2200481 4500008004100000022001400041245008100055210006900136260001300205300001400218490000700232520126700239100001701506700001901523700001301542700001501555700002101570700001601591700001301607700002501620700001701645700001901662700001601681700001801697700002301715700001901738700002001757700002701777700002001804700002301824700002001847700002601867700002201893700002001915700001901935700001601954700002001970700002501990700002302015700002402038710006502062856003602127 2023 eng d a1546-170X00aClonal hematopoiesis is associated with protection from Alzheimer's disease.0 aClonal hematopoiesis is associated with protection from Alzheime c2023 Jul a1662-16700 v293 aClonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.
1 aBouzid, Hind1 aBelk, Julia, A1 aJan, Max1 aQi, Yanyan1 aSarnowski, Chloe1 aWirth, Sara1 aMa, Lisa1 aChrostek, Matthew, R1 aAhmad, Herra1 aNachun, Daniel1 aYao, Winnie1 aBeiser, Alexa1 aBick, Alexander, G1 aBis, Joshua, C1 aFornage, Myriam1 aLongstreth, William, T1 aLopez, Oscar, L1 aNatarajan, Pradeep1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aWeinstock, Joshua1 aLarson, Eric, B1 aCrane, Paul, K1 aKeene, Dirk1 aSeshadri, Sudha1 aSatpathy, Ansuman, T1 aMontine, Thomas, J1 aJaiswal, Siddhartha1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/941103429nas a2200505 4500008004100000022001400041245009400055210006900149260001600218520189000234100002302124700002202147700002102169700002402190700002602214700002302240700002002263700002102283700001902304700001902323700002502342700001902367700002202386700001702408700002002425700002102445700001502466700002302481700002002504700002102524700002002545700001902565700002102584700001502605700002102620700002702641700002002668700002002688700002402708700002202732700001702754700002102771710009502792856003602887 2023 eng d a1935-554800aClonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.0 aClonal Hematopoiesis of Indeterminate Potential CHIP and Inciden c2023 Sep 273 aOBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.
RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis.
RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI = 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI = 1.05, 2.08) and ASXL1 (HR 1.76; CI = 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI = 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses.
CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.
1 aTobias, Deirdre, K1 aManning, Alisa, K1 aWessel, Jennifer1 aRaghavan, Sridharan1 aWesterman, Kenneth, E1 aBick, Alexander, G1 aDiCorpo, Daniel1 aWhitsel, Eric, A1 aCollins, Jason1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aDupuis, Josée1 aGoodarzi, Mark, O1 aGuo, Xiuqing1 aHoward, Barbara1 aLange, Leslie, A1 aLiu, Simin1 aRaffield, Laura, M1 aReiner, Alex, P1 aRich, Stephen, S1 aTaylor, Kent, D1 aTinker, Lesley1 aWilson, James, G1 aWu, Peitao1 aCarson, April, P1 aVasan, Ramachandran, S1 aFornage, Myriam1 aPsaty, Bruce, M1 aKooperberg, Charles1 aRotter, Jerome, I1 aMeigs, James1 aManson, JoAnn, E1 aTOPMed Diabetes Working Group; National Heart, Lung, and Blood Institute TOPMed Consortium uhttps://chs-nhlbi.org/node/950603349nas a2200433 4500008004100000245009200041210006900133260001600202520208100218100002502299700003002324700002202354700002202376700002002398700001602418700002302434700002002457700001702477700001602494700001702510700001502527700001702542700002102559700001902580700002302599700002002622700002202642700001902664700001902683700001802702700002802720700002102748700001802769700002502787700002102812700002302833700002302856856003602879 2023 eng d00aClonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.0 aClonal Hematopoiesis of Indeterminate Potential is Associated wi c2023 May 173 aAge is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as and and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non- CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in -CHIP mice. Kidney macrophage infiltration was markedly increased in -CHIP mice and -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.
1 aVlasschaert, Caitlyn1 aRobinson-Cohen, Cassianne1 aKestenbaum, Bryan1 aSilver, Samuel, A1 aChen, Jian-Chun1 aAkwo, Elvis1 aBhatraju, Pavan, K1 aZhang, Ming-Zhi1 aCao, Shirong1 aJiang, Ming1 aWang, Yinqiu1 aNiu, Aolei1 aSiew, Edward1 aKramer, Holly, J1 aKöttgen, Anna1 aFranceschini, Nora1 aPsaty, Bruce, M1 aTracy, Russell, P1 aAlonso, Alvaro1 aArking, Dan, E1 aCoresh, Josef1 aBallantyne, Christie, M1 aBoerwinkle, Eric1 aGrams, Morgan1 aLanktree, Matthew, B1 aRauh, Michael, J1 aHarris, Raymond, C1 aBick, Alexander, G uhttps://chs-nhlbi.org/node/938604434nas a2200361 4500008004100000022001400041245008300055210006900138260001600207300001300223490000600236520343700242653000903679653002203688653002203710653001403732653001903746653001103765653003103776653001103807653000903818653001703827100002303844700002203867700002703889700001403916700002503930700002003955700002203975700001703997700002204014856003604036 2023 eng d a2574-380500aCogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk.0 aCogDrisk ANUADRI CAIDE and LIBRA Risk Scores for Estimating Deme c2023 Aug 01 ae23314600 v63 aIMPORTANCE: While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited.
OBJECTIVE: To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI).
DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023.
MAIN OUTCOMES AND MEASURES: Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk.
RESULTS: Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar.
CONCLUSIONS AND RELEVANCE: CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.
10aAged10aAged, 80 and over10aAlzheimer Disease10aAustralia10aCohort Studies10aFemale10aHeart Disease Risk Factors10aHumans10aMale10aRisk Factors1 aHuque, Md, Hamidul1 aKootar, Scherazad1 aEramudugolla, Ranmalee1 aHan, Duke1 aCarlson, Michelle, C1 aLopez, Oscar, L1 aBennett, David, A1 aPeters, Ruth1 aAnstey, Kaarin, J uhttps://chs-nhlbi.org/node/948006165nas a2200505 4500008004100000245012200041210006900163260001600232520464400248100003304892700002104925700001904946700001704965700002204982700001705004700001905021700001605040700001605056700002605072700002605098700001905124700002305143700002105166700002305187700002105210700002005231700002205251700001705273700002005290700002405310700002205334700002005356700002805376700002705404700002405431700001705455700002405472700002005496700002205516700002005538700002005558700002205578700002305600856003605623 2023 eng d00aComplexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.0 aComplexities of cerebral small vessel disease blood pressure and c2023 Aug 133 aIMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.
OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.
DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.
EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.
MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.
RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.
CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.
KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.
1 aSargurupremraj, Muralidharan1 aSoumaré, Aïcha1 aBis, Joshua, C1 aSurakka, Ida1 aJürgenson, Tuuli1 aJoly, Pierre1 aKnol, Maria, J1 aWang, Ruiqi1 aYang, Qiong1 aSatizabal, Claudia, L1 aGudjonsson, Alexander1 aMishra, Aniket1 aBouteloup, Vincent1 aPhuah, Chia-Ling1 aDuijn, Cornelia, M1 aCruchaga, Carlos1 aDufouil, Carole1 aChene, Geneviève1 aLopez, Oscar1 aPsaty, Bruce, M1 aTzourio, Christophe1 aAmouyel, Philippe1 aAdams, Hieab, H1 aJacqmin-Gadda, Hélène1 aIkram, Mohammad, Arfan1 aGudnason, Vilmundur1 aMilani, Lili1 aWinsvold, Bendik, S1 aHveem, Kristian1 aMatthews, Paul, M1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/950502868nas a2200625 4500008004100000245005900041210005800100260001600158520116400174100001801338700001901356700002001375700002501395700002301420700002501443700002101468700002101489700001801510700002001528700001401548700002101562700002101583700002001604700001901624700002001643700001901663700001701682700002401699700002001723700001501743700001601758700001701774700002001791700002001811700001901831700001801850700001601868700002301884700001801907700002301925700002101948700002201969700001701991700001502008700001802023700002302041700001802064700001702082700001802099700001702117700002402134700002502158700002302183856003602206 2023 eng d00aDeterminants of mosaic chromosomal alteration fitness.0 aDeterminants of mosaic chromosomal alteration fitness c2023 Oct 213 aClonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.
1 aPershad, Yash1 aMack, Taralynn1 aPoisner, Hannah1 aJakubek, Yasminka, A1 aStilp, Adrienne, M1 aMitchell, Braxton, D1 aLewis, Joshua, P1 aBoerwinkle, Eric1 aLoos, Ruth, J1 aChami, Nathalie1 aWang, Zhe1 aBarnes, Kathleen1 aPankratz, Nathan1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aBis, Joshua, C1 aShojaie, Ali1 aSilverman, Edwin, K1 aCho, Michael, H1 aYun, Jeong1 aDeMeo, Dawn1 aLevy, Daniel1 aJohnson, Andrew1 aMathias, Rasika1 aTaub, Margaret1 aArnett, Donna1 aNorth, Kari1 aRaffield, Laura, M1 aCarson, April1 aDoyle, Margaret, F1 aRich, Stephen, S1 aRotter, Jerome, I1 aGuo, Xiuqing1 aCox, Nancy1 aRoden, Dan, M1 aFranceschini, Nora1 aDesai, Pinkal1 aReiner, Alex1 aAuer, Paul, L1 aScheet, Paul1 aJaiswal, Siddhartha1 aWeinstock, Joshua, S1 aBick, Alexander, G uhttps://chs-nhlbi.org/node/958802946nas a2200397 4500008004100000022001400041245009900055210006900154260001600223300001400239490000700253520183100260653003102091653002002122653001502142653001102157653001802168653001102186653002502197653001402222653001802236100001702254700001702271700001802288700002002306700001902326700002002345700002402365700001702389700002002406700002002426700002402446700002202470700002002492856003602512 2023 eng d a1558-359700aEffect of 2022 ACC/AHA/HFSA Criteria on Stages of Heart Failure in a Pooled Community Cohort.0 aEffect of 2022 ACCAHAHFSA Criteria on Stages of Heart Failure in c2023 Jun 13 a2231-22420 v813 aBACKGROUND: The 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) clinical practice guideline proposed an updated definition for heart failure (HF) stages.
OBJECTIVES: This study aimed to compare prevalence and prognosis of HF stages according to classification/definition originally described in 2013 and 2022 ACC/AHA/HFSA definitions.
METHODS: Study participants from 3 longitudinal cohorts (the MESA [Multi-Ethnic Study of Atherosclerosis], CHS [Cardiovascular Health Study], and the FHS [Framingham Heart Study]), were categorized into 4 HF stages according to the 2013 and 2022 criteria. Cox proportional hazards regression was used to assess predictors of progression to symptomatic HF and adverse clinical outcomes associated with each HF stage.
RESULTS: Among 11,618 study participants, according to the 2022 staging, 1,943 (16.7%) were healthy, 4,348 (37.4%) were in stage A (at risk), 5,019 (43.2%) were in stage B (pre-HF), and 308 (2.7%) were in stage C/D (symptomatic HF). Compared to the classification/definition originally described in 2013, the 2022 ACC/AHA/HFSA approach resulted in a higher proportion of individuals with stage B HF (increase from 15.9% to 43.2%); this shift disproportionately involved women as well as Hispanic and Black individuals. Despite the 2022 criteria designating a greater proportion of individuals as stage B, the relative risk of progression to symptomatic HF remained similar (HR: 10.61; 95% CI: 9.00-12.51; P < 0.001).
CONCLUSIONS: New standards for HF staging resulted in a substantial shift of community-based individuals from stage A to stage B. Those with stage B HF in the new system were at high risk for progression to symptomatic HF.
10aAmerican Heart Association10aAtherosclerosis10aCardiology10aFemale10aHeart Failure10aHumans10aLongitudinal Studies10aPrognosis10aUnited States1 aMohebi, Reza1 aWang, Dongyu1 aLau, Emily, S1 aParekh, Juhi, K1 aAllen, Norrina1 aPsaty, Bruce, M1 aBenjamin, Emelia, J1 aLevy, Daniel1 aWang, Thomas, J1 aShah, Sanjiv, J1 aGottdiener, John, S1 aJanuzzi, James, L1 aHo, Jennifer, E uhttps://chs-nhlbi.org/node/938202812nas a2200325 4500008004100000022001400041245014100055210006900196260001600265300001200281490000700293520182800300653000902128653001002137653002802147653001802175653001102193653001402204653001802218100002202236700002502258700001902283700002002302700002202322700002302344700003102367700002802398700002402426856003602450 2023 eng d a2047-998000aElevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS.0 aElevated Plasma Levels of Ketone Bodies Are Associated With AllC c2023 Sep 05 ae0299600 v123 aBackground Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0-1.9]; =0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95% CI, 1.0-1.3]; =0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 [95% CI, 1.1-2.7]; =0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.
10aAged10aAging10aCardiovascular Diseases10aHeart Failure10aHumans10aIncidence10aKetone Bodies1 aNiezen, Sebastian1 aConnelly, Margery, A1 aHirsch, Calvin1 aKizer, Jorge, R1 aBenitez, Maria, E1 aMinchenberg, Scott1 aPerez-Matos, Maria, Camila1 aJiang, Zhenghui, Gordon1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/948503124nas a2200769 4500008004100000022001400041245010100055210006900156260001600225300000900241490000700250520097600257653001901233653001401252653001101266653003801277653003401315653001101349653000901360653003101369653002201400653001701422100002501439700002401464700001901488700002001507700002101527700001901548700002201567700002501589700001801614700001801632700001701650700001901667700001801686700002001704700001301724700001801737700002301755700002301778700001301801700001501814700003201829700002101861700001801882700002201900700001401922700001601936700002701952700002401979700002002003700002402023700001902047700002002066700002102086700002102107700002102128700002202149700001902171700002502190700002302215700001702238700002202255700002402277700001702301856003602318 2023 eng d a2041-172300aEvaluating the use of blood pressure polygenic risk scores across race/ethnic background groups.0 aEvaluating the use of blood pressure polygenic risk scores acros c2023 Jun 02 a32020 v143 aWe assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.
10aBlood Pressure10aEthnicity10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMultifactorial Inheritance10aPopulation Health10aRisk Factors1 aKurniansyah, Nuzulul1 aGoodman, Matthew, O1 aKhan, Alyna, T1 aWang, Jiongming1 aFeofanova, Elena1 aBis, Joshua, C1 aWiggins, Kerri, L1 aHuffman, Jennifer, E1 aKelly, Tanika1 aElfassy, Tali1 aGuo, Xiuqing1 aPalmas, Walter1 aLin, Henry, J1 aHwang, Shih-Jen1 aGao, Yan1 aYoung, Kendra1 aKinney, Gregory, L1 aSmith, Jennifer, A1 aYu, Bing1 aLiu, Simin1 aWassertheil-Smoller, Sylvia1 aManson, JoAnn, E1 aZhu, Xiaofeng1 aChen, Yii-Der Ida1 aLee, I-Te1 aGu, Charles1 aLloyd-Jones, Donald, M1 aZöllner, Sebastian1 aFornage, Myriam1 aKooperberg, Charles1 aCorrea, Adolfo1 aPsaty, Bruce, M1 aArnett, Donna, K1 aIsasi, Carmen, R1 aRich, Stephen, S1 aKaplan, Robert, C1 aRedline, Susan1 aMitchell, Braxton, D1 aFranceschini, Nora1 aLevy, Daniel1 aRotter, Jerome, I1 aMorrison, Alanna, C1 aSofer, Tamar uhttps://chs-nhlbi.org/node/937902580nas a2200229 4500008004100000022001400041245019900055210006900254260001600323520178300339100002002122700001802142700001702160700001602177700002202193700001902215700002302234700002102257700001602278700002002294856003602314 2023 eng d a1758-535X00aEvaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8 and their Binding Proteins Follistatin and Follistatin-like protein-3 with Dementia and Cognition.0 aEvaluation of Associations of Growth Differentiation Factor11 Gr c2023 Jan 203 aBACKGROUND: Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models.
METHODS: We assessed Growth Differentiation Factor (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in in the Cardiovascular Health Study (N=1506) and the Health ABC study (N=1237). CLL-11 and Beta 2 microglobulin (B2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only) and incident dementia using correlations, linear regression and Cox proportional hazards models.
RESULTS: In CHS, levels of GDF-11, GDF-8 and follistatin were not correlated cross sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities and atrophy on MRI as well as with incident dementia with an adjusted HR of 1.72 (95% CI=1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95%CI 1.07, 2.10) per doubling of GDF-8.
CONCLUSIONS: Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicates TGF-B superfamily inhibition in the pathogenesis of dementia.
1 aNewman, Anne, B1 aPatel, Sheena1 aKizer, Jorge1 aLee, Se-Jin1 aBhasin, Shalinder1 aCawthon, Peggy1 aLeBrasseur, Nathan1 aTracy, Russel, P1 aGanz, Peter1 aCummings, Steve uhttps://chs-nhlbi.org/node/929008759nas a2202509 4500008004100000022001400041245012000055210006900175260000900244300001200253490000700265520183300272100002602105700002402131700002202155700002002177700002302197700001802220700002402238700002102262700001802283700002302301700002002324700002402344700002002368700002002388700002202408700002102430700001702451700002502468700002102493700001802514700001502532700001702547700002202564700002102586700002302607700002102630700002502651700002002676700002402696700002002720700002102740700002002761700002302781700001702804700002202821700002302843700002302866700001502889700002302904700002102927700001402948700001802962700002102980700002203001700001603023700002803039700001903067700001903086700002103105700001903126700002303145700001703168700002303185700002203208700002703230700001803257700001803275700001803293700001703311700001903328700001803347700001603365700001903381700002503400700002103425700002303446700002103469700002103490700002203511700001803533700002203551700001303573700003303586700002403619700001803643700002303661700002103684700002203705700001203727700002103739700002103760700002003781700002403801700002503825700002103850700001603871700002103887700002003908700002003928700001803948700001703966700002003983700002104003700002004024700002304044700002804067700001904095700002204114700002304136700002004159700001504179700001704194700001704211700001804228700002404246700002304270700002204293700002104315700002004336700002704356700002604383700002604409700002604435700001804461700002004479700001904499700002304518700001804541700001904559700002104578700002804599700002504627700001704652700002004669700001604689700002304705700001904728700002404747700001904771700002004790700002104810700002804831700002204859700002604881700001804907700001804925700002004943700001504963700001304978700001704991700001905008700001405027700002105041700002305062700002205085700002305107700001805130700001905148700001605167700002005183700002205203700002205225700001905247700001905266700001905285700001905304700002205323700002705345700001905372700001905391700002005410700002205430700002005452700002405472700001505496700001905511700002605530700001905556700002405575700001705599700001505616700001805631700002105649700002305670700002205693700001805715700002405733700002205757700002305779700002405802700002705826700002905853700002405882700002505906700002005931700001605951700001705967700002005984700002006004700002306024700002006047700002106067700002006088700002106108700001806129700002406147700002206171700002006193856003606213 2023 eng d a1664-802100aGene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.0 aGeneeducational attainment interactions in a multipopulation gen c2023 a12353370 v143 a Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.
1 aFuentes, Lisa, de Las1 aSchwander, Karen, L1 aBrown, Michael, R1 aBentley, Amy, R1 aWinkler, Thomas, W1 aSung, Yun, Ju1 aMunroe, Patricia, B1 aMiller, Clint, L1 aAschard, Hugo1 aAslibekyan, Stella1 aBartz, Traci, M1 aBielak, Lawrence, F1 aChai, Jin, Fang1 aCheng, Ching-Yu1 aDorajoo, Rajkumar1 aFeitosa, Mary, F1 aGuo, Xiuqing1 aHartwig, Fernando, P1 aHorimoto, Andrea1 aKolcic, Ivana1 aLim, Elise1 aLiu, Yongmei1 aManning, Alisa, K1 aMarten, Jonathan1 aMusani, Solomon, K1 aNoordam, Raymond1 aPadmanabhan, Sandosh1 aRankinen, Tuomo1 aRichard, Melissa, A1 aRidker, Paul, M1 aSmith, Albert, V1 aVojinovic, Dina1 aZonderman, Alan, B1 aAlver, Maris1 aBoissel, Mathilde1 aChristensen, Kaare1 aFreedman, Barry, I1 aGao, Chuan1 aGiulianini, Franco1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLi, Xiaoyin1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRobino, Antonietta1 aSofer, Tamar1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVerweij, Niek1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhan, Yiqiang1 aAmin, Najaf1 aArking, Dan, E1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aChai, Xiaoran1 aChen, Yii-Der Ida1 aChen, Xu1 aChitrala, Kumaraswamy, Naidu1 aConcas, Maria, Pina1 ade Faire, Ulf1 ade Mutsert, Renée1 ade Silva, Janaka1 ade Vries, Paul, S1 aDo, Ahn1 aFaul, Jessica, D1 aFisher, Virginia1 aFloyd, James, S1 aForrester, Terrence1 aFriedlander, Yechiel1 aGirotto, Giorgia1 aGu, Charles1 aHallmans, Göran1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHomuth, Georg1 aHunt, Steven1 aIkram, Arfan, M1 aJacobs, David, R1 aKavousi, Maryam1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aLangefeld, Carl, D1 aLiang, Jingjing1 aLiu, Kiang1 aLiu, Jianjun1 aLohman, Kurt1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMilaneschi, Yuri1 aNauck, Matthias1 aNelson, Christopher, P1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPereira, Alexandre, C1 aPerls, Thomas1 aPeters, Annette1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRice, Kenneth1 aRice, Treva, K1 aRich, Stephen, S1 aSabanayagam, Charumathi1 aSchreiner, Pamela, J1 aShu, Xiao-Ou1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aStarr, John, M1 aStrauch, Konstantin1 aTai, Shyong, E1 aTaylor, Kent, D1 aTsai, Michael, Y1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Ya-Xing1 aBin Wei, Wen-1 aWilson, Gregory1 aXuan, Deng1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aBecker, Diane, M1 aBonnefond, Amélie1 aBowden, Donald, W1 aCooper, Richard, S1 aDeary, Ian, J1 aDivers, Jasmin1 aEsko, Tõnu1 aFranks, Paul, W1 aFroguel, Philippe1 aGieger, Christian1 aJonas, Jost, B1 aKato, Norihiro1 aLakka, Timo, A1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aNorth, Kari, E1 aNtalla, Ioanna1 aPenninx, Brenda1 aSamani, Nilesh, J1 aSnieder, Harold1 aSpedicati, Beatrice1 aHarst, Pim1 aVölzke, Henry1 aWagenknecht, Lynne, E1 aWeir, David, R1 aWojczynski, Mary, K1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aBouchard, Claude1 aChasman, Daniel, I1 aEvans, Michele, K1 aFox, Ervin, R1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aKrieger, Jose, Eduardo1 aMook-Kanamori, Dennis, O1 aPeyser, Patricia, A1 aProvince, Michael, M1 aPsaty, Bruce, M1 aRudan, Igor1 aSim, Xueling1 aSmith, Blair, H1 avan Dam, Rob, M1 aDuijn, Cornelia, M1 aWong, Tien, Yin1 aArnett, Donna, K1 aRao, Dabeeru, C1 aGauderman, James1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aRotter, Jerome, I1 aFornage, Myriam uhttps://chs-nhlbi.org/node/953505138nas a2201357 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2023 eng d a2041-172300aGenetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.0 aGenetic architecture of spatial electrical biomarkers for cardia c2023 Mar 14 a14110 v143 aThe 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
10aArrhythmias, Cardiac10aAtrioventricular Block10aBiomarkers10aCardiovascular Diseases10aElectrocardiography10aGenome-Wide Association Study10aHumans10aRisk Factors1 aYoung, William, J1 aHaessler, Jeffrey1 aBenjamins, Jan-Walter1 aRepetto, Linda1 aYao, Jie1 aIsaacs, Aaron1 aHarper, Andrew, R1 aRamirez, Julia1 aGarnier, Sophie1 aVan Duijvenboden, Stefan1 aBaldassari, Antoine, R1 aConcas, Maria, Pina1 aDuong, ThuyVy1 aFoco, Luisa1 aIsaksen, Jonas, L1 aMei, Hao1 aNoordam, Raymond1 aNursyifa, Casia1 aRichmond, Anne1 aSantolalla, Meddly, L1 aSitlani, Colleen, M1 aSoroush, Negin1 aThériault, Sébastien1 aTrompet, Stella1 aAeschbacher, Stefanie1 aAhmadizar, Fariba1 aAlonso, Alvaro1 aBrody, Jennifer, A1 aCampbell, Archie1 aCorrea, Adolfo1 aDarbar, Dawood1 aDe Luca, Antonio1 aDeleuze, Jean-Francois1 aEllervik, Christina1 aFuchsberger, Christian1 aGoel, Anuj1 aGrace, Christopher1 aGuo, Xiuqing1 aHansen, Torben1 aHeckbert, Susan, R1 aJackson, Rebecca, D1 aKors, Jan, A1 aLima-Costa, Maria, Fernanda1 aLinneberg, Allan1 aMacfarlane, Peter, W1 aMorrison, Alanna, C1 aNavarro, Pau1 aPorteous, David, J1 aPramstaller, Peter, P1 aReiner, Alexander, P1 aRisch, Lorenz1 aSchotten, Ulrich1 aShen, Xia1 aSinagra, Gianfranco1 aSoliman, Elsayed, Z1 aStoll, Monika1 aTarazona-Santos, Eduardo1 aTinker, Andrew1 aTrajanoska, Katerina1 aVillard, Eric1 aWarren, Helen, R1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aArking, Dan, E1 aAvery, Christy, L1 aConen, David1 aGirotto, Giorgia1 aGrarup, Niels1 aHayward, Caroline1 aJukema, Wouter1 aMook-Kanamori, Dennis, O1 aOlesen, Morten, Salling1 aPadmanabhan, Sandosh1 aPsaty, Bruce, M1 aPattaro, Cristian1 aRibeiro, Antonio, Luiz P1 aRotter, Jerome, I1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aWilson, James, G1 aOrini, Michele1 aCharron, Philippe1 aWatkins, Hugh1 aKooperberg, Charles1 aLin, Henry, J1 aWilson, James, F1 aKanters, Jørgen, K1 aSotoodehnia, Nona1 aMifsud, Borbala1 aLambiase, Pier, D1 aTereshchenko, Larisa, G1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/932202705nas a2200505 4500008004100000245011300041210006900154260001600223520116400239100001801403700001801421700002101439700002001460700001901480700002301499700002101522700002001543700002001563700001801583700001901601700002001620700001801640700001901658700002301677700002401700700001701724700002001741700002301761700002501784700001701809700002701826700002101853700002201874700002201896700002101918700002401939700002101963700002601984700002202010700002402032700001902056700002302075710006502098856003602163 2023 eng d00aGenetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants.0 aGenetic control of mRNA splicing as a potential mechanism for in c2023 Jan 313 aExonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.
1 aEinson, Jonah1 aGlinos, Dafni1 aBoerwinkle, Eric1 aCastaldi, Peter1 aDarbar, Dawood1 ade Andrade, Mariza1 aEllinor, Patrick1 aFornage, Myriam1 aGabriel, Stacey1 aGermer, Soren1 aGibbs, Richard1 aHersh, Craig, P1 aJohnsen, Jill1 aKaplan, Robert1 aKonkle, Barbara, A1 aKooperberg, Charles1 aNassir, Rami1 aLoos, Ruth, J F1 aMeyers, Deborah, A1 aMitchell, Braxton, D1 aPsaty, Bruce1 aVasan, Ramachandran, S1 aRich, Stephen, S1 aRienstra, Michael1 aRotter, Jerome, I1 aSaferali, Aabida1 aShoemaker, Benjamin1 aSilverman, Edwin1 aSmith, Albert, Vernon1 aMohammadi, Pejman1 aCastel, Stephane, E1 aIossifov, Ivan1 aLappalainen, Tuuli1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/928604639nas a2201273 4500008004100000022001400041245008500055210006900140260001600209300001300225490000600238520107000244653002301314653001801337653001101355653001601366653001301382653002301395653001401418100002501432700002301457700001901480700002001499700001701519700002301536700002601559700002101585700002101606700002401627700002001651700002101671700002001692700002001712700001901732700001901751700002401770700001901794700002101813700001801834700002001852700002501872700002001897700001901917700002301936700002401959700001801983700001602001700002002017700002202037700001902059700002602078700002302104700002202127700002002149700002702169700002302196700001902219700002102238700001902259700001402278700001902292700002302311700002302334700002202357700002102379700002502400700001902425700001902444700002302463700001302486700002302499700002202522700002102544700002402565700002302589700002102612700002302633700002102656700002802677700002202705700001902727700001902746700001702765700002002782700002302802700001602825700001902841700002202860700001602882700002202898700001802920700002402938700001902962700001502981700002202996700002403018700001803042700002503060700002503085700002103110700001803131700002003149700002303169700002403192700002503216700002303241710006503264856003603329 2023 eng d a2375-254800aThe genetic determinants of recurrent somatic mutations in 43,693 blood genomes.0 agenetic determinants of recurrent somatic mutations in 43693 blo c2023 Apr 28 aeabm49450 v93 aNononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.
10aGerm-Line Mutation10aHematopoiesis10aHumans10aMiddle Aged10aMutation10aMutation, Missense10aPhenotype1 aWeinstock, Joshua, S1 aLaurie, Cecelia, A1 aBroome, Jai, G1 aTaylor, Kent, D1 aGuo, Xiuqing1 aShuldiner, Alan, R1 aO'Connell, Jeffrey, R1 aLewis, Joshua, P1 aBoerwinkle, Eric1 aBarnes, Kathleen, C1 aChami, Nathalie1 aKenny, Eimear, E1 aLoos, Ruth, J F1 aFornage, Myriam1 aRedline, Susan1 aCade, Brian, E1 aGilliland, Frank, D1 aChen, Zhanghua1 aGauderman, James1 aKumar, Rajesh1 aGrammer, Leslie1 aSchleimer, Robert, P1 aPsaty, Bruce, M1 aBis, Joshua, C1 aBrody, Jennifer, A1 aSilverman, Edwin, K1 aYun, Jeong, H1 aQiao, Dandi1 aWeiss, Scott, T1 aLasky-Su, Jessica1 aDeMeo, Dawn, L1 aPalmer, Nicholette, D1 aFreedman, Barry, I1 aBowden, Donald, W1 aCho, Michael, H1 aVasan, Ramachandran, S1 aJohnson, Andrew, D1 aYanek, Lisa, R1 aBecker, Lewis, C1 aKardia, Sharon1 aHe, Jiang1 aKaplan, Robert1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aArnett, Donna, K1 aIrvin, Marguerite, R1 aTiwari, Hemant1 aCorrea, Adolfo1 aRaffield, Laura, M1 aGao, Yan1 ade Andrade, Mariza1 aRotter, Jerome, I1 aRich, Stephen, S1 aManichaikul, Ani, W1 aKonkle, Barbara, A1 aJohnsen, Jill, M1 aWheeler, Marsha, M1 aCuster, Brian, S1 aDuggirala, Ravindranath1 aCurran, Joanne, E1 aBlangero, John1 aGui, Hongsheng1 aXiao, Shujie1 aWilliams, Keoki1 aMeyers, Deborah, A1 aLi, Xingnan1 aOrtega, Victor1 aMcGarvey, Stephen1 aGu, Charles1 aChen, Yii-Der Ida1 aLee, Wen-Jane1 aShoemaker, Benjamin1 aDarbar, Dawood1 aRoden, Dan1 aAlbert, Christine1 aKooperberg, Charles1 aDesai, Pinkal1 aBlackwell, Thomas, W1 aAbecasis, Goncalo, R1 aSmith, Albert, V1 aKang, Hyun, M1 aMathias, Rasika1 aNatarajan, Pradeep1 aJaiswal, Siddhartha1 aReiner, Alexander, P1 aBick, Alexander, G1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/941902334nas a2200349 4500008004100000245016400041210006900205260001600274520124900290100001801539700002001557700001701577700001801594700002001612700002201632700001801654700001701672700002301689700002101712700001801733700001701751700001801768700001701786700002201803700002501825700001801850700001901868700001901887700002101906700002101927856003601948 2023 eng d00aGenome-Wide Association Studies and fine-mapping of genomic loci for n-3 and n-6 Polyunsaturated Fatty Acids in Hispanic American and African American Cohorts.0 aGenomeWide Association Studies and finemapping of genomic loci f c2023 Feb 243 aOmega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of < 5 x 10 , we confirmed association of the signal and found evidence of two additional signals (in and ) within 200 kb of the originally reported signal. Outside of the region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including , , and spanning a > 9 Mb region on chromosome 11 (57.5Mb ~ 67.1Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.
1 aYang, Chaojie1 aVeenstra, Jenna1 aBartz, Traci1 aPahl, Matthew1 aHallmark, Brian1 aChen, Yii-Der Ida1 aWestra, Jason1 aSteffen, Lyn1 aBrown, Christopher1 aSiscovick, David1 aTsai, Michael1 aWood, Alexis1 aRich, Stephen1 aSmith, Caren1 aO'Connor, Timothy1 aMozaffarian, Dariush1 aGrant, Struan1 aChilton, Floyd1 aTintle, Nathan1 aLemaitre, Rozenn1 aManichaikul, Ani uhttps://chs-nhlbi.org/node/946503534nas a2200649 4500008004100000245010900041210006900150260001600219520168900235100002201924700001601946700002001962700002201982700001402004700002202018700001602040700002202056700002402078700002002102700002202122700001702144700002402161700001802185700002102203700002302224700002402247700001902271700002102290700002002311700001902331700002202350700002002372700001902392700002002411700001702431700001902448700001702467700002502484700002402509700001902533700002302552700001902575700002302594700002002617700002102637700001802658700002002676700002202696700002402718700002102742700002002763700001802783700001402801700001702815700001602832856003602848 2023 eng d00aGenome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.0 aGenomeWide Interaction Analysis with DASH Diet Score Identified c2023 Nov 113 aOBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).
METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.
RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1.
CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.
1 aGuirette, Melanie1 aLan, Jessie1 aMcKeown, Nicola1 aBrown, Michael, R1 aChen, Han1 ade Vries, Paul, S1 aKim, Hyunju1 aRebholz, Casey, M1 aMorrison, Alanna, C1 aBartz, Traci, M1 aFretts, Amanda, M1 aGuo, Xiuqing1 aLemaitre, Rozenn, N1 aLiu, Ching-Ti1 aNoordam, Raymond1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aWang, Carol, A1 aBeilin, Lawrence1 aMori, Trevor, A1 aOddy, Wendy, H1 aPennell, Craig, E1 aChai, Jin, Fang1 aWhitton, Clare1 avan Dam, Rob, M1 aLiu, Jianjun1 aTai, Shyong, E1 aSim, Xueling1 aNeuhouser, Marian, L1 aKooperberg, Charles1 aTinker, Lesley1 aFranceschini, Nora1 aHuan, Tianxiao1 aWinkler, Thomas, W1 aBentley, Amy, R1 aGauderman, James1 aHeerkens, Luc1 aTanaka, Toshiko1 avan Rooij, Jeroen1 aMunroe, Patricia, B1 aWarren, Helen, R1 aVoortman, Trudy1 aChen, Honglei1 aRao, D, C1 aLevy, Daniel1 aMa, Jiantao uhttps://chs-nhlbi.org/node/958302305nas a2200805 4500008004100000245012200041210006900163260000800232300000900240490000600249520021700255100001200472700001900484700001300503700001800516700001500534700001200549700001200561700001300573700002100586700001900607700001800626700001900644700002300663700001900686700001400705700001900719700001600738700001400754700002400768700001900792700002200811700002000833700001600853700002400869700001700893700001500910700001600925700001500941700002100956700001700977700001600994700001801010700001601028700002101044700001701065700002101082700001901103700001901122700001501141700001701156700001801173700001201191700001201203700001601215700001901231700001901250700001701269700001101286700002401297700001601321700001601337700001901353700002101372700001901393700001801412700001701430700001601447856003601463 2023 eng d00a{Identification of circulating proteins associated with general cognitive function among middle-aged and older adults0 aIdentification of circulating proteins associated with general c cNov a11170 v63 a2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.1 aTin, A.1 aFohner, A., E.1 aYang, Q.1 aBrody, J., A.1 aDavies, G.1 aYao, J.1 aLiu, D.1 aCaro, I.1 aLindbohm, J., V.1 aDuggan, M., R.1 aMeirelles, O.1 aHarris, S., E.1 aGudmundsdottir, V.1 aTaylor, A., M.1 aHenry, A.1 aBeiser, A., S.1 aShojaie, A.1 aCoors, A.1 aFitzpatrick, A., L.1 aLangenberg, C.1 aSatizabal, C., L.1 aSitlani, C., M.1 aWheeler, E.1 aTucker-Drob, E., M.1 aBressler, J.1 aCoresh, J.1 aBis, J., C.1 aCandia, J.1 aJennings, L., L.1 aPietzner, M.1 aLathrop, M.1 aLopez, O., L.1 aRedmond, P.1 aGerszten, R., E.1 aRich, S., S.1 aHeckbert, S., R.1 aAustin, T., R.1 aHughes, T., M.1 aTanaka, T.1 aEmilsson, V.1 aVasan, R., S.1 aGuo, X.1 aZhu, Y.1 aTzourio, C.1 aRotter, J., I.1 aWalker, K., A.1 aFerrucci, L.1 aki, M.1 aBreteler, M., M. B.1 aCox, S., R.1 aDebette, S.1 aMosley, T., H.1 aGudnason, V., G.1 aLauner, L., J.1 aPsaty, B., M.1 aSeshadri, S.1 aFornage, M. uhttps://chs-nhlbi.org/node/954600800nas a2200277 4500008004100000022001400041245005000055210004900105260001600154300001200170490000700182653003800189653002400227653001600251653001100267653001700278100003100295700002400326700002400350700002000374700002200394700002000416700002700436700002300463856003600486 2023 eng d a2047-998000aInflammation and Incident Conduction Disease.0 aInflammation and Incident Conduction Disease c2023 Jan 03 ae0272470 v1210aCardiac Conduction System Disease10aElectrocardiography10aHeart Block10aHumans10aInflammation1 aFrimodt-Møller, Emilie, K1 aGottdiener, John, S1 aSoliman, Elsayed, Z1 aKizer, Jorge, R1 aVittinghoff, Eric1 aPsaty, Bruce, M1 aBiering-Sørensen, Tor1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/923702821nas a2200289 4500008004100000022001400041245010000055210006900155260001600224520195600240100001602196700002202212700002502234700001802259700002002277700002302297700001802320700002302338700001702361700002002378700002102398700001802419700001802437700001802455700002202473856003602495 2023 eng d a1474-972600aLate-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis.0 aLatelife plasma proteins associated with prevalent and incident c2023 Sep 113 aProteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; p = 1 × 10 , p = 2 × 10 ), transgelin (TAGLN; p = 2 × 10 , p = 6 × 10 ), and insulin-like growth factor-binding protein 2 (IGFBP2; p = 5 × 10 , p = 1 × 10 ) and with a lower level of growth hormone receptor (GHR, p = 3 × 10 , p = 2 × 10 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.
1 aLiu, Fangyu1 aAustin, Thomas, R1 aSchrack, Jennifer, A1 aChen, Jingsha1 aWalston, Jeremy1 aMathias, Rasika, A1 aGrams, Morgan1 aOdden, Michelle, C1 aNewman, Anne1 aPsaty, Bruce, M1 aRamonfaur, Diego1 aShah, Amil, M1 aWindham, Gwen1 aCoresh, Josef1 aWalker, Keenan, A uhttps://chs-nhlbi.org/node/948302451nas a2200205 4500008004100000022001400041245006500055210006400120260001600184520181800200100003102018700002402049700002002073700002202093700002002115700002702135700002402162700002302186856003602209 2023 eng d a1522-964500aLifestyle habits associated with cardiac conduction disease.0 aLifestyle habits associated with cardiac conduction disease c2023 Jan 203 aAIMS: Cardiac conduction disease can lead to syncope, heart failure, and death. The only available therapy is pacemaker implantation, with no established prevention strategies. Research to identify modifiable risk factors has been scant.
METHODS AND RESULTS: Data from the Cardiovascular Health Study, a population-based cohort study of adults ≥ 65 years with annual 12-lead electrocardiograms obtained over 10 years, were utilized to examine relationships between baseline characteristics, including lifestyle habits, and conduction disease. Of 5050 participants (mean age 73 ± 6 years; 52% women), prevalent conduction disease included 257 with first-degree atrioventricular block, 99 with left anterior fascicular block, 9 with left posterior fascicular block, 193 with right bundle branch block (BBB), 76 with left BBB, and 102 with intraventricular block at baseline. After multivariable adjustment, older age, male sex, a larger body mass index, hypertension, and coronary heart disease were associated with a higher prevalence of conduction disease, whereas White race and more physical activity were associated with a lower prevalence. Over a median follow-up on 7 (interquartile range 1-9) years, 1036 developed incident conduction disease. Older age, male sex, a larger BMI, and diabetes were each associated with incident conduction disease. Of lifestyle habits, more physical activity (hazard ratio 0.91, 95% confidence interval 0.84-0.98, P = 0.017) was associated with a reduced risk, while smoking and alcohol did not exhibit a significant association.
CONCLUSION: While some difficult to control comorbidities were associated with conduction disease as expected, a readily modifiable lifestyle factor, physical activity, was associated with a lower risk.
1 aFrimodt-Møller, Emilie, K1 aSoliman, Elsayed, Z1 aKizer, Jorge, R1 aVittinghoff, Eric1 aPsaty, Bruce, M1 aBiering-Sørensen, Tor1 aGottdiener, John, S1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/928801076nas a2200373 4500008004100000245012100041210006900162260000800231520006100239100002000300700001700320700001300337700001600350700001400366700001800380700001100398700001500409700001800424700001900442700001700461700001600478700001400494700001200508700001600520700001400536700001600550700001800566700001800584700001300602700001500615700001500630700002100645856003600666 2023 eng d00aloss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology0 alossoffunction variants Compatible with longevity and associated cJul3 a4 or its protein product as a viable therapeutic option.1 aChemparathy, A.1 aGuen, Y., L.1 aChen, S.1 aLee, E., G.1 aLeong, L.1 aGorzynski, J.1 aXu, G.1 aBelloy, M.1 aKasireddy, N.1 aTauber, A., P.1 aWilliams, K.1 aStewart, I.1 aWingo, T.1 aLah, J.1 aJayadev, S.1 aHales, C.1 aPeskind, E.1 aChild, D., D.1 aKeene, C., D.1 aCong, L.1 aAshley, E.1 aYu, C., E.1 aGreicius, M., D. uhttps://chs-nhlbi.org/node/944702914nas a2200553 4500008004100000245010000041210006900141260001600210520130500226100002001531700001901551700002001570700002501590700002101615700002401636700002101660700002101681700002401702700002001726700002101746700001601767700002401783700001701807700002401824700001701848700002301865700002301888700002201911700001801933700002001951700001601971700002001987700002002007700001902027700001902046700002002065700002402085700002102109700001902130700001802149700002202167700001402189700001502203700001702218700002302235700001702258710004902275856003602324 2023 eng d00aMachine learning models for blood pressure phenotypes combining multiple polygenic risk scores.0 aMachine learning models for blood pressure phenotypes combining c2023 Dec 143 aWe construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1% to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8% to 5.1% (SBP) and 4.7% to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs.
1 aHrytsenko, Yana1 aShea, Benjamin1 aElgart, Michael1 aKurniansyah, Nuzulul1 aLyons, Genevieve1 aMorrison, Alanna, C1 aCarson, April, P1 aHaring, Bernhard1 aMitchel, Braxton, D1 aPsaty, Bruce, M1 aJaeger, Byron, C1 aGu, Charles1 aKooperberg, Charles1 aLevy, Daniel1 aLloyd-Jones, Donald1 aChoi, Eunhee1 aBrody, Jennifer, A1 aSmith, Jennifer, A1 aRotter, Jerome, I1 aMoll, Matthew1 aFornage, Myriam1 aSimon, Noah1 aCastaldi, Peter1 aCasanova, Ramon1 aChung, Ren-Hua1 aKaplan, Robert1 aLoos, Ruth, J F1 aKardia, Sharon, L R1 aRich, Stephen, S1 aRedline, Susan1 aKelly, Tanika1 aO'Connor, Timothy1 aZhao, Wei1 aKim, Wonji1 aGuo, Xiuqing1 aChen, Yii, Der Ida1 aSofer, Tamar1 aTrans-Omics in Precision Medicine Consortium uhttps://chs-nhlbi.org/node/958603311nas a2200829 4500008004100000022001400041245009300055210006900148260001300217300001400230490000700244520101000251653001701261653001801278653003401296653002301330653001101353653001401364653002301378100002501401700001501426700002001441700001701461700002001478700001701498700001801515700002101533700001901554700002101573700002301594700002101617700002301638700001701661700001701678700002401695700001501719700002301734700002001757700001701777700002401794700002101818700002001839700001701859700002601876700002201902700002301924700002501947700002601972700001601998700002102014700002402035700002302059700001702082700002302099700002702122700001902149700002102168700002202189700002402211700002302235700002002258700001902278700002002297700001502317700001202332700001802344700002302362700002502385700001702410700001802427856003602445 2023 eng d a1546-171800aMosaic chromosomal alterations in blood across ancestries using whole-genome sequencing.0 aMosaic chromosomal alterations in blood across ancestries using c2023 Nov a1912-19190 v553 aMegabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.
10aBlack People10aGenome, Human10aGenome-Wide Association Study10aHispanic or Latino10aHumans10aMosaicism10aPrecision Medicine1 aJakubek, Yasminka, A1 aZhou, Ying1 aStilp, Adrienne1 aBacon, Jason1 aWong, Justin, W1 aOzcan, Zuhal1 aArnett, Donna1 aBarnes, Kathleen1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aCarson, April, P1 aChasman, Daniel, I1 aChen, Jiawen1 aCho, Michael1 aConomos, Matthew, P1 aCox, Nancy1 aDoyle, Margaret, F1 aFornage, Myriam1 aGuo, Xiuqing1 aKardia, Sharon, L R1 aLewis, Joshua, P1 aLoos, Ruth, J F1 aMa, Xiaolong1 aMachiela, Mitchell, J1 aMack, Taralynn, M1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aMychaleckyj, Josyf, C1 aNorth, Kari1 aPankratz, Nathan1 aPeyser, Patricia, A1 aPreuss, Michael, H1 aPsaty, Bruce1 aRaffield, Laura, M1 aVasan, Ramachandran, S1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSilverman, Edwin, K1 aSmith, Jennifer, A1 aSmith, Aaron, P1 aTaub, Margaret1 aTaylor, Kent, D1 aYun, Jeong1 aLi, Yun1 aDesai, Pinkal1 aBick, Alexander, G1 aReiner, Alexander, P1 aScheet, Paul1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/953804607nas a2201201 4500008004100000022001400041245012100055210006900176260001300245300001400258490000700272520112800279100002001407700001901427700002101446700003201467700001601499700001501515700002301530700002801553700002001581700001701601700002401618700002201642700002201664700002101686700001801707700002801725700001701753700001701770700002001787700002001807700002801827700002001855700002101875700002801896700002401924700001701948700001901965700002101984700002002005700002302025700002102048700001702069700002402086700002402110700002202134700001902156700002302175700002202198700001902220700003302239700001802272700002202290700002302312700002002335700002002355700002602375700002102401700002902422700001702451700002102468700002102489700002002510700002902530700002102559700001602580700001802596700002502614700003002639700002202669700002702691700002002718700002302738700002402761700002402785700002202809700002002831700001802851700002102869700002002890700002102910700002202931700002302953700002302976700002002999700002003019700002803039700002303067700001903090700002303109700002003132700001903152700002203171700002803193700003003221700002403251700002403275700002103299700002803320700002103348856003603369 2023 eng d a1546-171800aMulti-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.0 aMultiancestry genomewide study identifies effector genes and dru c2023 Oct a1651-16640 v553 aCoronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.
1 aKavousi, Maryam1 aBos, Maxime, M1 aBarnes, Hanna, J1 aCardenas, Christian, L Lino1 aWong, Doris1 aLu, Haojie1 aHodonsky, Chani, J1 aLandsmeer, Lennart, P L1 aTurner, Adam, W1 aKho, Minjung1 aHasbani, Natalie, R1 ade Vries, Paul, S1 aBowden, Donald, W1 aChopade, Sandesh1 aDeelen, Joris1 aBenavente, Ernest, Diez1 aGuo, Xiuqing1 aHofer, Edith1 aHwang, Shih-Jen1 aLutz, Sharon, M1 aLyytikäinen, Leo-Pekka1 aSlenders, Lotte1 aSmith, Albert, V1 aStanislawski, Maggie, A1 avan Setten, Jessica1 aWong, Quenna1 aYanek, Lisa, R1 aBecker, Diane, M1 aBeekman, Marian1 aBudoff, Matthew, J1 aFeitosa, Mary, F1 aFinan, Chris1 aHilliard, Austin, T1 aKardia, Sharon, L R1 aKovacic, Jason, C1 aKral, Brian, G1 aLangefeld, Carl, D1 aLauner, Lenore, J1 aMalik, Shaista1 aHoesein, Firdaus, A A Mohame1 aMokry, Michal1 aSchmidt, Reinhold1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aTerry, James, G1 avan der Grond, Jeroen1 avan Meurs, Joyce1 aVliegenthart, Rozemarijn1 aXu, Jianzhao1 aYoung, Kendra, A1 aZilhão, Nuno, R1 aZweiker, Robert1 aAssimes, Themistocles, L1 aBecker, Lewis, C1 aBos, Daniel1 aCarr, Jeffrey1 aCupples, Adrienne, L1 ade Kleijn, Dominique, P V1 ade Winther, Menno1 aRuijter, Hester, M den1 aFornage, Myriam1 aFreedman, Barry, I1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aHokanson, John, E1 aIkram, Arfan, M1 aIšgum, Ivana1 aJacobs, David, R1 aKähönen, Mika1 aLange, Leslie, A1 aLehtimäki, Terho1 aPasterkamp, Gerard1 aRaitakari, Olli, T1 aSchmidt, Helena1 aSlagboom, Eline1 aUitterlinden, André, G1 aVernooij, Meike, W1 aBis, Joshua, C1 aFranceschini, Nora1 aPsaty, Bruce, M1 aPost, Wendy, S1 aRotter, Jerome, I1 aBjörkegren, Johan, L M1 aO'Donnell, Christopher, J1 aBielak, Lawrence, F1 aPeyser, Patricia, A1 aMalhotra, Rajeev1 avan der Laan, Sander, W1 aMiller, Clint, L uhttps://chs-nhlbi.org/node/950113865nas a2204393 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2023 eng d00aMulti-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.0 aMultiancestry genomewide study in 25 million individuals reveals c2023 Mar 313 aType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.
1 aSuzuki, Ken1 aHatzikotoulas, Konstantinos1 aSoutham, Lorraine1 aTaylor, Henry, J1 aYin, Xianyong1 aLorenz, Kim, M1 aMandla, Ravi1 aHuerta-Chagoya, Alicia1 aRayner, Nigel, W1 aBocher, Ozvan1 ade, S, V Arruda A1 aSonehara, Kyuto1 aNamba, Shinichi1 aLee, Simon, S K1 aPreuss, Michael, H1 aPetty, Lauren, E1 aSchroeder, Philip1 aVanderwerff, Brett1 aKals, Mart1 aBragg, Fiona1 aLin, Kuang1 aGuo, Xiuqing1 aZhang, Weihua1 aYao, Jie1 aKim, Young, Jin1 aGraff, Mariaelisa1 aTakeuchi, Fumihiko1 aNano, Jana1 aLamri, Amel1 aNakatochi, Masahiro1 aMoon, Sanghoon1 aScott, Robert, A1 aCook, James, P1 aLee, Jung-Jin1 aPan, Ian1 aTaliun, Daniel1 aParra, Esteban, J1 aChai, Jin-Fang1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aThorleifsson, Gudmar1 aGrarup, Niels1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aKwak, Soo-Heon1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aNongmaithem, Suraj, S1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aBrody, Jennifer, A1 aKabagambe, Edmond1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aBroadaway, Alaine1 aWilliamson, Alice1 aKamali, Zoha1 aCui, Jinrui1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAhluwalia, Tarunveer, S1 aAnand, Sonia, S1 aBertoni, Alain1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBuchanan, Thomas, A1 aBurant, Charles, F1 aButterworth, Adam, S1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDanesh, John1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGordon-Larsen, Penny1 aGross, Myron1 aGuare, Lindsay, A1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHorikoshi, Momoko1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Torben1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Kyung, Min1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLithgart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLynch, Julie, A1 aLyssenko, Valeriya1 aMaeda, Shiro1 aMamakou, Vasiliki1 aMansuri, Sohail, Rafik1 aMatsuda, Koichi1 aMeitinger, Thomas1 aMetspalu, Andres1 aMo, Huan1 aMorris, Andrew, D1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPatil, Snehal1 aPei, Pei1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPolikowsky, Hannah, G1 aPorneala, Bianca1 aPrasad, Gauri1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Katheryn1 aSabanayagam, Charumathi1 aSandow, Kevin1 aSankareswaran, Alagu1 aSattar, Naveed1 aSchönherr, Sebastian1 aShahriar, Mohammad1 aShen, Botong1 aShi, Jinxiu1 aShin, Dong, Mun1 aShojima, Nobuhiro1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aSteinthorsdottir, Valgerdur1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aTaylor, Kent, D1 aThorand, Barbara1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTran, Tam, C1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamamoto, Kenichi1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZawistowski, Matthew1 aZhang, Liang1 aZheng, Wei1 aProject, Biobank, Japan1 aBioBank, Penn, Medicine1 aCenter, Regeneron, Genetics1 aConsortium, eMERGE1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aFornage, Myriam1 aHanis, Craig, L1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aYokota, Mitsuhiro1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aPankow, James, S1 aEngert, James, C1 aBonnefond, Amélie1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aMook-Kanamori, Dennis, O1 aTuomi, Tiinamaija1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aChen, Yii-Der Ida1 aRich, Stephen, S1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aGhanbari, Mohsen1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aBowden, Donald, W1 aPalmer, Colin, N A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aLiu, Simin1 aNorth, Kari, E1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aWareham, Nicholas, J1 aLee, Juyoung1 aKim, Bong-Jo1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aGoodarzi, Mark, O1 aMohlke, Karen, L1 aLangenberg, Claudia1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aFlorez, Jose, C1 aRader, Daniel, J1 aRitchie, Marylyn, D1 aZöllner, Sebastian1 aMägi, Reedik1 aDenny, Joshua, C1 aYamauchi, Toshimasa1 aKadowaki, Takashi1 aChambers, John, C1 aC Y Ng, Maggie1 aSim, Xueling1 aBelow, Jennifer, E1 aTsao, Philip, S1 aChang, Kyong-Mi1 aMcCarthy, Mark, I1 aMeigs, James, B1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aMercader, Josep, M1 aBoehnke, Michael1 aRotter, Jerome, I1 aVujkovic, Marijana1 aVoight, Benjamin, F1 aMorris, Andrew, P1 aZeggini, Eleftheria1 aVA Million Veteran Program, AMED GRIFIN Diabetes Initiative Japan1 aInternational Consortium for Blood Pressure (ICBP)1 aMeta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) uhttps://chs-nhlbi.org/node/938504817nas a2201309 4500008004100000022001400041245012100055210006900176260001300245300001200258490000700270520111100277653001201388653002301400653003801423653003401461653001101495653003601506653001601542653001801558100001501576700001801591700002201609700002001631700002501651700003001676700001501706700002101721700002501742700002801767700002101795700002801816700002401844700001701868700002101885700002401906700001901930700001901949700002901968700002301997700001902020700002102039700002102060700001902081700002202100700001902122700002602141700001702167700002802184700002102212700002402233700002002257700001702277700002102294700002202315700001402337700002002351700002202371700002002393700002002413700002002433700002502453700002102478700002102499700001902520700002402539700002102563700002102584700002202605700002402627700001402651700001702665700002002682700002402702700002002726700001702746700002502763700002102788700001802809700002202827700001702849700001902866700002602885700002102911700002402932700002002956700002202976700002302998700003403021700002103055700002203076700002303098700002403121700002103145700001603166700002303182700001403205700002003219700002203239700001903261700002103280700001903301700001903320700002103339700002203360700001403382700002103396700001603417700001803433700002003451856003603471 2023 eng d a1546-171800aMulti-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.0 aMultiancestry transcriptomewide association analyses yield insig c2023 Feb a291-3000 v553 aMost transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.
10aBiology10aDrug Repositioning10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aTobacco Use10aTranscriptome1 aChen, Fang1 aWang, Xingyan1 aJang, Seon-Kyeong1 aQuach, Bryan, C1 aWeissenkampen, Dylan1 aKhunsriraksakul, Chachrit1 aYang, Lina1 aSauteraud, Renan1 aAlbert, Christine, M1 aAllred, Nicholette, D D1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBarr, Graham1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoorgula, Meher, Preethi1 aChasman, Daniel, I1 aChavan, Sameer1 aChen, Yii-der, I1 aChuang, Lee-Ming1 aCorrea, Adolfo1 aCurran, Joanne, E1 aDavid, Sean, P1 aFuentes, Lisa, de Las1 aDeka, Ranjan1 aDuggirala, Ravindranath1 aFaul, Jessica, D1 aGarrett, Melanie, E1 aGharib, Sina, A1 aGuo, Xiuqing1 aHall, Michael, E1 aHawley, Nicola, L1 aHe, Jiang1 aHobbs, Brian, D1 aHokanson, John, E1 aHsiung, Chao, A1 aHwang, Shih-Jen1 aHyde, Thomas, M1 aIrvin, Marguerite, R1 aJaffe, Andrew, E1 aJohnson, Eric, O1 aKaplan, Robert1 aKardia, Sharon, L R1 aKaufman, Joel, D1 aKelly, Tanika, N1 aKleinman, Joel, E1 aKooperberg, Charles1 aLee, I-Te1 aLevy, Daniel1 aLutz, Sharon, M1 aManichaikul, Ani, W1 aMartin, Lisa, W1 aMarx, Olivia1 aMcGarvey, Stephen, T1 aMinster, Ryan, L1 aMoll, Matthew1 aMoussa, Karine, A1 aNaseri, Take1 aNorth, Kari, E1 aOelsner, Elizabeth, C1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRafaels, Nicholas1 aRaffield, Laura, M1 aReupena, Muagututi'a, Sefuiva1 aRich, Stephen, S1 aRotter, Jerome, I1 aSchwartz, David, A1 aShadyab, Aladdin, H1 aSheu, Wayne, H-H1 aSims, Mario1 aSmith, Jennifer, A1 aSun, Xiao1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aWatson, Harold1 aWeeks, Daniel, E1 aWeir, David, R1 aYanek, Lisa, R1 aYoung, Kendra, A1 aYoung, Kristin, L1 aZhao, Wei1 aHancock, Dana, B1 aJiang, Bibo1 aVrieze, Scott1 aLiu, Dajiang, J uhttps://chs-nhlbi.org/node/941202893nas a2200385 4500008004100000022001400041245010300055210006900158260001600227520174600243100001801989700002602007700001802033700001702051700002202068700002202090700002202112700002202134700001702156700002002173700002202193700001602215700002602231700002102257700002102278700002402299700002702323700001702350700001702367700002302384700002402407700002002431700002002451856003602471 2023 eng d a1532-841400aMultiple Prior Live Births are Associated with Cardiac Remodeling and Heart Failure Risk in Women.0 aMultiple Prior Live Births are Associated with Cardiac Remodelin c2023 Jan 103 aINTRODUCTION: Greater parity has been associated with cardiovascular disease risk, though effects on cardiac remodeling and heart failure risk remain unclear.
METHODS: We examined the association of number of live births and echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n=12,635 participants of FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major CVD, MI, and stroke.
RESULTS: Among n=3931 FHS participants (mean age 48 ± 13 years), higher number of live births was associated with worse LV fractional shortening (multivariable β -1.11 (0.31), p= 0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics including global circumferential strain and longitudinal and radial dyssynchrony (p< 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19-3.12, p=0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37-0.91, p=0.02).
CONCLUSIONS: Greater number of live births are associated with worse cardiac structure and function. While there was no association with overall HF, a higher number of live births was associated with greater risk for incident HFrEF.
1 aSarma, Amy, A1 aPaniagua, Samantha, M1 aLau, Emily, S1 aWang, Dongyu1 aLiu, Elizabeth, E1 aLarson, Martin, G1 aHamburg, Naomi, M1 aMitchell, Gary, F1 aKizer, Jorge1 aPsaty, Bruce, M1 aAllen, Norrina, B1 aLely, Titia1 aGansevoort, Ronald, T1 aRosenberg, Emily1 aMukamal, Kenneth1 aBenjamin, Emelia, J1 aVasan, Ramachandran, S1 aCheng, Susan1 aLevy, Daniel1 ade Boer, Rudolf, A1 aGottdiener, John, S1 aShah, Sanjiv, J1 aHo, Jennifer, E uhttps://chs-nhlbi.org/node/924102505nas a2200277 4500008004100000022001400041245007600055210006900131260001600200300001100216490000700227520169000234100002001924700002101944700002001965700002101985700002002006700002502026700002102051700002302072700002802095700002002123700002502143700002302168856003602191 2023 eng d a1873-205400aNeighborhood greenspace and cognition: The cardiovascular health study.0 aNeighborhood greenspace and cognition The cardiovascular health c2023 Jan 03 a1029600 v793 aOBJECTIVES: We examined whether greenspace measures (overall percent greenspace and forest, and number of greenspace types) were associated with clinically adjudicated dementia status.
METHODS: In a sample of non-demented older adults (n = 2141, average age = 75.3 years) from the Cardiovascular Health and Cognition Study, Cox proportional hazard and logistic regression analyses were used to estimate associations of baseline greenspace with risks of incident dementia and MCI, respectively, while adjusting for demographics, co-morbidities, and other neighborhood factors. We derived quartiles of percent greenness (greenspace), forest (percent tree canopy cover), and tertiles of greenspace diversity (number of greenspace types) for 5-km radial buffers around participant's residences at study entry (1989-1990) from the 1992 National Land Cover Dataset. Dementia status and mild cognitive impairment (MCI) over 10 years was clinically adjudicated.
RESULTS: We observed no significant association between overall percent greenspace and risk of mild cognitive impairment or dementia and mostly null results for forest and greenspace diversity. Forest greenspace was associated with lower odds of MCI (OR quartile 4 versus 1: 0.54, 95% CI: 0.29-0.98) and greenspace diversity was associated with lower hazard of incident dementia (HR tertile 2 versus 1: 0.70, 95% CI = 0.50-0.99).
DISCUSSION: We found divergent results for different types of greenspace and mild cognitive impairment or dementia. Improved greenspace type and diversity measurement could better characterize the association between greenspace and cognition.
1 aGodina, Sara, L1 aRosso, Andrea, L1 aHirsch, Jana, A1 aBesser, Lilah, M1 aLovasi, Gina, S1 aDonovan, Geoffrey, H1 aGarg, Parveen, K1 aPlatt, Jonathan, M1 aFitzpatrick, Annette, L1 aLopez, Oscar, L1 aCarlson, Michelle, C1 aMichael, Yvonne, L uhttps://chs-nhlbi.org/node/923803876nas a2200397 4500008004100000022001400041245010100055210006900156260001600225300001300241490000600254520276700260653000903027653001403036653001903050653002703069653002103096653001603117653001103133653001103144653000903155653001803164653001903182100001903201700002003220700002203240700002503262700002203287700002403309700002403333700001903357700002003376700002203396700002403418856003603442 2023 eng d a2574-380500aPlasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study.0 aPlasma Ceramides and Sphingomyelins and Sudden Cardiac Death in c2023 Nov 01 ae23438540 v63 aIMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.
OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.
DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.
EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.
MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.
RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]).
CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.
10aAged10aCeramides10aCohort Studies10aDeath, Sudden, Cardiac10aEicosanoic Acids10aFatty Acids10aFemale10aHumans10aMale10aSphingolipids10aSphingomyelins1 aBockus, Lee, B1 aJensen, Paul, N1 aFretts, Amanda, M1 aHoofnagle, Andrew, N1 aMcKnight, Barbara1 aSitlani, Colleen, M1 aSiscovick, David, S1 aKing, Irena, B1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/953303141nas a2200265 4500008004100000022001400041245011400055210006900169260001600238520230500254100001902559700002002578700002002598700002602618700002002644700002402664700001702688700002302705700001902728700002202747700002502769700002502794700002002819856003602839 2023 eng d a1526-632X00aPlasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study.0 aPlasma Proteomic Associations With Incident Ischemic Stroke in O c2023 Apr 043 aBACKGROUND: Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS).
METHODS: Eligible CHS participants were free of prevalent stroke and underwent quantification of 1298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-standard deviation increase in the log-2 transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and non-cardioembolic IS as well as proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation.
RESULTS: Of 2983 eligible participants, the mean age was 74.3 (± 4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal pro-brain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, P=2.08x10) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, P=4.55x10) were independently associated with IS risk. These two associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident non-cardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction.
CONCLUSIONS: In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and non-cardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.
1 aKalani, Rizwan1 aBartz, Traci, M1 aPsaty, Bruce, M1 aElkind, Mitchell, S V1 aFloyd, James, S1 aGerszten, Robert, E1 aShojaie, Ali1 aHeckbert, Susan, R1 aBis, Joshua, C1 aAustin, Thomas, R1 aTirschwell, David, L1 aDelaney, Joseph, A C1 aLongstreth, W T uhttps://chs-nhlbi.org/node/933102360nas a2200229 4500008004100000022001400041245008300055210006900138260001300207490000600220520167200226100002001898700002001918700002001938700002501958700002101983700002002004700002402024700002202048700002402070856003602094 2023 eng d a2312-054100aPlasma sphingolipids, lung function and COPD: the Cardiovascular Health Study.0 aPlasma sphingolipids lung function and COPD the Cardiovascular H c2023 Mar0 v93 aRATIONALE: COPD is the third leading cause of death in the United States. Sphingolipids, structural membrane constituents that play a role in cellular stress and apoptosis signalling, may be involved in lung function.
METHODS: In the Cardiovascular Health Study, a prospective cohort of older adults, we cross-sectionally examined the association of plasma levels of 17 sphingolipid species with lung function and COPD. Multivariable linear regression and logistic regression were used to evaluate associations of sphingolipid concentrations with forced expiratory volume in 1 s (FEV) and odds of COPD, respectively.
RESULTS: Of the 17 sphingolipids evaluated, ceramide-18 (Cer-18) and sphingomyelin-18 (SM-18) were associated with lower FEV values (-0.061 L per two-fold higher Cer-18, p=0.001; -0.092 L per two-fold higher SM-18, p=0.002) after correction for multiple testing. Several other associations were significant at a 0.05 level, but did not reach statistical significance after correction for multiple testing. Specifically, Cer-18 and SM-18 were associated with higher odds of COPD (odds ratio per two-fold higher Cer-18 1.29, p=0.03 and SM-18 1.73, p=0.008). Additionally, Cer-16 and SM-16 were associated with lower FEV values, and Cer-14, SM-14 and SM-16 with a higher odds of COPD.
CONCLUSION: In this large cross-sectional study, specific ceramides and sphingomyelins were associated with reduced lung function in a population-based study. Future studies are needed to examine whether these biomarkers are associated with longitudinal change in FEV within individuals or with incident COPD.
1 aGharib, Arya, R1 aJensen, Paul, N1 aPsaty, Bruce, M1 aHoofnagle, Andrew, N1 aSiscovick, David1 aGharib, Sina, A1 aSitlani, Colleen, M1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/933002887nas a2200445 4500008004100000022001400041245014200055210006900197260001600266300001000282490000700292520162000299653000901919653002001928653001101948653001101959653002001970653001701990653001102007653002402018653001702042653001102059653001802070100002402088700002002112700001702132700002202149700002402171700001502195700002202210700002902232700001602261700001702277700002002294700002002314700002402334700002202358700002502380856003602405 2023 eng d a2047-998000aPlasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis.0 aPlasma TrimethylamineOxide and Incident Ischemic Stroke The Card c2023 Aug 15 ae87110 v123 aBackground The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60% (CHS) and 53% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.
10aAged10aAtherosclerosis10aFemale10aHumans10aIschemic Stroke10aMethylamines10aOxides10aProspective Studies10aRisk Factors10aStroke10aUnited States1 aLemaitre, Rozenn, N1 aJensen, Paul, N1 aWang, Zeneng1 aFretts, Amanda, M1 aSitlani, Colleen, M1 aNemet, Ina1 aSotoodehnia, Nona1 aOtto, Marcia, C de Olive1 aZhu, Weifei1 aBudoff, Matt1 aLongstreth, W T1 aPsaty, Bruce, M1 aSiscovick, David, S1 aHazen, Stanley, L1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/945100892nas a2200157 4500008004100000245009300041210006900134260000800203520038600211100001600597700001600613700001900629700002500648700002500673856003600698 2023 eng d00a{Polygenic burden of short tandem repeat expansions promote risk for Alzheimer's disease0 aPolygenic burden of short tandem repeat expansions promote risk cNov3 a30 STR expansions had 3.62-fold higher odds of having AD and had more severe AD neuropathology. AD STR expansions were highly enriched within active promoters in post-mortem hippocampal brain tissues and particularly within SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate that expanded STRs within active promoter regions of the genome promote risk of AD.1 aGuo, M., H.1 aLee, W., P.1 aVardarajan, B.1 aSchellenberg, G., D.1 aPhillips-Cremins, J. uhttps://chs-nhlbi.org/node/958503951nas a2200925 4500008004100000022001400041245013100055210006900186260001300255300001200268490000700280520122300287653002101510653003401531653001101565653001401576653002801590100001401618700001801632700001701650700002201667700001501689700001401704700003201718700001401750700001601764700002101780700002401801700001901825700001901844700002101863700002201884700002301906700001901929700001901948700002501967700002201992700002202014700002802036700002302064700002502087700001702112700002202129700002102151700002402172700001902196700002102215700002102236700002002257700002502277700002502302700002202327700002402349700001702373700002602390700002602416700002402442700002002466700002302486700001902509700002502528700003402553700002102587700002102608700002402629700002302653700002002676700002702696700002302723700002102746700001902767700001402786700002202800700002302822700002002845700001402865700001602879710009402895856003602989 2023 eng d a1546-171800aPowerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.0 aPowerful scalable and resourceefficient metaanalysis of rare var c2023 Jan a154-1640 v553 aMeta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.
10aExome Sequencing10aGenome-Wide Association Study10aLipids10aPhenotype10aWhole Genome Sequencing1 aLi, Xihao1 aQuick, Corbin1 aZhou, Hufeng1 aGaynor, Sheila, M1 aLiu, Yaowu1 aChen, Han1 aSelvaraj, Margaret, Sunitha1 aSun, Ryan1 aDey, Rounak1 aArnett, Donna, K1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 ade Vries, Paul, S1 aDuggirala, Ravindranath1 aFreedman, Barry, I1 aGöring, Harald, H H1 aGuo, Xiuqing1 aHaessler, Jeffrey1 aKalyani, Rita, R1 aKooperberg, Charles1 aKral, Brian, G1 aLange, Leslie, A1 aManichaikul, Ani1 aMartin, Lisa, W1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRedline, Susan1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aRice, Kenneth, M1 aRich, Stephen, S1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aWiller, Cristen, J1 aWilson, James, G1 aYanek, Lisa, R1 aZhao, Wei1 aRotter, Jerome, I1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aLi, Zilin1 aLin, Xihong1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/923903136nas a2200253 4500008004100000245009000041210006900131260001600200520233000216100002302546700002402569700002002593700002302613700002102636700002002657700002402677700002602701700002302727700002702750700002002777700002602797700002302823856003602846 2023 eng d00aPrediction of Multiple Individual Primary Cardiovascular Events Using Pooled Cohorts.0 aPrediction of Multiple Individual Primary Cardiovascular Events c2023 Aug 023 aINTRODUCTION: Most current clinical risk prediction scores for cardiovascular disease prevention use a composite outcome. Risk prediction scores for specific cardiovascular events could identify people who are at higher risk for some events than others informing personalized care and trial recruitment. We sought to predict risk for multiple different events, describe how those risks differ, and examine if these differences could improve treatment priorities.
METHODS: We used participant-level data from five cohort studies. We included participants between 40 and 79 years old who had no history of myocardial infarction (MI), stroke, or heart failure (HF). We made separate models to predict 10-year rates of first atherosclerotic cardiovascular disease (ASCVD), first fatal or nonfatal MI, first fatal or nonfatal stroke, new-onset HF, fatal ASCVD, fatal MI, fatal stroke, and all-cause mortality using established ASCVD risk factors. To limit overfitting, we used elastic net regularization with alpha = 0.75. We assessed the models for calibration, discrimination, and for correlations between predicted risks for different events. We also estimated the potential impact of varying treatment based on patients who are high risk for some ASCVD events, but not others.
RESULTS: Our study included 24,505 people; 55.6% were women, and 20.7% were non-Hispanic Black. Our models had C-statistics between 0.75 for MI and 0.85 for HF, good calibration, and minimal overfitting. The models were least similar for fatal stroke and all MI (0.58). In 1,840 participants whose risk of MI but not stroke or all-cause mortality was in the top quartile, we estimate one blood pressure-lowering medication would have a 2.4% chance of preventing any ASCVD event per 10 years. A moderate-strength statin would have a 2.1% chance. In 1,039 participants who had top quartile risk of stroke but not MI or mortality, a blood pressure-lowering medication would have a 2.5% chance of preventing an event, but a moderate-strength statin, 1.6%.
CONCLUSION: We developed risk scores for eight key clinical events and found that cardiovascular risk varies somewhat for different clinical events. Future work could determine if tailoring decisions by risk of separate events can improve care.
1 aSussman, Jeremy, B1 aWhitney, Rachael, T1 aBurke, James, F1 aHayward, Rodney, A1 aGalecki, Andrzej1 aSidney, Stephen1 aAllen, Norrina, Bai1 aGottesman, Rebecca, F1 aHeckbert, Susan, R1 aLongstreth, William, T1 aPsaty, Bruce, M1 aElkind, Mitchell, S V1 aLevine, Deborah, A uhttps://chs-nhlbi.org/node/943703409nas a2200433 4500008004100000022001400041245010900055210006900164260001600233490000700249520207000256653002402326653001502350653005502365653001102420653003102431653005002462653002202512653001402534653002402548653001502572653001702587100002702604700002902631700002202660700002302682700002302705700001902728700002002747700002102767700002102788700001902809700002002828700002002848700001902868700002402887700002802911856003602939 2023 eng d a1532-209200aA proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study).0 aproteomic analysis of atrial fibrillation in a prospective longi c2023 Nov 020 v253 aAIMS: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study.
METHODS AND RESULTS: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points.
CONCLUSION: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.
10aAtrial Fibrillation10aBiomarkers10aEndosomal Sorting Complexes Required for Transport10aHumans10aNatriuretic Peptide, Brain10aOxidoreductases Acting on Sulfur Group Donors10aPeptide Fragments10aPrognosis10aProspective Studies10aProteomics10aRisk Factors1 aJonmundsson, Thorarinn1 aSteindorsdottir, Anna, E1 aAustin, Thomas, R1 aFrick, Elisabet, A1 aAxelsson, Gisli, T1 aLauner, Lenore1 aPsaty, Bruce, M1 aLoureiro, Joseph1 aOrth, Anthony, P1 aAspelund, Thor1 aEmilsson, Valur1 aFloyd, James, S1 aJennings, Lori1 aGudnason, Vilmundur1 aGudmundsdottir, Valborg uhttps://chs-nhlbi.org/node/953903043nas a2200361 4500008004100000022001400041245007400055210006900129260001600198520194700214100002002161700002702181700002202208700002802230700002302258700002302281700002702304700002902331700002102360700002302381700001902404700002202423700002802445700002602473700002102499700002102520700001802541700002002559700002002579700002202599700002402621856003602645 2023 eng d a1879-084400aProteomic prediction of incident heart failure and its main subtypes.0 aProteomic prediction of incident heart failure and its main subt c2023 Nov 083 aAIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables.
METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with nonparametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on NT-proBNP and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study (CHS).
CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to eight years, with predictor performance significantly improving for events occurring less than one year ahead, a finding replicated in an external cohort study. This article is protected by copyright. All rights reserved.
1 aEmilsson, Valur1 aJonsson, Brynjolfur, G1 aAustin, Thomas, R1 aGudmundsdottir, Valborg1 aAxelsson, Gisli, T1 aFrick, Elisabet, A1 aJonmundsson, Thorarinn1 aSteindorsdottir, Anna, E1 aLoureiro, Joseph1 aBrody, Jennifer, A1 aAspelund, Thor1 aLauner, Lenore, J1 aThorgeirsson, Gudmundur1 aKortekaas, Kirsten, A1 aLindeman, Jan, H1 aOrth, Anthony, P1 aLamb, John, R1 aPsaty, Bruce, M1 aKizer, Jorge, R1 aJennings, Lori, L1 aGudnason, Vilmundur uhttps://chs-nhlbi.org/node/953604538nas a2200997 4500008004100000245012600041210006900167260001600236520164000252100001701892700003201909700001401941700001401955700002401969700002101993700001902014700001902033700002102052700002202073700001902095700002202114700002102136700002202157700002202179700002202201700002202223700002402245700002002269700002002289700002302309700002002332700001802352700002202370700001702392700001402409700002302423700002102446700001602467700002502483700001902508700002202527700002302549700002102572700001402593700002402607700001902631700001702650700001702667700001602684700002002700700001902720700002402739700002002763700002302783700002102806700002502827700002202852700002402874700002402898700001702922700002602939700002602965700002302991700002003014700002303034700002003057700001903077700002503096700002103121700003403142700002103176700002303197700001803220700002203238700002103260700003003281700001403311700001903325700001403344700002203358700001603380700002303396700002003419710006503439856003603504 2023 eng d00aRare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.0 aRare variants in long noncoding RNAs are associated with blood l c2023 Jun 293 aLong non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.
1 aWang, Yuxuan1 aSelvaraj, Margaret, Sunitha1 aLi, Xihao1 aLi, Zilin1 aHoldcraft, Jacob, A1 aArnett, Donna, K1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aCade, Brian, E1 aCarlson, Jenna, C1 aCarson, April, P1 aChen, Yii-Der Ida1 aCurran, Joanne, E1 ade Vries, Paul, S1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aFloyd, James, S1 aFornage, Myriam1 aFreedman, Barry, I1 aGabriel, Stacey1 aGermer, Soren1 aGibbs, Richard, A1 aGuo, Xiuqing1 aHe, Jiang1 aHeard-Costa, Nancy1 aHildalgo, Bertha1 aHou, Lifang1 aIrvin, Marguerite, R1 aJoehanes, Roby1 aKaplan, Robert, C1 aKardia, Sharon, Lr1 aKelly, Tanika, N1 aKim, Ryan1 aKooperberg, Charles1 aKral, Brian, G1 aLevy, Daniel1 aLi, Changwei1 aLiu, Chunyu1 aLloyd-Jone, Don1 aLoos, Ruth, Jf1 aMahaney, Michael, C1 aMartin, Lisa, W1 aMathias, Rasika, A1 aMinster, Ryan, L1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aMurabito, Joanne, M1 aNaseri, Take1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPreuss, Michael, H1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRao, Dabeeru, C1 aRedline, Susan1 aReiner, Alexander, P1 aRich, Stephen, S1 aRuepena, Muagututi'a, Sefuiva1 aSheu, Wayne, H-H1 aSmith, Jennifer, A1 aSmith, Albert1 aTiwari, Hemant, K1 aTsai, Michael, Y1 aViaud-Martinez, Karine, A1 aWang, Zhe1 aYanek, Lisa, R1 aZhao, Wei1 aRotter, Jerome, I1 aLin, Xihong1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/941801562nas a2200277 4500008004100000245013400041210006900175260000800244520072900252100001500981700001200996700001801008700002101026700001701047700002201064700001801086700001601104700001101120700001901131700001801150700001801168700002301186700001901209700002001228856003601248 2023 eng d00a{Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study0 aSerum NfL and GFAP are associated with incident dementia and dem cJul3 aCirculating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated.\ We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline.\ 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline.\ Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.1 aé, H., T.1 aLiu, X.1 aOdden, M., C.1 aMoseholm, K., F.1 aSeshadri, S.1 aSatizabal, C., L.1 aLopez, O., L.1 aBis, J., C.1 aé, L.1 aFohner, A., E.1 aPsaty, B., M.1 aTracy, R., P.1 aLongstreth, W., T.1 aJensen, M., K.1 aMukamal, K., J. uhttps://chs-nhlbi.org/node/941504199nas a2200385 4500008004100000022001400041245008300055210006900138260001600207300001300223490000600236520309600242100002103338700002403359700002503383700002603408700002003434700002203454700002603476700001903502700001803521700001403539700001603553700002003569700001803589700002603607700001903633700001703652700002203669700002003691700002003711700002203731700002403753856003603777 2023 eng d a2574-380500aSleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults.0 aSleep Architecture Obstructive Sleep Apnea and Cognitive Functio c2023 Jul 03 ae23251520 v63 aIMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.
OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.
DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.
EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG.
MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.
RESULTS: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.
CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.
1 aPase, Matthew, P1 aHarrison, Stephanie1 aMisialek, Jeffrey, R1 aKline, Christopher, E1 aCavuoto, Marina1 aBaril, Andree-Ann1 aYiallourou, Stephanie1 aBisson, Alycia1 aHimali, Dibya1 aLeng, Yue1 aYang, Qiong1 aSeshadri, Sudha1 aBeiser, Alexa1 aGottesman, Rebecca, F1 aRedline, Susan1 aLopez, Oscar1 aLutsey, Pamela, L1 aYaffe, Kristine1 aStone, Katie, L1 aPurcell, Shaun, M1 aHimali, Jayandra, J uhttps://chs-nhlbi.org/node/941703992nas a2200925 4500008004100000245012300041210006900164260001600233520132600249100001401575700001401589700003201603700002001635700001701655700001701672700001401689700002201703700001201725700002101737700001901758700001901777700002101796700002201817700002301839700001901862700002101881700002201902700002001924700002201944700002201966700002201988700002002010700002302030700002302053700001602076700002602092700001402118700001602132700001702148700002502165700002202190700002402212700001802236700002102254700002402275700001902299700001702318700002002335700002402355700002002379700002302399700002102422700002502443700002202468700002402490700002602514700002402540700002002564700002302584700001902607700002502626700002102651700002402672700002302696700002002719700001902739700002702758700001402785700001902799700001302818700002102831700002202852700002002874700002302894700001402917700001802931700001602949710006502965856003603030 2023 eng d00aA statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.0 astatistical framework for powerful multitrait rare variant analy c2023 Nov 023 aLarge-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.
1 aLi, Xihao1 aChen, Han1 aSelvaraj, Margaret, Sunitha1 aVan Buren, Eric1 aZhou, Hufeng1 aWang, Yuxuan1 aSun, Ryan1 aMcCaw, Zachary, R1 aYu, Zhi1 aArnett, Donna, K1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aCarson, April, P1 aCarlson, Jenna, C1 aChami, Nathalie1 aChen, Yii-Der Ida1 aCurran, Joanne, E1 ade Vries, Paul, S1 aFornage, Myriam1 aFranceschini, Nora1 aFreedman, Barry, I1 aGu, Charles1 aHeard-Costa, Nancy, L1 aHe, Jiang1 aHou, Lifang1 aHung, Yi-Jen1 aIrvin, Marguerite, R1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKelly, Tanika1 aKonigsberg, Iain1 aKooperberg, Charles1 aKral, Brian, G1 aLi, Changwei1 aLoos, Ruth, J F1 aMahaney, Michael, C1 aMartin, Lisa, W1 aMathias, Rasika, A1 aMinster, Ryan, L1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aPalmer, Nicholette, D1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRedline, Susan1 aReiner, Alexander, P1 aRich, Stephen, S1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aTiwari, Hemant1 aVasan, Ramachandran, S1 aWang, Zhe1 aYanek, Lisa, R1 aYu, Bing1 aRice, Kenneth, M1 aRotter, Jerome, I1 aPeloso, Gina, M1 aNatarajan, Pradeep1 aLi, Zilin1 aLiu, Zhonghua1 aLin, Xihong1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/954305739nas a2200901 4500008004100000245012500041210006900166260001600235520316300251100002003414700003103434700002303465700002103488700001803509700001503527700002303542700001303565700001703578700002203595700001803617700001803635700002303653700001503676700002203691700001703713700001803730700002503748700001703773700001803790700002103808700001903829700002203848700002003870700001503890700002003905700001603925700002503941700002403966700001903990700002404009700002404033700002504057700002104082700002404103700002404127700002204151700002004173700002104193700002104214700003004235700002004265700002104285700001204306700002104318700001904339700002004358700001904378700002104397700002304418700002104441700001604462700002504478700002104503700002404524700001904548700002204567700002004589700002304609700002304632700002404655700001904679700002104698700002204719700001804741700002204759700002004781856003604801 2023 eng d00aTime-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.0 aTimetoEvent GenomeWide Association Study for Incident Cardiovasc c2023 Jul 283 aBACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.
METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.
RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0×10 ).
CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.
CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.
1 aKwak, Soo, Heon1 aHernandez-Cancela, Ryan, B1 aDiCorpo, Daniel, A1 aCondon, David, E1 aMerino, Jordi1 aWu, Peitao1 aBrody, Jennifer, A1 aYao, Jie1 aGuo, Xiuqing1 aAhmadizar, Fariba1 aMeyer, Mariah1 aSincan, Murat1 aMercader, Josep, M1 aLee, Sujin1 aHaessler, Jeffrey1 aVy, Ha, My T1 aLin, Zhaotong1 aArmstrong, Nicole, D1 aGu, Shaopeng1 aTsao, Noah, L1 aLange, Leslie, A1 aWang, Ningyuan1 aWiggins, Kerri, L1 aTrompet, Stella1 aLiu, Simin1 aLoos, Ruth, J F1 aJudy, Renae1 aSchroeder, Philip, H1 aHasbani, Natalie, R1 aBos, Maxime, M1 aMorrison, Alanna, C1 aJackson, Rebecca, D1 aReiner, Alexander, P1 aManson, JoAnn, E1 aChaudhary, Ninad, S1 aCarmichael, Lynn, K1 aChen, Yii-Der Ida1 aTaylor, Kent, D1 aGhanbari, Mohsen1 avan Meurs, Joyce1 aPitsillides, Achilleas, N1 aPsaty, Bruce, M1 aNoordam, Raymond1 aDo, Ron1 aPark, Kyong, Soo1 aJukema, Wouter1 aKavousi, Maryam1 aCorrea, Adolfo1 aRich, Stephen, S1 aDamrauer, Scott, M1 aHajek, Catherine1 aCho, Nam, H1 aIrvin, Marguerite, R1 aPankow, James, S1 aNadkarni, Girish, N1 aSladek, Robert1 aGoodarzi, Mark, O1 aFlorez, Jose, C1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aKooperberg, Charles1 aDupuis, Josée1 aMalhotra, Rajeev1 ade Vries, Paul, S1 aLiu, Ching-Ti1 aRotter, Jerome, I1 aMeigs, James, B uhttps://chs-nhlbi.org/node/945002684nas a2200229 4500008004100000022001400041245010400055210006900159260001600228520196100244100002102205700002002226700001902246700002202265700002502287700002202312700002402334700002002358700002002378700002002398856003602418 2023 eng d a1468-201X00aTraditional and novel risk factors for incident aortic stenosis in community-dwelling older adults.0 aTraditional and novel risk factors for incident aortic stenosis c2023 Jul 183 aOBJECTIVES: Calcific aortic stenosis (AS) is the most common valvular disease in older adults, yet its risk factors remain insufficiently studied in this population. Such studies are necessary to enhance understanding of mechanisms, disease management and therapeutics.
METHODS: The Cardiovascular Health Study is a population-based investigation of older adults that completed adjudication of incident AS over long-term follow-up. We evaluated traditional cardiovascular risk factors or disease, as well as novel risk factors from lipid, inflammatory and mineral metabolism pathways, in relation to incident moderate or severe AS (including AS procedures) and clinically significant AS (severe AS, including procedures).
RESULTS: Of 5390 participants (age 72.9±5.6 years, 57.6% female, 12.5% black), 287 developed moderate or severe AS, and 175 clinically significant AS, during median follow-up of 13.1 years. After full adjustment, age (HR=1.66 per SD (95% CI=1.45, 1.91)), male sex (HR=1.41 (1.06, 1.87)), diabetes (HR=1.53 (1.10, 2.13)), coronary heart disease (CHD, HR=1.36 (1.01, 1.84)), lipoprotein-associated phospholipase-A (LpPLA) activity (HR=1.21 per SD (1.07, 1.37)) and sCD14 (HR=1.16 per SD (1.01, 1.34)) were associated with incident moderate/severe AS, while black race demonstrated an inverse association (HR=0.40 (0.24, 0.65)), and creatinine-based estimated glomerular filtration rate (eGFR) showed a U-shaped relationship. Findings were similar for clinically significant AS, although CHD and sCD14 fell short of significance, but interleukin-(IL) 6 showed a positive association.
CONCLUSION: This comprehensive evaluation of risk factors for long-term incidence of AS identified associations for diabetes and prevalent CHD, LpPLA activity, sCD14 and IL-6, and eGFR. These factors may hold clues to biology, preventive efforts and potential therapeutics for those at highest risk.
1 aMassera, Daniele1 aBartz, Traci, M1 aBiggs, Mary, L1 aSotoodehnia, Nona1 aReiner, Alexander, P1 aSemba, Richard, D1 aGottdiener, John, S1 aPsaty, Bruce, M1 aOwens, David, S1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/941602774nas a2200397 4500008004100000022001400041245011600055210006900171260001600240300001200256490000600268520162400274100002401898700001501922700002301937700002101960700002401981700002002005700002002025700002102045700001702066700002202083700002402105700001302129700001902142700002002161700001802181700002202199700002002221700002002241700002202261700002102283700001902304700001702323856003602340 2023 eng d a2472-197200aA Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies.0 aType 1 Diabetes Polygenic Score Is Not Associated With Prevalent c2023 Oct 09 abvad1230 v73 aCONTEXT: Both type 1 diabetes (T1D) and type 2 diabetes (T2D) have significant genetic contributions to risk and understanding their overlap can offer clinical insight.
OBJECTIVE: We examined whether a T1D polygenic score (PS) was associated with a diagnosis of T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: We constructed a T1D PS using 79 known single nucleotide polymorphisms associated with T1D risk. We analyzed 13 792 T2D cases and 14 169 controls from CHARGE cohorts to determine the association between the T1D PS and T2D prevalence. We validated findings in an independent sample of 2256 T2D cases and 27 052 controls from the Mass General Brigham Biobank (MGB Biobank). As secondary analyses in 5228 T2D cases from CHARGE, we used multivariable regression models to assess the association of the T1D PS with clinical outcomes associated with T1D.
RESULTS: The T1D PS was not associated with T2D both in CHARGE ( = .15) and in the MGB Biobank ( = .87). The partitioned human leukocyte antigens only PS was associated with T2D in CHARGE (OR 1.02 per 1 SD increase in PS, 95% CI 1.01-1.03, = .006) but not in the MGB Biobank. The T1D PS was weakly associated with insulin use (OR 1.007, 95% CI 1.001-1.012, = .03) in CHARGE T2D cases but not with other outcomes.
CONCLUSION: In large biobank samples, a common variant PS for T1D was not consistently associated with prevalent T2D. However, possible heterogeneity in T2D cannot be ruled out and future studies are needed do subphenotyping.
1 aSrinivasan, Shylaja1 aWu, Peitao1 aMercader, Josep, M1 aUdler, Miriam, S1 aPorneala, Bianca, C1 aBartz, Traci, M1 aFloyd, James, S1 aSitlani, Colleen1 aGuo, Xiquing1 aHaessler, Jeffrey1 aKooperberg, Charles1 aLiu, Jun1 aAhmad, Shahzad1 aDuijn, Cornelia1 aLiu, Ching-Ti1 aGoodarzi, Mark, O1 aFlorez, Jose, C1 aMeigs, James, B1 aRotter, Jerome, I1 aRich, Stephen, S1 aDupuis, Josée1 aLeong, Aaron uhttps://chs-nhlbi.org/node/954404412nas a2200865 4500008004100000022001400041245010800055210006900163260001600232300001200248520183100260100002402091700002602115700002002141700001402161700001402175700002002189700002102209700001902230700002102249700001502270700002402285700001702309700002302326700002002349700002402369700002202393700002602415700002302441700002002464700001902484700001702503700002202520700002302542700002802565700002102593700002102614700002102635700002502656700002302681700002002704700001802724700002202742700002002764700002302784700002002807700002202827700001902849700002402868700001902892700001902911700002002930700001902950700003002969700002102999700002103020700001903041700001903060700001803079700002203097700002003119700002103139700001803160700002103178700002403199700002403223700002703247700001603274700002203290700002003312700002203332700002203354710013403376856003603510 2023 eng d a2574-830000aType 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.0 aType 2 Diabetes Modifies the Association of CAD Genomic Risk Var c2023 Nov 28 ae0041763 aBACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.
METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.
RESULTS: Using a Bonferroni-corrected significance threshold of <1.6×10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.
CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.
1 aHasbani, Natalie, R1 aWesterman, Kenneth, E1 aKwak, Soo, Heon1 aChen, Han1 aLi, Xihao1 aDiCorpo, Daniel1 aWessel, Jennifer1 aBis, Joshua, C1 aSarnowski, Chloe1 aWu, Peitao1 aBielak, Lawrence, F1 aGuo, Xiuqing1 aHeard-Costa, Nancy1 aKinney, Gregory1 aMahaney, Michael, C1 aMontasser, May, E1 aPalmer, Nicholette, D1 aRaffield, Laura, M1 aTerry, James, G1 aYanek, Lisa, R1 aBon, Jessica1 aBowden, Donald, W1 aBrody, Jennifer, A1 aDuggirala, Ravindranath1 aJacobs, David, R1 aKalyani, Rita, R1 aLange, Leslie, A1 aMitchell, Braxton, D1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aCarson, April1 aCurran, Joanne, E1 aFornage, Myriam1 aFreedman, Barry, I1 aGabriel, Stacey1 aGibbs, Richard, A1 aGupta, Namrata1 aKardia, Sharon, L R1 aKral, Brian, G1 aMomin, Zeineen1 aNewman, Anne, B1 aPost, Wendy, S1 aViaud-Martinez, Karine, A1 aYoung, Kendra, A1 aBecker, Lewis, C1 aBertoni, Alain1 aBlangero, John1 aCarr, John, J1 aPratte, Katherine1 aPsaty, Bruce, M1 aRich, Stephen, S1 aWu, Joseph, C1 aMalhotra, Rajeev1 aPeyser, Patricia, A1 aMorrison, Alanna, C1 aVasan, Ramachandran, S1 aLin, Xihong1 aRotter, Jerome, I1 aMeigs, James, B1 aManning, Alisa, K1 ade Vries, Paul, S1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Atherosclerosis Working Group; TOPMed Diabetes Working Group uhttps://chs-nhlbi.org/node/953702614nas a2200361 4500008004100000022001400041245011600055210006900171260000900240300001200249490000700261520164200268653001001910653002201920653001901942653001301961653001101974653002301985100001402008700001602022700002002038700001502058700001802073700001602091700001602107700001102123700001902134700001402153700001802167700001402185700001702199856003602216 2023 eng d a2426-026600aValidation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations.0 aValidation of the CogDrisk Instrument as Predictive of Dementia c2023 a478-4870 v103 aBACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research.
OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer's disease (AD) using cohort studies.
DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model.
RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project.
CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.
10aAging10aAlzheimer Disease10aCohort Studies10aDementia10aHumans10aIndependent Living1 aKootar, S1 aHuque, M, H1 aEramudugolla, R1 aRizzuto, D1 aCarlson, M, C1 aOdden, M, C1 aLopez, O, L1 aQiu, C1 aFratiglioni, L1 aHan, S, D1 aBennett, D, A1 aPeters, R1 aAnstey, K, J uhttps://chs-nhlbi.org/node/940807212nas a2201753 4500008004100000245012700041210006900168260001600237520220800253100002502461700001902486700001602505700001902521700002302540700001902563700002302582700002102605700001802626700002002644700002402664700002302688700002902711700002302740700002002763700002102783700002102804700002102825700002402846700002202870700001902892700001502911700002102926700002002947700001802967700001902985700002103004700002503025700002603050700002103076700001903097700001903116700002803135700002203163700002203185700001903207700002003226700001803246700001703264700001503281700002003296700002803316700001703344700001703361700002703378700002503405700002003430700002003450700002003470700002403490700001203514700001603526700002003542700002803562700001603590700002103606700001903627700002103646700002703667700002103694700002403715700001603739700002203755700002403777700002503801700001703826700001403843700002103857700002003878700002203898700001903920700002003939700001503959700002003974700002203994700002404016700002004040700001804060700002004078700002704098700001804125700001704143700002104160700001604181700001804197700002404215700002004239700002004259700002604279700001904305700002004324700002304344700002304367700002504390700002004415700003004435700001804465700002304483700001804506700002104524700001904545700002004564700001804584700001904602700002304621700002204644700002004666700001904686700002204705700002004727700001904747700002304766700002104789700002004810700002304830700002504853700002904878700002904907700001904936700002604955700001904981700002205000700002005022700002405042700002005066700001705086700001805103700002105121700001305142700003205155700002305187700002205210700002205232700002505254700002405279700002305303710003105326710006505357856003605422 2023 eng d00aWhole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.0 aWhole genome analysis of plasma fibrinogen reveals populationdif c2023 Jun 123 aUNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
1 aHuffman, Jennifer, E1 aNicolas, Jayna1 aHahn, Julie1 aHeath, Adam, S1 aRaffield, Laura, M1 aYanek, Lisa, R1 aBrody, Jennifer, A1 aThibord, Florian1 aAlmasy, Laura1 aBartz, Traci, M1 aBielak, Lawrence, F1 aBowler, Russell, P1 aCarrasquilla, Germán, D1 aChasman, Daniel, I1 aChen, Ming-Huei1 aEmmert, David, B1 aGhanbari, Mohsen1 aHaessle, Jeffery1 aHottenga, Jouke-Jan1 aKleber, Marcus, E1 aLe, Ngoc-Quynh1 aLee, Jiwon1 aLewis, Joshua, P1 aLi-Gao, Ruifang1 aLuan, Jian'an1 aMalmberg, Anni1 aMangino, Massimo1 aMarioni, Riccardo, E1 aMartinez-Perez, Angel1 aPankratz, Nathan1 aPolasek, Ozren1 aRichmond, Anne1 aRodriguez, Benjamin, At1 aRotter, Jerome, I1 aSteri, Maristella1 aSuchon, Pierre1 aTrompet, Stella1 aWeiss, Stefan1 aZare, Marjan1 aAuer, Paul1 aCho, Michael, H1 aChristofidou, Paraskevi1 aDavies, Gail1 ade Geus, Eco1 aDeleuze, Jean-Francois1 aDelgado, Graciela, E1 aEkunwe, Lynette1 aFaraday, Nauder1 aGögele, Martin1 aGreinacher, Andreas1 aHe, Gao1 aHoward, Tom1 aJoshi, Peter, K1 aKilpeläinen, Tuomas, O1 aLahti, Jari1 aLinneberg, Allan1 aNaitza, Silvia1 aNoordam, Raymond1 aPaüls-Vergés, Ferran1 aRich, Stephen, S1 aRosendaal, Frits, R1 aRudan, Igor1 aRyan, Kathleen, A1 aSouto, Juan, Carlos1 avan Rooij, Frank, Ja1 aWang, Heming1 aZhao, Wei1 aBecker, Lewis, C1 aBeswick, Andrew1 aBrown, Michael, R1 aCade, Brian, E1 aCampbell, Harry1 aCho, Kelly1 aCrapo, James, D1 aCurran, Joanne, E1 ade Maat, Moniek, Pm1 aDoyle, Margaret1 aElliott, Paul1 aFloyd, James, S1 aFuchsberger, Christian1 aGrarup, Niels1 aGuo, Xiuqing1 aHarris, Sarah, E1 aHou, Lifang1 aKolcic, Ivana1 aKooperberg, Charles1 aMenni, Cristina1 aNauck, Matthias1 aO'Connell, Jeffrey, R1 aOrrù, Valeria1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aSmith, Jennifer, A1 aSoria, José, Manuel1 aStott, David, J1 aVlieg, Astrid, van Hylcka1 aWatkins, Hugh1 aWillemsen, Gonneke1 aWilson, Peter1 aBen-Shlomo, Yoav1 aBlangero, John1 aBoomsma, Dorret1 aCox, Simon, R1 aDehghan, Abbas1 aEriksson, Johan, G1 aFiorillo, Edoardo1 aFornage, Myriam1 aHansen, Torben1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, Lr1 aLange, Leslie, A1 aMärz, Winfried1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aMook-Kanamori, Dennis, O1 aMorange, Pierre-Emmanuel1 aPedersen, Oluf1 aPramstaller, Peter, P1 aRedline, Susan1 aReiner, Alexander1 aRidker, Paul, M1 aSilverman, Edwin, K1 aSpector, Tim, D1 aVölker, Uwe1 aWareham, Nick1 aWilson, James, F1 aYao, Jie1 aTrégouët, David-Alexandre1 aJohnson, Andrew, D1 aWolberg, Alisa, S1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aMorrison, Alanna, C1 aSmith, Nicholas, L1 aVA Million Veteran Program1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/944903549nas a2200541 4500008004100000022001400041245010100055210006900156260001600225300001200241520193400253100002302187700002302210700002402233700001702257700002402274700002002298700002002318700002702338700002402365700001902389700002302408700002402431700002302455700001402478700002102492700002202513700002302535700002402558700002502582700001702607700001802624700002202642700002102664700002302685700002302708700002202731700002102753700002002774700002702794700001402821700002402835700002102859700002302880700002102903710004702924856003602971 2023 eng d a2574-830000aWhole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program.0 aWhole Genome Analysis of Venous Thromboembolism the TransOmics f c2023 Mar 24 ae0035323 aBackground Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4×10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6×10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8×10 with the secondary filter), while did not (minimum =4.4×10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4×10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.
1 aSeyerle, Amanda, A1 aLaurie, Cecelia, A1 aCoombes, Brandon, J1 aJain, Deepti1 aConomos, Matthew, P1 aBrody, Jennifer1 aChen, Ming-Huei1 aGogarten, Stephanie, M1 aBeutel, Kathleen, M1 aGupta, Namrata1 aHeckbert, Susan, R1 aJackson, Rebecca, D1 aJohnson, Andrew, D1 aKo, Darae1 aManson, JoAnn, E1 aMcKnight, Barbara1 aMetcalf, Ginger, A1 aMorrison, Alanna, C1 aReiner, Alexander, P1 aSofer, Tamar1 aTang, Weihong1 aWiggins, Kerri, L1 aBoerwinkle, Eric1 ade Andrade, Mariza1 aGabriel, Stacey, B1 aGibbs, Richard, A1 aLaurie, Cathy, C1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aRice, Ken1 aKooperberg, Charles1 aPankow, James, S1 aSmith, Nicholas, L1 aPankratz, Nathan1 aTrans-Omics for Precision Medicine Program uhttps://chs-nhlbi.org/node/932103713nas a2200661 4500008004100000022001400041245015600055210006900211260000900280300001200289490000700301520176300308100002502071700003302096700001802129700002902147700002602176700002002202700001902222700002302241700001402264700002202278700002002300700002302320700001702343700002502360700001902385700001802404700002402422700002002446700002102466700002602487700002202513700002602535700002002561700001402581700002102595700001402616700001402630700002102644700002102665700002102686700002102707700002402728700002002752700002402772700002702796700002002823700002002843700001902863700002102882700002202903700002302925700002102948700002502969700002102994856003603015 2023 eng d a1664-802100aWhole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.0 aWhole genome sequence analysis of apparent treatment resistant h c2023 a12782150 v143 a Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.
1 aArmstrong, Nicole, D1 aSrinivasasainagendra, Vinodh1 aAmmous, Farah1 aAssimes, Themistocles, L1 aBeitelshees, Amber, L1 aBrody, Jennifer1 aCade, Brian, E1 aChen, Yii-Der, Ida1 aChen, Han1 ade Vries, Paul, S1 aFloyd, James, S1 aFranceschini, Nora1 aGuo, Xiuqing1 aHellwege, Jacklyn, N1 aHouse, John, S1 aHwu, Chii-Min1 aKardia, Sharon, L R1 aLange, Ethan, M1 aLange, Leslie, A1 aMcDonough, Caitrin, W1 aMontasser, May, E1 aO'Connell, Jeffrey, R1 aShuey, Megan, M1 aSun, Xiao1 aTanner, Rikki, M1 aWang, Zhe1 aZhao, Wei1 aCarson, April, P1 aEdwards, Todd, L1 aKelly, Tanika, N1 aKenny, Eimear, E1 aKooperberg, Charles1 aLoos, Ruth, J F1 aMorrison, Alanna, C1 aMotsinger-Reif, Alison1 aPsaty, Bruce, M1 aRao, Dabeeru, C1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Jennifer, A1 aSmith, Albert, V1 aIrvin, Marguerite, R1 aArnett, Donna, K uhttps://chs-nhlbi.org/node/958105493nas a2201573 4500008004100000245011200041210006900153260001600222520100600238100001801244700002301262700002201285700002501307700002001332700001501352700001401367700002001381700002101401700002201422700001401444700001401458700002401472700002101496700002401517700001901541700002901560700002201589700001901611700001801630700002801648700002001676700001901696700001901715700002101734700002401755700001901779700001701798700002801815700001701843700002201860700002301882700002401905700001701929700001801946700002501964700002001989700002102009700001602030700002002046700001602066700001302082700001802095700002402113700001702137700002102154700002402175700002102199700002002220700002002240700001702260700002202277700002802299700002302327700002402350700001702374700002302391700003002414700002602444700002102470700002002491700001902511700002302530700001402553700002402567700002402591700001802615700002802633700002402661700002302685700002202708700002702730700001702757700002102774700002102795700002202816700002202838700002302860700001902883700002302902700001402925700002402939700002102963700002802984700002403012700001903036700002103055700002503076700002103101700002303122700002203145700002203167700002003189700002303209700001403232700002303246700001603269700002503285700002403310700002103334700002503355700001903380700002003399700002303419700002503442700002103467700002203488700002403510700002303534700002003557700002203577700002003599700001803619700002503637700001603662700001603678700002503694700002103719700001803740700002003758700001903778700002103797710006503818856003603883 2023 eng d00aWHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.0 aWHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES N c2023 Aug 223 aObesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.
1 aZhang, Xinruo1 aBrody, Jennifer, A1 aGraff, Mariaelisa1 aHighland, Heather, M1 aChami, Nathalie1 aXu, Hanfei1 aWang, Zhe1 aFerrier, Kendra1 aChittoor, Geetha1 aJosyula, Navya, S1 aLi, Xihao1 aLi, Zilin1 aAllison, Matthew, A1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBoorgula, Meher, Preethi1 aBowden, Donald, W1 aBroome, Jai, G1 aButh, Erin, J1 aCarlson, Christopher, S1 aChang, Kyong-Mi1 aChavan, Sameer1 aChiu, Yen-Feng1 aChuang, Lee-Ming1 aConomos, Matthew, P1 aDeMeo, Dawn, L1 aDu, Margaret1 aDuggirala, Ravindranath1 aEng, Celeste1 aFohner, Alison, E1 aFreedman, Barry, I1 aGarrett, Melanie, E1 aGuo, Xiuqing1 aHaiman, Chris1 aHeavner, Benjamin, D1 aHidalgo, Bertha1 aHixson, James, E1 aHo, Yuk-Lam1 aHobbs, Brian, D1 aHu, Donglei1 aHui, Qin1 aHwu, Chii-Min1 aJackson, Rebecca, D1 aJain, Deepti1 aKalyani, Rita, R1 aKardia, Sharon, L R1 aKelly, Tanika, N1 aLange, Ethan, M1 aLeNoir, Michael1 aLi, Changwei1 aLe Marchand, Loic1 aMcDonald, Merry-Lynn, N1 aMcHugh, Caitlin, P1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey1 aO'Donnell, Christopher, J1 aPalmer, Nicholette, D1 aPankow, James, S1 aPerry, James, A1 aPeters, Ulrike1 aPreuss, Michael, H1 aRao, D, C1 aRegan, Elizabeth, A1 aReupena, Sefuiva, M1 aRoden, Dan, M1 aRodriguez-Santana, Jose1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aTiwari, Hemant, K1 aVasan, Ramachandran, S1 aWang, Zeyuan1 aWeeks, Daniel, E1 aWessel, Jennifer1 aWiggins, Kerri, L1 aWilkens, Lynne, R1 aWilson, Peter, W F1 aYanek, Lisa, R1 aYoneda, Zachary, T1 aZhao, Wei1 aZöllner, Sebastian1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBlangero, John1 aBoerwinkle, Eric1 aBurchard, Esteban, G1 aCarson, April, P1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aCurran, Joanne, E1 aFornage, Myriam1 aGordeuk, Victor, R1 aHe, Jiang1 aHeckbert, Susan, R1 aHou, Lifang1 aIrvin, Marguerite, R1 aKooperberg, Charles1 aMinster, Ryan, L1 aMitchell, Braxton, D1 aNouraie, Mehdi1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aReiner, Alexander, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aShoemaker, Benjamin1 aSmith, Nicholas, L1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aWeiss, Scott, T1 aZhang, Yingze1 aCosta, Nancy, Heard-1 aSun, Yan, V1 aLin, Xihong1 aCupples, Adrienne, L1 aLange, Leslie, A1 aLiu, Ching-Ti1 aLoos, Ruth, J F1 aNorth, Kari, E1 aJustice, Anne, E1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/948403779nas a2200673 4500008004100000245013300041210006900174260001600243520177100259100001902030700002202049700001402071700002002085700002002105700001502125700001902140700002202159700002702181700001402208700002102222700002002243700001902263700002102282700001902303700001702322700002202339700002102361700002202382700002502404700002102429700002002450700002502470700002402495700002202519700001902541700001602560700002302576700002002599700001902619700001502638700002102653700002302674700002202697700002402719700002002743700001902763700001902782700001602801700002002817700002402837700002502861700002302886700001602909700001802925700002302943710006502966710003803031856003603069 2023 eng d00aWhole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium.0 aWhole Genome Sequencing Based Analysis of Inflammation Biomarker c2023 Sep 123 aInflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.
1 aJiang, Min-Zhi1 aGaynor, Sheila, M1 aLi, Xihao1 aVan Buren, Eric1 aStilp, Adrienne1 aButh, Erin1 aWang, Fei, Fei1 aManansala, Regina1 aGogarten, Stephanie, M1 aLi, Zilin1 aPolfus, Linda, M1 aSalimi, Shabnam1 aBis, Joshua, C1 aPankratz, Nathan1 aYanek, Lisa, R1 aDurda, Peter1 aTracy, Russell, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aMitchell, Braxton, D1 aLewis, Joshua, P1 aPsaty, Bruce, M1 aPratte, Katherine, A1 aSilverman, Edwin, K1 aKaplan, Robert, C1 aAvery, Christy1 aNorth, Kari1 aMathias, Rasika, A1 aFaraday, Nauder1 aLin, Honghuang1 aWang, Biqi1 aCarson, April, P1 aNorwood, Arnita, F1 aGibbs, Richard, A1 aKooperberg, Charles1 aLundin, Jessica1 aPeters, Ulrike1 aDupuis, Josée1 aHou, Lifang1 aFornage, Myriam1 aBenjamin, Emelia, J1 aReiner, Alexander, P1 aBowler, Russell, P1 aLin, Xihong1 aAuer, Paul, L1 aRaffield, Laura, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Inflammation Working Group uhttps://chs-nhlbi.org/node/950002945nas a2200397 4500008004100000245009500041210006900136260001600205520178200221100001802003700002002021700001502041700001402056700003002070700001302100700001902113700001702132700001502149700002302164700002202187700002102209700002202230700002102252700002702273700001902300700002002319700002102339700002802360700002602388700001902414700001402433700001702447700001602464710003102480856003602511 2024 eng d00aAssociation analysis of mitochondrial DNA heteroplasmic variants: methods and application.0 aAssociation analysis of mitochondrial DNA heteroplasmic variants c2024 Jan 133 aWe rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.
1 aSun, Xianbang1 aBulekova, Katia1 aYang, Jian1 aLai, Meng1 aPitsillides, Achilleas, N1 aLiu, Xue1 aZhang, Yuankai1 aGuo, Xiuqing1 aYong, Qian1 aRaffield, Laura, M1 aRotter, Jerome, I1 aRich, Stephen, S1 aAbecasis, Goncalo1 aCarson, April, P1 aVasan, Ramachandran, S1 aBis, Joshua, C1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aFitzpatrick, Annette, L1 aSatizabal, Claudia, L1 aArking, Dan, E1 aDing, Jun1 aLevy, Daniel1 aLiu, Chunyu1 aTOPMed mtDNA working group uhttps://chs-nhlbi.org/node/958004426nas a2200493 4500008004100000022001400041245010800055210006900163260001600232520296700248100001603215700002403231700002403255700001903279700001603298700002203314700002603336700002103362700002103383700001503404700002003419700002303439700002203462700002003484700002103504700002803525700002203553700002003575700002703595700001603622700002003638700001903658700002003677700002703697700002603724700002103750700002103771700002103792700001703813700001903830700002603849700002103875856003603896 2024 eng d a2380-659100aFamilial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol.0 aFamilial Hypercholesterolemia Variant and Cardiovascular Risk in c2024 Jan 313 aIMPORTANCE: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.
OBJECTIVE: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.
DESIGN, SETTING, AND PARTICIPANTS: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.
EXPOSURES: LDL-C, cumulative past LDL-C, FH variant status.
MAIN OUTCOMES AND MEASURES: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.
RESULTS: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.
CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.
1 aZhang, Yiyi1 aDron, Jacqueline, S1 aBellows, Brandon, K1 aKhera, Amit, V1 aLiu, Junxiu1 aBalte, Pallavi, P1 aOelsner, Elizabeth, C1 aAmr, Sami, Samir1 aLebo, Matthew, S1 aNagy, Anna1 aPeloso, Gina, M1 aNatarajan, Pradeep1 aRotter, Jerome, I1 aWiller, Cristen1 aBoerwinkle, Eric1 aBallantyne, Christie, M1 aLutsey, Pamela, L1 aFornage, Myriam1 aLloyd-Jones, Donald, M1 aHou, Lifang1 aPsaty, Bruce, M1 aBis, Joshua, C1 aFloyd, James, S1 aVasan, Ramachandran, S1 aHeard-Costa, Nancy, L1 aCarson, April, P1 aHall, Michael, E1 aRich, Stephen, S1 aGuo, Xiuqing1 aKazi, Dhruv, S1 ade Ferranti, Sarah, D1 aMoran, Andrew, E uhttps://chs-nhlbi.org/node/962014002nas a2204477 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2024 eng d a1476-468700aGenetic drivers of heterogeneity in type 2 diabetes pathophysiology.0 aGenetic drivers of heterogeneity in type 2 diabetes pathophysiol c2024 Feb 193 aType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
1 aSuzuki, Ken1 aHatzikotoulas, Konstantinos1 aSoutham, Lorraine1 aTaylor, Henry, J1 aYin, Xianyong1 aLorenz, Kim, M1 aMandla, Ravi1 aHuerta-Chagoya, Alicia1 aMelloni, Giorgio, E M1 aKanoni, Stavroula1 aRayner, Nigel, W1 aBocher, Ozvan1 aArruda, Ana, Luiza1 aSonehara, Kyuto1 aNamba, Shinichi1 aLee, Simon, S K1 aPreuss, Michael, H1 aPetty, Lauren, E1 aSchroeder, Philip1 aVanderwerff, Brett1 aKals, Mart1 aBragg, Fiona1 aLin, Kuang1 aGuo, Xiuqing1 aZhang, Weihua1 aYao, Jie1 aKim, Young, Jin1 aGraff, Mariaelisa1 aTakeuchi, Fumihiko1 aNano, Jana1 aLamri, Amel1 aNakatochi, Masahiro1 aMoon, Sanghoon1 aScott, Robert, A1 aCook, James, P1 aLee, Jung-Jin1 aPan, Ian1 aTaliun, Daniel1 aParra, Esteban, J1 aChai, Jin-Fang1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aThorleifsson, Gudmar1 aGrarup, Niels1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aKwak, Soo-Heon1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aNongmaithem, Suraj, S1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aBrody, Jennifer, A1 aKabagambe, Edmond1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aBroadaway, Alaine1 aWilliamson, Alice1 aKamali, Zoha1 aCui, Jinrui1 aThangam, Manonanthini1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAhluwalia, Tarunveer, S1 aAnand, Sonia, S1 aBertoni, Alain1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBuchanan, Thomas, A1 aBurant, Charles, F1 aButterworth, Adam, S1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDanesh, John1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGordon-Larsen, Penny1 aGross, Myron1 aGuare, Lindsay, A1 aHackinger, Sophie1 aHakaste, Liisa1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHorikoshi, Momoko1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Torben1 aKamanu, Frederick, K1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Kyung, Min1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLigthart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLynch, Julie, A1 aLyssenko, Valeriya1 aMaeda, Shiro1 aMamakou, Vasiliki1 aMansuri, Sohail, Rafik1 aMatsuda, Koichi1 aMeitinger, Thomas1 aMelander, Olle1 aMetspalu, Andres1 aMo, Huan1 aMorris, Andrew, D1 aMoura, Filipe, A1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPatil, Snehal1 aPei, Pei1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPolikowsky, Hannah, G1 aPorneala, Bianca1 aPrasad, Gauri1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Katheryn1 aSabanayagam, Charumathi1 aSandow, Kevin1 aSankareswaran, Alagu1 aSattar, Naveed1 aSchönherr, Sebastian1 aShahriar, Mohammad1 aShen, Botong1 aShi, Jinxiu1 aShin, Dong, Mun1 aShojima, Nobuhiro1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aSteinthorsdottir, Valgerdur1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aTaylor, Kent, D1 aThorand, Barbara1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTran, Tam, C1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamamoto, Kenichi1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZawistowski, Matthew1 aZhang, Liang1 aZheng, Wei1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aFornage, Myriam1 aHanis, Craig, L1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aYokota, Mitsuhiro1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aPankow, James, S1 aEngert, James, C1 aBonnefond, Amélie1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aMook-Kanamori, Dennis, O1 aTuomi, Tiinamaija1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aChen, Yii-Der Ida1 aRich, Stephen, S1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aGhanbari, Mohsen1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aBowden, Donald, W1 aPalmer, Colin, N A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aLiu, Simin1 aNorth, Kari, E1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aWareham, Nicholas, J1 aLee, Juyoung1 aKim, Bong-Jo1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aAhlqvist, Emma1 aGoodarzi, Mark, O1 aMohlke, Karen, L1 aLangenberg, Claudia1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aFlorez, Jose, C1 aRader, Daniel, J1 aRitchie, Marylyn, D1 aZöllner, Sebastian1 aMägi, Reedik1 aMarston, Nicholas, A1 aRuff, Christian, T1 avan Heel, David, A1 aFiner, Sarah1 aDenny, Joshua, C1 aYamauchi, Toshimasa1 aKadowaki, Takashi1 aChambers, John, C1 aC Y Ng, Maggie1 aSim, Xueling1 aBelow, Jennifer, E1 aTsao, Philip, S1 aChang, Kyong-Mi1 aMcCarthy, Mark, I1 aMeigs, James, B1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aMercader, Josep, M1 aBoehnke, Michael1 aRotter, Jerome, I1 aVujkovic, Marijana1 aVoight, Benjamin, F1 aMorris, Andrew, P1 aZeggini, Eleftheria1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/961902608nas a2200541 4500008004100000022001400041245006100055210005800116260001600174300000800190490000700198520111600205653002201321653002601343653001801369653001001387653001301397653001101410100002001421700001701441700001701458700002101475700002101496700002601517700002201543700001901565700002901584700001501613700001801628700002101646700001801667700002001685700002301705700002101728700002001749700002001769700001901789700002101808700002801829700002301857700002101880700002101901700001701922700002801939700001801967710004501985856003602030 2024 eng d a2041-172300aHuman whole-exome genotype data for Alzheimer's disease.0 aHuman wholeexome genotype data for Alzheimers disease c2024 Jan 23 a6840 v153 aThe heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.
10aAlzheimer Disease10aComputational Biology10aData Accuracy10aExome10aGenotype10aHumans1 aLeung, Yuk, Yee1 aNaj, Adam, C1 aChou, Yi-Fan1 aValladares, Otto1 aSchmidt, Michael1 aHamilton-Nelson, Kara1 aWheeler, Nicholas1 aLin, Honghuang1 aGangadharan, Prabhakaran1 aQu, Liming1 aClark, Kaylyn1 aKuzma, Amanda, B1 aLee, Wan-Ping1 aCantwell, Laura1 aNicaretta, Heather1 aHaines, Jonathan1 aFarrer, Lindsay1 aSeshadri, Sudha1 aBrkanac, Zoran1 aCruchaga, Carlos1 aPericak-Vance, Margaret1 aMayeux, Richard, P1 aBush, William, S1 aDeStefano, Anita1 aMartin, Eden1 aSchellenberg, Gerard, D1 aSan Wang, Li-1 aAlzheimer’s Disease Sequencing Project uhttps://chs-nhlbi.org/node/957704874nas a2201033 4500008004100000022001400041245014100055210006900196260001600265300000700281490000700288520197200295653000902267653001402276653003402290653001102324653001102335653001402346653001502360653003602375100001302411700002202424700001502446700001502461700001902476700001702495700001602512700001702528700002402545700001602569700001602585700002302601700001702624700002102641700002502662700002102687700001802708700002302726700002202749700002702771700002002798700002002818700001402838700002602852700001902878700002302897700002202920700001802942700002302960700002102983700001803004700002203022700001903044700001903063700002703082700002603109700002203135700001603157700001903173700002403192700002203216700002503238700002203263700001903285700002303304700001803327700002003345700002103365700002303386700002403409700002603433700002303459700002203482700002103504700002303525700002403548700001903572700002203591700002003613700001803633700002303651700001903674700002803693700002003721700001803741700002303759700002203782856003603804 2024 eng d a1758-919300aMulti-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.0 aMultiomics and pathway analyses of genomewide associations impli c2024 Jan 20 a140 v163 aBACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.
METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.
RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.
CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.
10aAged10aCognition10aGenome-Wide Association Study10aHumans10aMemory10aMicroRNAs10aMultiomics10aPolymorphism, Single Nucleotide1 aMei, Hao1 aSimino, Jeannette1 aLi, Lianna1 aJiang, Fan1 aBis, Joshua, C1 aDavies, Gail1 aHill, David1 aXia, Charley1 aGudnason, Vilmundur1 aYang, Qiong1 aLahti, Jari1 aSmith, Jennifer, A1 aKirin, Mirna1 aDe Jager, Philip1 aArmstrong, Nicola, J1 aGhanbari, Mohsen1 aKolcic, Ivana1 aMoran, Christopher1 aTeumer, Alexander1 aSargurupremraj, Murali1 aMahmud, Shamsed1 aFornage, Myriam1 aZhao, Wei1 aSatizabal, Claudia, L1 aPolasek, Ozren1 aRäikkönen, Katri1 aLiewald, David, C1 aHomuth, Georg1 aCallisaya, Michele1 aMather, Karen, A1 aWindham, Gwen1 aZemunik, Tatijana1 aPalotie, Aarno1 aPattie, Alison1 avan der Auwera, Sandra1 aThalamuthu, Anbupalam1 aKnopman, David, S1 aRudan, Igor1 aStarr, John, M1 aWittfeld, Katharina1 aKochan, Nicole, A1 aGriswold, Michael, E1 aVitart, Veronique1 aBrodaty, Henry1 aGottesman, Rebecca1 aCox, Simon, R1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aChasman, Daniel, I1 aGrodstein, Francine1 aSachdev, Perminder, S1 aSrikanth, Velandai1 aHayward, Caroline1 aWilson, James, F1 aEriksson, Johan, G1 aKardia, Sharon, L R1 aGrabe, Hans, J1 aBennett, David, A1 aIkram, Arfan, M1 aDeary, Ian, J1 aDuijn, Cornelia, M1 aLauner, Lenore1 aFitzpatrick, Annette, L1 aSeshadri, Sudha1 aBressler, Jan1 aDebette, Stephanie1 aMosley, Thomas, H uhttps://chs-nhlbi.org/node/957805139nas a2201813 4500008004100000245013500041210006900176260000800245300000800253490000700261520048900268100002900757700002100786700001100807700001900818700001400837700001600851700002200867700001700889700001800906700001500924700001800939700001900957700001600976700001900992700002001011700001501031700001801046700001801064700001701082700002101099700002001120700001701140700001501157700002001172700001901192700002501211700001801236700001401254700001801268700002301286700002901309700001701338700002101355700001701376700002001393700002001413700001501433700001901448700001301467700001901480700001501499700001101514700001501525700002001540700001901560700001101579700001601590700001201606700001801618700001901636700001701655700002001672700001701692700002701709700002001736700001301756700001401769700001901783700001501802700001401817700001101831700002301842700001801865700002501883700001301908700001901921700001501940700001801955700001801973700001901991700002102010700002002031700001302051700001502064700001402079700002402093700001602117700001702133700001402150700001402164700002102178700002202199700001602221700001702237700001502254700001702269700001102286700002402297700001802321700001402339700001202353700001602365700002102381700001902402700001702421700001702438700001902455700002402474700001502498700002102513700001502534700002102549700002202570700001902592700002002611700001802631700001902649700001802668700001802686700001502704700001502719700001602734700001702750700002502767700002602792700002202818700002602840700001902866700001702885700001902902700001802921700001302939700002102952700001802973700002002991700001403011700001903025700001903044700002903063700002603092700001903118700001303137700001603150700001303166700001203179700001403191700002003205700002003225700001403245700001503259700001503274856003603289 2024 eng d00a{Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications0 aMultitrait analysis characterizes the genetics of thyroid functi cJan a8880 v153 aT3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.1 aSterenborg, R., B. T. M.1 aSteinbrenner, I.1 aLi, Y.1 aBujnis, M., N.1 aNaito, T.1 aMarouli, E.1 aGalesloot, T., E.1 aBabajide, O.1 aAndreasen, L.1 aAstrup, A.1 asvold, B., O.1 aBandinelli, S.1 aBeekman, M.1 aBeilby, J., P.1 aBork-Jensen, J.1 aBoutin, T.1 aBrody, J., A.1 aBrown, S., J.1 aBrumpton, B.1 aCampbell, P., J.1 aCappola, A., R.1 aCeresini, G.1 aChaker, L.1 aChasman, D., I.1 aConcas, M., P.1 ade Almeida, Coutinho1 aCross, S., M.1 aCucca, F.1 aDeary, I., J.1 aKjaergaard, A., D.1 aTcheugui, J., B. Echouff1 aEllervik, C.1 aEriksson, J., G.1 aFerrucci, L.1 aFreudenberg, J.1 aFuchsberger, C.1 aGieger, C.1 aGiulianini, F.1 agele, M.1 aGraham, S., E.1 aGrarup, N.1 aä, I.1 aHansen, T.1 aHarding, B., N.1 aHarris, S., E.1 aø, S.1 aHayward, C.1 aHui, J.1 aIttermann, T.1 aJukema, J., W.1 aKajantie, E.1 aKanters, J., K.1 arhus, L., L.1 aKiemeney, L., A. L. M.1 aKloppenburg, M.1 ahnel, B.1 aLahti, J.1 aLangenberg, C.1 aLapauw, B.1 aLeese, G.1 aLi, S.1 aLiewald, D., C. M.1 aLinneberg, A.1 aLominchar, J., V. T.1 aLuan, J.1 aMartin, N., G.1 aMatana, A.1 aMeima, M., E.1 aMeitinger, T.1 aMeulenbelt, I.1 aMitchell, B., D.1 allehave, L., T.1 aMora, S.1 aNaitza, S.1 aNauck, M.1 aNetea-Maier, R., T.1 aNoordam, R.1 aNursyifa, C.1 aOkada, Y.1 aOnano, S.1 aPapadopoulou, A.1 aPalmer, C., N. A.1 aPattaro, C.1 aPedersen, O.1 aPeters, A.1 aPietzner, M.1 aek, O.1 aPramstaller, P., P.1 aPsaty, B., M.1 aPunda, A.1 aRay, D.1 aRedmond, P.1 aRichards, J., B.1 aRidker, P., M.1 aRuss, T., C.1 aRyan, K., A.1 aOlesen, M., S.1 aSchultheiss, U., T.1 aSelvin, E.1 aSiddiqui, M., K.1 aSidore, C.1 aSlagboom, P., E.1 arensen, T., I. A.1 aSoto-Pedre, E.1 aSpector, T., D.1 aSpedicati, B.1 aSrinivasan, S.1 aStarr, J., M.1 aStott, D., J.1 aTanaka, T.1 aTorlak, V.1 aTrompet, S.1 aTuhkanen, J.1 aUitterlinden, A., G.1 avan den Akker, E., B.1 avan den Eynde, T.1 avan der Klauw, M., M.1 avan Heemst, D.1 aVerroken, C.1 aVisser, W., E.1 aVojinovic, D.1 alzke, H.1 aWaldenberger, M.1 aWalsh, J., P.1 aWareham, N., J.1 aWeiss, S.1 aWiller, C., J.1 aWilson, S., G.1 aWolffenbuttel, B., H. R.1 aWouters, H., J. C. M.1 aWright, M., J.1 aYang, Q.1 aZemunik, T.1 aZhou, W.1 aZhu, G.1 allner, S.1 aSmit, J., W. A.1 aPeeters, R., P.1 attgen, A.1 aTeumer, A.1 aMedici, M. uhttps://chs-nhlbi.org/node/961802832nas a2200289 4500008004100000022001400041245010600055210006900161260001600230520196800246100001702214700001202231700002002243700002002263700001702283700002302300700001902323700002202342700002402364700002802388700001802416700002102434700002002455700001802475700001302493856003602506 2024 eng d a2055-582200aA polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure.0 apolygenic risk score of atrial fibrillation improves prediction c2024 Jan 223 aAIMS: Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk-factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi-racial populations.
METHODS AND RESULTS: Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30 years of follow-up. PRSs of AF, BMI, and CHD were associated with incident HF (P < 0.001), where PRS showed the strongest association [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.41-1.53]. Only the addition of PRS to the ARIC study HF risk equation improved C statistics for 10 year risk prediction from 0.812 to 0.829 (∆C: 0.017, 95% CI: 0.009-0.026). The PRS was associated with both incident HF with reduced ejection fraction (HR: 1.43, 95% CI: 1.27-1.60) and incident HF with preserved ejection fraction (HR: 1.46, 95% CI: 1.33-1.62). The associations between PRS and incident HF and its subtypes, as well as the improved risk prediction, were replicated in the ARIC study Blacks and the CHS Whites (P < 0.050). Protein analyses revealed that N-terminal pro-brain natriuretic peptide and other 98 proteins were associated with PRS .
CONCLUSIONS: The PRS was associated with incident HF and its subtypes and had significant incremental value over an established HF risk prediction equation.
1 aAlkis, Taryn1 aLuo, Xi1 aWall, Katherine1 aBrody, Jennifer1 aBartz, Traci1 aChang, Patricia, P1 aNorby, Faye, L1 aHoogeveen, Ron, C1 aMorrison, Alanna, C1 aBallantyne, Christie, M1 aCoresh, Josef1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aShah, Amil, M1 aYu, Bing uhttps://chs-nhlbi.org/node/957304184nas a2200829 4500008004100000022001400041245017700055210006900232260001600301300001200317490000800329520172300337653001202060653001502072653002802087653002602115653002502141653001702166100002202183700002102205700002002226700001602246700001902262700002002281700002202301700001802323700001902341700002302360700002102383700002002404700002002424700002202444700002002466700002002486700001902506700002302525700002402548700002102572700002502593700001802618700002402636700002002660700002102680700002602701700002202727700001902749700001902768700001702787700002702804700002502831700001602856700002102872700002402893700001802917700002402935700002402959700001902983700002003002700002203022700002503044700002103069700002003090700002503110700001803135700002003153700002303173700002103196700002503217700001903242710005703261856003603318 2024 eng d a1524-453900aRole of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.0 aRole of Polyunsaturated Fat in Modifying Cardiovascular Risk Ass c2024 Jan 23 a305-3160 v1493 aBACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.
METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.
RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.
CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.
10aAnimals10aBiomarkers10aCardiovascular Diseases10aDocosahexaenoic Acids10aFatty Acids, Omega-310aRisk Factors1 aLaguzzi, Federica1 aÅkesson, Agneta1 aMarklund, Matti1 aQian, Frank1 aGigante, Bruna1 aBartz, Traci, M1 aBassett, Julie, K1 aBirukov, Anna1 aCampos, Hannia1 aHirakawa, Yoichiro1 aImamura, Fumiaki1 aJäger, Susanne1 aLankinen, Maria1 aMurphy, Rachel, A1 aSenn, Mackenzie1 aTanaka, Toshiko1 aTintle, Nathan1 aVirtanen, Jyrki, K1 aYamagishi, Kazumasa1 aAllison, Matthew1 aBrouwer, Ingeborg, A1 ade Faire, Ulf1 aEiriksdottir, Gudny1 aFerrucci, Luigi1 aForouhi, Nita, G1 aGeleijnse, Johanna, M1 aHodge, Allison, M1 aKimura, Hitomi1 aLaakso, Markku1 aRiserus, Ulf1 avan Westing, Anniek, C1 aBandinelli, Stefania1 aBaylin, Ana1 aGiles, Graham, G1 aGudnason, Vilmundur1 aIso, Hiroyasu1 aLemaitre, Rozenn, N1 aNinomiya, Toshiharu1 aPost, Wendy, S1 aPsaty, Bruce, M1 aSalonen, Jukka, T1 aSchulze, Matthias, B1 aTsai, Michael, Y1 aUusitupa, Matti1 aWareham, Nicholas, J1 aOh, Seung-Won1 aWood, Alexis, C1 aHarris, William, S1 aSiscovick, David1 aMozaffarian, Dariush1 aLeander, Karin1 aFatty Acids and Outcomes Research Consortium (FORCE) uhttps://chs-nhlbi.org/node/958707235nas a2202173 4500008004100000022001400041245020700055210006900262260001600331300000800347490000700355520114400362653001401506653002601520653001101546653003801557653003401595653001101629653001101640653000901651653003601660653002201696653001701718100001901735700001701754700001601771700002101787700002401808700001601832700002001848700001301868700002101881700002001902700001901922700001201941700001801953700001901971700002401990700001502014700001902029700002002048700002602068700001802094700001902112700002002131700002102151700001802172700002102190700001702211700002102228700002002249700001902269700002302288700002102311700001902332700001302351700002002364700002002384700002102404700002202425700002202447700002102469700002202490700002102512700001602533700002302549700002102572700002802593700001802621700001702639700002602656700002202682700001802704700002502722700002102747700001602768700002602784700002002810700002102830700001902851700002002870700002302890700002002913700002102933700002302954700001902977700002202996700001903018700001803037700002603055700001803081700002503099700002103124700002003145700002103165700001903186700002203205700001703227700002003244700001703264700002103281700002803302700002703330700002403357700002003381700002103401700002503422700001803447700002503465700002903490700002603519700002003545700002003565700001703585700001903602700002103621700002003642700002303662700002903685700002703714700001903741700002003760700001903780700002303799700001903822700002003841700002103861700002303882700002303905700002103928700002203949700002103971700001903992700002004011700002204031700001604053700002804069700002004097700002304117700002004140700001604160700002004176700002004196700002104216700002004237700002204257700001904279700002704298700002104325700001804346700002004364700002204384700001804406700002004424700002004444700002104464700002304485700002204508700001804530700002704548700002204575700001704597700001904614700001904633700001704652700002304669700001904692700002104711700002304732700001904755700001904774700001704793700001904810700002104829700002804850700002104878700002204899700002304921700001804944700001904962700002204981700002205003856003605025 2024 eng d a2041-172300aX-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.0 aXchromosome and kidney function evidence from a multitrait genet c2024 Jan 18 a5860 v153 aX-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
10aAndrogens10aChromosomes, Human, X10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aKidney10aMale10aPolymorphism, Single Nucleotide10aResponse Elements10aTetraspanins1 aScholz, Markus1 aHorn, Katrin1 aPott, Janne1 aWuttke, Matthias1 aKühnapfel, Andreas1 aNasr, Kamal1 aKirsten, Holger1 aLi, Yong1 aHoppmann, Anselm1 aGorski, Mathias1 aGhasemi, Sahar1 aLi, Man1 aTin, Adrienne1 aChai, Jin-Fang1 aCocca, Massimiliano1 aWang, Judy1 aNutile, Teresa1 aAkiyama, Masato1 aÅsvold, Bjørn, Olav1 aBansal, Nisha1 aBiggs, Mary, L1 aBoutin, Thibaud1 aBrenner, Hermann1 aBrumpton, Ben1 aBurkhardt, Ralph1 aCai, Jianwen1 aCampbell, Archie1 aCampbell, Harry1 aChalmers, John1 aChasman, Daniel, I1 aChee, Miao, Ling1 aChee, Miao, Li1 aChen, Xu1 aCheng, Ching-Yu1 aCifkova, Renata1 aDaviglus, Martha1 aDelgado, Graciela1 aDittrich, Katalin1 aEdwards, Todd, L1 aEndlich, Karlhans1 aGaziano, Michael1 aGiri, Ayush1 aGiulianini, Franco1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aHallan, Stein1 aHamet, Pavel1 aHartman, Catharina, A1 aHayward, Caroline1 aHeid, Iris, M1 aHellwege, Jacklyn, N1 aHolleczek, Bernd1 aHolm, Hilma1 aHutri-Kähönen, Nina1 aHveem, Kristian1 aIsermann, Berend1 aJonas, Jost, B1 aJoshi, Peter, K1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKastarinen, Mika1 aKhor, Chiea, Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKörner, Antje1 aKovacs, Peter1 aKrajcoviechova, Alena1 aKramer, Holly1 aKrämer, Bernhard, K1 aKuokkanen, Mikko1 aKähönen, Mika1 aLange, Leslie, A1 aLash, James, P1 aLehtimäki, Terho1 aLi, Hengtong1 aLin, Bridget, M1 aLiu, Jianjun1 aLoeffler, Markus1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMartin, Nicholas, G1 aMatsuda, Koichi1 aMilaneschi, Yuri1 aMishra, Pashupati, P1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMychaleckyj, Josyf, C1 aMärz, Winfried1 aNauck, Matthias1 aNikus, Kjell1 aNolte, Ilja, M1 aNoordam, Raymond1 aOkada, Yukinori1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPirastu, Nicola1 aPolasek, Ozren1 aPorteous, David, J1 aPoulain, Tanja1 aPsaty, Bruce, M1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRasheed, Humaira1 aReilly, Dermot, F1 aRice, Kenneth, M1 aRichmond, Anne1 aRidker, Paul, M1 aRotter, Jerome, I1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSchneiderman, Neil1 aSchöttker, Ben1 aSims, Mario1 aSnieder, Harold1 aStark, Klaus, J1 aStefansson, Kari1 aStocker, Hannah1 aStumvoll, Michael1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSvensson, Per, O1 aTai, E-Shyong1 aTaylor, Kent, D1 aTayo, Bamidele, O1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomas, Laurent, F1 aTremblay, Johanne1 aTönjes, Anke1 avan der Most, Peter, J1 aVitart, Veronique1 aVölker, Uwe1 aWang, Ya, Xing1 aWang, Chaolong1 aBin Wei, Wen1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWinkler, Thomas, W1 aWong, Tien-Yin1 aWoodward, Mark1 aSim, Xueling1 aChu, Audrey, Y1 aFeitosa, Mary, F1 aThorsteinsdottir, Unnur1 aHung, Adriana, M1 aTeumer, Alexander1 aFranceschini, Nora1 aParsa, Afshin1 aKöttgen, Anna1 aSchlosser, Pascal1 aPattaro, Cristian uhttps://chs-nhlbi.org/node/9579